Compositions containing cyticine in subjects requiring the treatment and / or prevention of addiction.

Abstract

Methods for treating addiction and / or dependence, methods for promoting the cessation of various addictions such as smoking and / or vaping, methods for promoting reduction in various addictions such as smoking and / or vaping, the use of cyticine as an addiction cessation treatment, and administration regimens for the above are provided.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 498,399, filed on 26 April 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Nicotine is an addictive substance that is rapidly absorbed during cigarette smoking. The drug is thought to be rapidly distributed and interact with neuronal nicotinic acetylcholine receptors (nAChRs) in the central nervous system (CNS). Nicotine addiction is at least partially caused by this interaction. Many smokers attempt to quit, but few succeed without pharmacological supportive care.

[0003] Tobacco smoking contributes to approximately 7 million premature deaths worldwide each year. Smoking is highly addictive, and more than 95% of unassisted attempts to quit fail to last six months. It is estimated that delaying quitting beyond the mid-30s results in a loss of an average of three months of life each year. The World Health Organization Framework Convention on Tobacco Control identifies evidence-based approaches to promote smoking cessation, including mass media campaigns, increased taxes on tobacco, and incentives for smokers who wish to quit.

[0004] Drug therapies currently available in the US and Western Europe to help smokers quit include nicotine replacement therapy (NRT) and two non-nicotine medications: bupropion (Zyban®, Glaxo-SmithKline) and varenicline (Chantix® / Champix®, Pfizer). NRT and bupropion appear to have roughly equivalent efficacy. Varenicline is more effective than NRT and bupropion alone, but the combination of NRT is comparable in efficacy.

[0005] (-)-Citsine (commonly referred to simply as cytsine or cytsine) is a plant-based alkaloid isolated from the seeds of Cytisus laburnum L. (Laburnum), Thermopsis lanceolata (Ranunculus sieboldii), and other plant sources.

[0006] The mechanism of action of cyticine helps basic pharmacologists understand the complex pharmacology of various subtypes of nicotinic acetylcholine receptors. These studies have shown that both nicotine and cyticine bind strongly and preferentially to neuronal alpha-4, beta-2 (α4β2) receptors, which mediate dopamine release in the nucleus accumbens shell and elsewhere. This receptor subtype is involved in the development and maintenance of nicotine dependence and was a major target of the aforementioned drug varenicline.

[0007] Tabex®, containing the active ingredient cyticine, has been licensed and sold in Central and Eastern Europe for several decades by Sopharma PLC (Sophia, Bulgaria).

[0008] There is a need for a patient-friendly regimen for treating nicotine addiction that is less expensive, more effective, has an improved safety profile, and / or can be successful in treating individuals who have failed to quit nicotine using known treatments. [Overview of the project] [Problems that the invention aims to solve]

[0009] In some embodiments, methods for treating nicotine addiction, nicotine dependence, promoting the cessation of smoking and / or vaping, and / or promoting reduction in smoking and / or vaping are provided herein, comprising administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, to the subject three times a day.

[0010] In some embodiments, methods for doing so in subjects requiring prevention of smoking and / or vaping relapse are provided herein, comprising administering cyticin three times daily to subjects provided with a unit dose of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine.

[0011] In some embodiments, methods for doing so in subjects requiring treatment for nicotine addiction and / or nicotine dependence are provided herein, the method comprising administering cyticine to a subject, wherein the subject is a refractory patient who has failed to be treated with one or more nicotine addiction treatments.

[0012] In some embodiments, methods for preventing smoking relapse and / or vaping relapse in subjects requiring such prevention are provided herein, the method comprising administering cyticine to a subject, wherein the subject is a refractory patient who has failed to receive treatment with one or more smoking cessation therapies, and the one or more smoking cessation therapies are selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping.

[0013] In some embodiments, a method is provided herein for preventing the onset and / or progression of adverse events in subjects being treated for nicotine addiction and / or nicotine dependence, being treated to facilitate cessation of smoking and / or vaping, and / or being treated to facilitate reduction in smoking and / or vaping, the method comprising administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, three times daily to subjects in need thereof.

[0014] In some embodiments, a method is provided herein for preventing the onset and / or progression of an adverse event in a subject being treated for the prevention of smoking and / or vaping relapse, the method comprising administering cyticine, provided in a unit dose of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine, to a subject in need three times a day.

[0015] In some embodiments, methods for preventing the onset and / or progression of adverse events in subjects being treated for nicotine addiction and / or nicotine dependence are provided herein, the method comprising administering cyticine to a subject in need thereof, wherein the subject is a refractory patient who has failed to be treated with one or more nicotine addiction treatments.

[0016] In some embodiments, a method is provided herein for preventing the onset and / or progression of an adverse event in a subject being treated for the prevention of smoking relapse and / or vaping relapse, the method comprising administering cyticine to a subject in need thereof, wherein the subject is a refractory patient who has failed to be treated with one or more smoking cessation therapies, and one or more smoking cessation therapies are selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping.

[0017] In some embodiments, a method is provided herein for reducing the risk of adverse events occurring in subjects being treated for nicotine addiction and / or nicotine dependence, being treated to facilitate cessation of smoking and / or vaping, and / or being treated to facilitate reduction in smoking and / or vaping, the method comprising administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, three times daily to subjects in need thereof.

[0018] In some embodiments, a method is provided herein for reducing the risk of adverse events occurring in a subject being treated for the prevention of smoking and / or vaping relapse, the method comprising administering cyticine, provided in unit doses of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine, to a subject in need three times a day.

[0019] In some embodiments, methods are provided herein for reducing the risk of adverse events occurring in subjects being treated for nicotine addiction and / or nicotine dependence compared to a control subject, the method comprising administering cyticine to a subject in need thereof, wherein the subject is a refractory patient who has failed to be treated with one or more nicotine addiction treatments.

[0020] A method of reducing the risk of occurrence of adverse events in a subject being treated for the prevention of smoking relapse and / or vaping relapse as compared to a control subject in the subject, the method comprising administering cytisine to a subject in need thereof, the subject being a refractory patient who has failed treatment with one or more smoking cessation treatments, and one or more smoking cessation treatments being selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, electronic cigarettes, and vaping, the method being provided herein.

[0021] In some embodiments, cytisine is provided to the subject three to six times a day in a unit dose of cytisine of about 1.0 mg to about 6.0 mg, or is provided to the subject three times a day in a unit dose of 3.0 mg of cytisine.

[0022] In some embodiments, cytisine is provided in a unit dose comprising (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0023] In some embodiments, the subject is a refractory patient who has failed treatment with one or more nicotine addictions or smoking cessation treatments.

[0024] In some embodiments, the nicotine addiction or smoking cessation treatment is selected from nicotine replacement therapy, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and combinations thereof.

[0025] In some embodiments, the subject does not experience an adverse event selected from the group of adverse events consisting of upper respiratory tract infections, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after administration of cytisine.

[0026] In some embodiments, cyticine is administered for about 6 weeks or about 12 weeks.

[0027] In some embodiments, the subjects are those who (a) smoked 10 or more cigarettes per day prior to administration of cyticine, (b) had an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to administration of cyticine, or (c) a combination of (a) and (b).

[0028] In some embodiments, adverse events are selected from the group consisting of nausea, headache, anxiety, depression, and suicidal ideation.

[0029] In some embodiments, adverse events include nausea and headache.

[0030] In some embodiments, the adverse event is nausea.

[0031] In some embodiments, the adverse event is headache.

[0032] In some embodiments, subjects requiring it experience reduced anxiety, reduced depression, and / or the same or less suicidal ideation compared to or with a control subject.

[0033] In some embodiments, the control group is administered a placebo.

[0034] In some embodiments, the use of a unit dose of cyticine of 3.0 mg, 1.5 mg, or 1.0 mg is provided herein for the prevention of the onset and / or progression of adverse events in subjects being treated for nicotine addiction and / or nicotine dependence, being treated to facilitate cessation of smoking and / or vaping, and / or being treated to facilitate reduction in smoking and / or vaping, wherein the cyticine is for oral administration three times daily to subjects in need.

[0035] In some embodiments, the use of a unit dose of cyticine in the form of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine, for the prevention of the onset and / or progression of adverse events in subjects being treated for the prevention of smoking and / or vaping relapse, is provided herein.

[0036] In some embodiments, the use of cyticine for preventing the onset and / or progression of adverse events in subjects being treated for nicotine addiction or nicotine dependence, wherein the subjects are refractory patients who have failed to treat with one or more nicotine addiction treatments, and the cyticine is for oral administration to the subjects three times daily, is provided herein.

[0037] In some embodiments, the use of cyticine is provided herein for the prevention of the onset and / or progression of adverse events in a subject being treated for the prevention of smoking relapse and / or vaping relapse, wherein the subject is a refractory patient who has failed to treat one or more nicotine addiction treatments, and one or more nicotine addiction treatments are selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping, and the use of cyticine is for oral administration to the subject three times a day.

[0038] In some embodiments, the use of a unit dose of cyticine of 3.0 mg, 1.5 mg, or 1.0 mg is provided herein for reducing the risk of adverse events occurring in subjects who are being treated for nicotine addiction and / or nicotine dependence, who are being treated to facilitate cessation of smoking and / or vaping, and / or who are being treated to facilitate reduction in smoking and / or vaping, wherein the cyticine is for oral administration three times daily to subjects in need.

[0039] In some embodiments, the use of a unit dose of cyticine in the form of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine, for reducing the risk of adverse events occurring in a subject being treated for the prevention of smoking and / or vaping relapse compared to a control subject, is provided herein.

[0040] In some embodiments, the use of cyticine to reduce the risk of adverse events compared to a control group, in a subject being treated for nicotine addiction and / or nicotine dependence, wherein the subject is a refractory patient who has failed to treat with one or more nicotine addiction treatments, and the use of cyticine is for oral administration to the subject three times daily, is provided herein.

[0041] In some embodiments, the use of cyticine to reduce the risk of adverse events occurring in a subject being treated for the prevention of smoking relapse and / or vaping relapse, wherein the subject is a refractory patient who has failed to treat one or more nicotine addiction treatments, and the one or more nicotine addiction treatments are selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping, and the use of cyticine is for oral administration to the subject three times a day, is provided herein.

[0042] In some embodiments, the use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine is provided herein for the prevention in subjects being treated for nicotine addiction, nicotine dependence, and who are being treated to promote cessation of smoking and / or vaping, and / or who are being treated to promote reduction in smoking and / or vaping, by orally administering approximately 3.0 mg of cyticine three times a day to the subject.

[0043] In some embodiments, the use of tablets containing approximately 1.0 mg or approximately 1.5 mg of cyticine is provided herein for treating nicotine addiction and / or nicotine dependence in subjects who are refractory patients who have failed to be treated with one or more nicotine addiction treatments, by orally administering approximately 3.0 mg of cyticine three times a day.

[0044] In some embodiments, the use of tablets containing approximately 1.0 mg or approximately 1.5 mg of cyticine is provided herein, for preventing the onset and / or progression of adverse events in subjects being treated for nicotine addiction or nicotine dependence, or for preventing smoking and / or vaping relapse in subjects, by orally administering approximately 3.0 mg of cyticine to a subject three times a day.

[0045] In some embodiments, the use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine is provided herein for subjects who have failed to receive treatment with one or more nicotine addiction treatments selected from the group consisting of nicotine replacement therapy, bupropion administration, varenicline administration, e-cigarettes, and vaping, by orally administering approximately 3.0 mg of cyticine three times a day to prevent the onset and / or progression of adverse events in subjects and to prevent smoking relapse.

[0046] In some embodiments, cyticine is provided to subjects requiring it in unit doses of approximately 1.0 mg to approximately 6.0 mg of cyticine three to six times a day, or to subjects requiring it in unit doses of 3.0 mg of cyticine three times a day.

[0047] In some embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine.

[0048] In some embodiments, the subjects are refractory patients who have failed to treat one or more nicotine addictions or smoking cessation therapies.

[0049] In some embodiments, nicotine addiction or smoking cessation treatment is selected from nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, vaping, and combinations thereof.

[0050] In some embodiments, subjects do not experience any adverse events selected from the group of adverse events consisting of upper respiratory tract infection, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after administration of cyticine.

[0051] In some embodiments, cyticine is administered for about 6 weeks or about 12 weeks.

[0052] In some embodiments, the subjects are those who (a) smoked 10 or more cigarettes per day prior to administration of cyticine, (b) had an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to administration of cyticine, or (c) a combination of (a) and (b).

[0053] In some embodiments, a unit dose of cyticine comprises either (a) two tablets, each containing 1.5 mg of cyticine, or (b) a single tablet containing 3.0 mg of cyticine.

[0054] In some embodiments, adverse events are selected from the group consisting of nausea, headache, anxiety, depression, and suicidal ideation.

[0055] In some embodiments, adverse events include nausea and headache.

[0056] In some embodiments, the adverse event is nausea.

[0057] In some embodiments, the adverse event is headache.

[0058] In some embodiments, subjects requiring it experience reduced anxiety, reduced depression, and / or the same or less suicidal ideation compared to or with a control subject.

[0059] In some embodiments, the control group is administered a placebo. [Brief explanation of the drawing]

[0060] [Figure 1] This is a schematic diagram of the medication schedule according to the research design of Example 1 using this technology. [Figure 2] This is a schematic diagram of the research design for Example 1 using this technology. [Figure 3]This is a schematic diagram of the drug dosage intensity, schedule, and duration according to the research design of Example 1 using this technology. [Figure 4] This is a schematic diagram showing the target population arrangement according to the study in Example 1 using this technology. [Figure 5] This is a representative graph showing the number of cigarettes smoked per treatment arm on a treatment day, according to the study in Example 1 using this technology. [Figure 6] This is a representative graph showing the reduction in exhaled carbon monoxide (CO) from smoked cigarettes in the target population of Example 1, using this technology. [Figure 7] This is a representative graph showing a comparison between the smoking cessation rate after 4 weeks of abstinence and the smoking cessation rate during continued abstinence (weeks 5-8) in the target population of Example 1 using this technology. [Figure 8] This is a representative graph comparing the smoking cessation rates between 3.0 mg three times a day (TID) and placebo, both after 4 weeks of abstinence and during continued abstinence (weeks 5-8). [Figure 9] This is a representative plot showing exhaled carbon monoxide (CO) levels in parts per million at screening visits, week 4, and week 8 for a pooled placebo, a commercially available dosing schedule (COM) with TID 1.5 mg, TID 3.0 mg, and 1.5 mg, and a COM treatment arm with 3.0 mg, using this technology. [Figure 10] This is a representative plot showing serum cotinine levels at screening visits using this technology, at 4 weeks, and at 8 weeks for pooled placebo, TID 1.5 mg, TID 3.0 mg, COM 1.5 mg, and COM 3.0 mg. [Figure 11A] This is a representative plot showing a comparison of group homogenizations for the predicted proportion of cigarettes smoked (cigarette score) between COM 0mg and TID 0mg, and between TID 0mg and TID 3.0mg, using this technology. [Figure 11B]This is a representative plot showing a comparison of group homogenizations for the predicted proportion of cigarettes smoked (cigarette score) between COM 0mg and TID 0mg, and between TID 0mg and TID 3.0mg, using this technology. [Figure 12] This is a schematic diagram of the research design for comparing cyticinicline (cyticine) and Chantix® using this technology. [Figure 13] This is a representative graph showing the carbon monoxide (CO)-confirmed smoking cessation rates between 3.0 mg of citicinicline and 3.0 mg of Chantix® at 4 and 12 weeks of treatment using this technology. [Figure 14] This is a representative plot comparing the odds ratios of citicinicline and Chantix® using this technology at 4 weeks, at the end of treatment, and 4 weeks after the end of treatment. [Figure 15] This is a representative plot comparing the odds ratio of citicinicline using this technology with that of the current product at 4 weeks, at the end of treatment, and 4 weeks after the end of treatment. [Figure 16] This is a representative plot showing the interaction between the 3.0 mg TID arm and the BMI stratifier using this technology. [Figure 17] This is a representative plot showing an evaluation of the linear correlation between the cigarette score and the baseline average number of cigarettes using this technology, based on the parallelism between the arms. [Figure 18] This is a representative plot showing the effect modification factor analysis (EMA) of cigarette score across clinical sites for cyticine 1.5 mg TID compared to a pooled placebo using this technology. [Figure 19] This is a representative plot showing the EMA of cigarette scores across clinical sites for cyticine 3.0 mg TID compared to a pooled placebo using this technology. [Figure 20] This is a representative plot showing the EMA of cigarette scores across clinical sites for cyticine 1.5 mg COM compared to a pooled placebo using this technology. [Figure 21]This is a representative plot showing the EMA of cigarette scores across clinical sites for cyticine 3.0 mg COM compared to a pooled placebo using this technology. [Figure 22] This is a representative plot showing the EMA (Exponential Movement) for cyticine 1.5 mg TID compared to a pooled placebo, across clinical sites, for a continuous 4-week withdrawal (Cess / W5~8 / CO success) from weeks 5 to 8, confirmed by exhaled carbon monoxide (CO) at less than 10 ppm. [Figure 23] This is a representative plot showing the EMA (Exponential Movement) for cyticine at 3.0 mg TID compared to a pooled placebo, across clinical sites, for a continuous 4-week withdrawal (Cess / W5~8 / CO success) from weeks 5 to 8, confirmed by exhaled carbon monoxide (CO) at less than 10 ppm. [Figure 24] This is a representative plot showing the EMA (Exponential Movement) for 1.5 mg COM cyticine compared to a pooled placebo, across clinical sites, for a continuous 4-week withdrawal (Cess / W5~8 / CO success) from weeks 5 to 8, confirmed by exhaled carbon monoxide (CO) at less than 10 ppm. [Figure 25] This is a representative plot showing the EMA (Exponential Movement) for cyticine at 3.0 mg COM compared to a pooled placebo, across clinical sites, for a continuous 4-week withdrawal (Cess / W5~8 / CO success) from weeks 5 to 8, confirmed by exhaled carbon monoxide (CO) at less than 10 ppm. [Figure 26] This is a representative plot showing the EMA of cigarette scores across baseline attributes (race, Hispanic, sex, age (M), age (T), stratified BMI, smoking Hx Dur(y)(M), smoking Hx Dur(y)(T), smoking Hx Dur(y)(Q), >2 smoking cessation Hx, and average cigarettes / day screened (M)) for cyticine at 3.0 mg TID using this technology compared to a pooled placebo. [Figure 27]This is a representative plot showing the EMA for a sustained 4-week withdrawal (Cess / W5~8 / CO success) from weeks 5 to 8, confirmed by exhaled carbon monoxide (CO) <10 ppm, across baseline attributes (race, Hispanic, sex, age (M), age (T), stratified BMI, smoking Hx Dur(y)(M), smoking Hx Dur(y)(T), smoking Hx Dur(y)(Q), >2 smoking cessation Hx, average cigarettes / day screened (M)) for cyticine at 3.0 mg TID using this technology compared to a pooled placebo. [Figure 28] This is a representative plot showing the EMA in cigarette scores across previous anti-smoking interventions (>2 smoking cessation Tx, Chantix® Hx, Zyban® Hx, Vape Hx, NRT Hx, Chantix® (most recent), Zyban® (most recent), Vape (most recent), and NRT (most recent) with cyticine 3.0 mg TID) compared to a pooled placebo using this technology. [Figure 29] This is a representative plot showing the EMA for a sustained 4-week withdrawal (Cess / W5~8 / CO success) over weeks 5-8, confirmed by exhaled carbon monoxide (CO) <10 ppm, compared to a pooled placebo, using this technology, across previous anti-smoking interventions (>2 smoking cessation Tx, Chantix® Hx, Zyban® Hx, Vape Hx, NRT Hx, Chantix® (most recent), Zyban® (most recent), Vape (most recent), and NRT (most recent)). [Figure 30] This is a representative plot showing the EMA (Exponential Movement) of cigarette scores across baseline test markers (NMR, CO, cotinine) in cyticine 3.0 mg TID compared to a pooled placebo using this technology. [Figure 31]This is a representative plot showing the EMA for a continuous 4-week withdrawal (Cess / W5~8 / CO success) from weeks 5 to 8, confirmed by exhaled carbon monoxide (CO) of less than 10 ppm, across baseline test markers (NMR, CO, cotinine) using this technology, compared to a pooled placebo. [Figure 32] This is a representative graph showing a turning point analysis of the cyticeine arm with 3.0 mg TID compared to a pooled placebo arm, regarding the 4-week withdrawal period from week 5 to week 8, confirmed by exhaled carbon monoxide (CO) levels below 10 ppm (Cess / W5~8 / CO success), using this technology. [Figure 33] This is a schematic diagram of the research design for Example 2 using current technology. [Figure 34] This is a schematic diagram (CONSORT diagram) of the study design, including screening, randomization, and follow-up of clinical trial participants, using this technology. [Figure 35] This is a representative graph showing the time-based prevalence of tobacco withdrawal at each follow-up for each arm. The estimation of the past 7 days of prevalence of tobacco withdrawal using a general linear model (logit link function with repeated measures) based on this technique is shown for each visit from weeks 2 to 24. [Figure 36] This is a representative plot of effect-modifying factor analysis for continued withdrawal at treatment completion. The odds ratio (OR) shows odds (experimental) / odds (control). CI shows the confidence interval. EMA shows the effect-modifying factor analysis (small P suggests group OR heterogeneity). A logistic regression model of the analytical variables with terms for group, factor, and group × factor interaction. The forest graph provides results from the EMA for two primary endpoints: withdrawal at weeks 3–6. Results are shown for selected baseline factors of particular interest. Group (arm) effect OR estimates for each subset defined by each factor are shown. OR is estimated using a statistical model designed to assess the presence of OR heterogeneity (effect modification) by this technique. [Figure 37]This is a representative plot of EMA for continuous withdrawal at treatment termination: effect-modifying factor analysis. The logistic regression model of the analytical variables has terms for group, factor, and group × factor interactions. The forest graph provides results from EMA for two primary endpoints: withdrawal at weeks 9–12. Results are shown for selected baseline factors of particular interest. Group (arm) effect OR estimates for each subset defined by each factor are shown. OR is estimated using a statistical model designed to assess the presence of OR heterogeneity (effect modification) by this technique. [Figure 38] This is a representative graph of the total score from the simplified questionnaire on smoking urges over time for each arm, as determined by this technology. [Figure 39] This is a representative plot of a stratified primary outcome analysis using this technology for smoking cessation at weeks 9-12 (N=160), where more than 100 cigarettes were used as the stratifier. [Figure 40] This is a representative plot of a stratified primary outcome analysis (N=160) for smoking cessation at weeks 9-12 (using Cochran-Mantel-Haenszel analysis with a stratifier of 100+ cigarettes) using this technology. [Figure 41] This is a representative plot of the primary outcome effect modification at weeks 9-12 (N=160) using this technology, with over 100 cigarettes as the stratifier. [Figure 42] This is a representative plot of primary outcome effect modification for weeks 9-12 (N=160) using a linear regression model and logit links, with 100+ cigarettes as the stratifier. [Figure 43] This is a typical pot for first-order and second-order outcome analysis using Fisher's direct test analysis with MIDP confidence intervals. The denominator represents the control odds, where the odds are the probability (success) / probability (failure) in determining the odds ratio group effect using this technique. [Figure 44]This is a typical plot of the analysis of point-in-time prevalence at each patient visit. Direct group analysis and Fisher analysis are used. The denominator represents the control odds, where the odds are the probability (success) / probability (failure) in determining the odds ratio group effect using this technique. [Figure 45] This is a representative graph of the analysis of a time-point prevalence repeated measures model (time-point prevalence N=160). The analysis is presented using a general linear model, logit links, repeated measures, and an unstructured covariance matrix, according to this technique. [Figure 46] This is a representative graph of the analysis of a time-point prevalence repeated measures model (time-point prevalence N=160). The analysis is presented using a general linear model, logit links, repeated measures, and an unstructured covariance matrix. The denominator represents the control odds, where the odds are the probability (success) / probability (failure) in determining the odds ratio group effect using this technique. [Figure 47] This is a representative plot of primary outcome effect modification for cessation during weeks 9-12 (N=160) using this technology. [Figure 48] This is a representative plot of primary outcome effect modification for cessation during weeks 9–12 (N=160). The analysis is shown using a general linear model and logit links. The denominator represents the control odds, where odds are the probability (success) / probability (failure) in determining the odds ratio group effect according to this technique. [Figure 49] This is a representative plot of primary outcome effect modification for cessation during weeks 9-12 (N=160) using this technology. [Figure 50] This is a representative plot of primary outcome effect modification for cessation during weeks 9–12 (N=160). The analysis is shown using a general linear model and logit links. The denominator represents the control odds, where odds are the probability (success) / probability (failure) in determining the odds ratio group effect according to this technique. [Figure 51] This is a typical graph of weekly cotinine measurements using this technology. [Figure 52]This is a representative graph of cotinine response probability and cotinine negativity assessment (95% confidence interval) using a repeated measures model. The analysis is presented using a general linear model, logit link, repeated measures, and unstructured covariance matrix, as demonstrated by this technique. [Figure 53] This is a representative graph of the cotinine response probability and the evaluation of cotinine negativity using arm-effect odds ratios (95% confidence interval) with a repeated measures model. The analysis is shown using a general linear model, logit link, repeated measures, and unstructured covariance matrix with this technique. [Figure 54] This is a representative graph of cotinine response probability and cotinine response (ITT) (95% confidence interval) using a repeated measures model (ITT). The analysis is presented using a general linear model, logit link, repeated measures, and unstructured covariance matrix, according to this technique. [Figure 55] This is a representative graph of cotinine response probability and cotinine response (ITT) (95% confidence interval) using a repeated measures model (ITT). The analysis is presented using a general linear model, logit link, repeated measures, and unstructured covariance matrix, according to this technique. [Figure 56] This is a representative chart of the nicotine vaping and e-cigarette cessation trial framework using this technology. [Figure 57] This is a representative chart of the subject placement and screening process for nicotine vaping and e-cigarette cessation clinical trials using this technology. [Figure 58] Figure 59A shows a representative chart of smoking cessation rates for 3 mg TID versus placebo using this technology, and Figure 59B shows a representative plot of stratified primary outcome analysis. [Figure 59] This is a representative plot of primary outcome effect modification for stopping at weeks 9–12 (N=160) using a general linear model and logit links. The denominator represents the control odds, where odds are the probability (success) / probability (failure) in determining the odds ratio group effect using this technique. [Figure 60]This is a representative plot of primary outcome effect modification and effect modification factor analysis for vaping cessation at weeks 9-12. The denominator represents the control odds, where the odds are the probability (success) / probability (failure) in determining the odds ratio group effect using this technique. [Figure 61] This is a representative plot of primary outcome effect modification and effect modifying factor analysis for vaping discontinuation at weeks 9–12. It includes trends in the beneficial effects of citicinicline on age and body mass, as demonstrated by this technique. [Figure 62] This is a representative plot of first-order and second-order outcome analysis using Fisher's direct test analysis with MDIP confidence intervals. The denominator represents the control odds, where the odds are the probability (success) / probability (failure) in determining the odds ratio group effect using this technique. [Figure 63] This is a representative plot of the analysis of point prevalence at each visit and point prevalence during treatment. The denominator represents the control odds, where the odds are the probability (success) / probability (failure) in determining the odds ratio group effect using this technique. [Figure 64] This is a representative plot of point prevalence using a repeated measures model. Point prevalence, N=160. The model includes a general linear model, logit link, repeated measures, and an unstructured covariance matrix. The denominator represents the control odds, where odds are the probability (success) / probability (failure) in determining the odds ratio group effect using this technique. [Figure 65] This is a representative plot of weekly cotinine levels for each treatment arm. The model is shown using a general linear model, repeated measures, and an unstructured covariance matrix, as developed by this technique. [Modes for carrying out the invention]

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[0125] While this disclosure can be embodied in various forms, the following descriptions of some embodiments are made with the understanding that this disclosure is intended as an illustration of the technology and is not intended to limit the technology to the specific embodiments shown. Headings are provided for convenience only and should not be construed as limiting the technology in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0126] The use of numerical values ​​in the various quantitative values ​​expressed in this application is described as an approximation, as if preceded by the word “about” both the minimum and maximum values ​​within the range described, unless otherwise explicitly stated. It should be understood that all numerical specifications are preceded by the term “about,” even if not explicitly stated. Such range formats are used for convenience and brevity and include numerical values ​​explicitly designated as limits to the range, but should be understood flexibly to also include all individual numerical values ​​or subranges encompassed within that range, as if each numerical value and subrange were explicitly designated. For example, a ratio in the range of about 1 to about 200 should be understood to include the explicitly listed limits of about 1 and about 200, as well as individual ratios, e.g., about 2, about 3, and about 4, and subranges, e.g., about 10 to about 50, and about 20 to about 100, etc. Furthermore, it should be understood that the reagents described herein are merely illustrative, and such equivalents are known in the art, even if not explicitly stated.

[0127] As used herein, the term "approximately" refers to a measurable value such as a quantity or concentration, and means to include variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified quantity.

[0128] Furthermore, the disclosure of ranges is intended as a continuous range, which includes all values ​​between the enumerated minimum and maximum values, as well as any range that can be formed by such values. Also disclosed herein are all ratios (and any ranges of such ratios) that can be formed by dividing a disclosed numerical value into any other disclosed numerical value. Thus, those skilled in the art will understand that many such ratios, ranges, and ranges of ratios can be clearly derived from the numerical values ​​presented herein, and in all cases, such ratios, ranges, and ranges of ratios represent various embodiments of this disclosure.

[0129] As used herein, the term “statistical significance” refers to a result from data generated by a test or experiment that is unlikely to occur randomly or by chance, but is instead likely to be attributable to a specific cause. Statistical significance is assessed from a calculated probability (p-value), where the p-value is a function of the mean and standard deviation of the data sample and indicates the probability that the statistical result occurred by chance or sampling error. A p-value of 0.05 or less is considered statistically significant and corresponds to a 95% confidence level.

[0130] "Comprising" or "comprises" means that a composition or method includes the enumerated elements but does not exclude other elements. When used to define a composition or method, "essentially consisting of" means excluding other elements that have any essential importance to the combination of the elements in question. Thus, a composition essentially consisting of the elements defined herein does not exclude other materials or steps that do not substantially affect the basis and novel features of the claimed Art. "Consists of" means excluding elements that are not in any substantial amount to other components and substantial method steps. Embodiments defined by each of these transitional terms are within the scope of the Art.

[0131] As used herein, the term “control subject” refers to any subject used as a criterion for comparison with the test subject. A control subject includes, but is not limited to, any subject that has not been administered the composition, has been administered a composition other than the test composition (e.g., 1.5 mg of cyticine three times daily, or 3.0 mg of cyticine three times daily), or has been administered a placebo.

[0132] The term “treatment” in relation to a given disease or disability includes, but is not limited to, inhibiting the disease or disability, for example, stopping its progression; alleviating the disease or disability, for example, causing regression of the disease or disability; or alleviating conditions caused by or resulting from the disease or disability, for example, alleviating or treating the symptoms of the disease or disability. The term “prevention” in relation to a given disease or disability means preventing the onset of disease progression when nothing is happening; preventing the disease or disability from occurring in a person who is susceptible to the disability or disease but has not yet been diagnosed with the disability or disease; and / or, if the disease or disability is already present, preventing further progression of the disease / disability.

[0133] "Vaping" refers to the act of inhaling vapor produced by a device from a solution carried in a cartridge or chamber. In some embodiments, the device is electronic and mimics smoking. A vaping device may include, but is not limited to, a power source, an atomizer, and a cartridge or chamber. In some embodiments, vaping refers to the consumption of ejuice or vaping activities, such as taking in or otherwise consuming vapor from a vaping device, performing a vaping activity with a vaping device, or otherwise using a vaping device to inhale vapor. In another embodiment, vaping refers to the consumption of ejuice. In an alternative embodiment, vaping refers to the consumption of ejuice, or taking in or otherwise consuming vapor from a vaping device. In yet another embodiment, vaping refers to a vaping activity. In other embodiments, vaping refers to taking in or otherwise consuming vapor from a vaping device, performing a vaping activity with a vaping device, or otherwise using a vaping device to inhale vapor. In a further embodiment, vaping refers to taking in or otherwise consuming a vapor stream from a vaping device, or otherwise inhaling vapor using a vaping device. In yet another embodiment, vaping refers to inhaling vapor using a vaping device.

[0134] As used herein, the terms “reduced vaping,” “reduced vaping,” and “reduce vaping” mean reducing the frequency or amount of vaping per hour, day, week, month, or year, such as reducing the amount of e-liquid consumed, reducing the number or frequency of vapor exhalations taken from or otherwise consumed by a vaping device, reducing the number or frequency of vaping activities performed with a vaping device, or reducing the use of a vaping device for vapor inhalation.

[0135] As used herein, the term “adverse event” (AE) refers to any undesirable medical occurrence in a subject administered with the composition, which is not necessarily caused by the treatment. Therefore, an AE may be an undesirable and unintended sign (including abnormal laboratory findings), symptom, or disease that is temporarily associated with the use of the composition, whether or not it is considered to be related to the composition.

[0136] As used herein, the term “adverse drug reaction” refers to any undesirable and unintended response to an administered composition. The term “response to composition” means that attribution is at least reasonably possible (i.e., the relationship cannot be ruled out and is at least possible as determined by the principal investigator) (see definitions below).

[0137] The terms "Serious Adverse Event" (SAE) and "Serious Adverse Reaction" (SAR) refer to an AE that results in at least one of the following outcomes: death, life-threatening, requiring hospitalization or prolonging the subject's current hospitalization, resulting in persistent or significant incapacitation or disability, resulting in a birth defect or birth defect, or a significant medical event requiring medical intervention to prevent any of the above outcomes.

[0138] As used herein, the term “Suspected Unexpected Serious Adverse Reaction” (SUSAR) means a serious and unexpected AE in which there is at least a reasonable possibility that there is an attribution between the event and the composition. A significant medical event is one that is not immediately life-threatening but could endanger the subject and may require intervention to prevent one of the other serious outcomes listed above. Examples of such events include allergic bronchospasm or hematological cachexia or intensive care in the emergency room or at home for seizures that do not result in hospitalization. The term “life-threatening” refers to an event in which the subject was at risk of death at the time of the event and does not refer to an event that, hypothetically, could have resulted in death if it had been more severe. For example, drug-induced hepatitis that resolves without evidence of liver failure is not considered life-threatening, even though drug-induced hepatitis can be fatal. Hospitalization or extension of current hospitalization means that the hospitalization and / or extension of hospitalization of a hospitalized patient was required for the treatment of the AE or occurred as a result of the event. This does not refer to pre-planned elective hospitalizations for the treatment of existing conditions that have not significantly worsened, or to diagnostic procedures.

[0139] The terms “cyticine therapeutic arm,” “activating arm,” “therapeutic arm,” “activating therapeutic arm,” and “investigative arm” are used interchangeably throughout and refer to subjects to whom compositions containing cyticine are administered.

[0140] List of abbreviations: ADR, adverse drug reaction; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; Cmax, maximum observed plasma concentration; CrCl, creatinine clearance; CRF, case report form; DSM, data safety monitor; ECG, electrocardiogram; GCP, standards for conducting clinical trials of medicinal products; ICH, International Conference on Harmonisation of Regulations for Pharmaceuticals for Human Use; IMP, investigational product (in this protocol, this refers to a film-coated tablet of 3.0 mg citicinicline); MedDRA, regulatory glossary for pharmaceuticals; SAE, serious adverse event; SAR, serious adverse reaction; SmPC, European product overview; SOC, MedDRA organ-specific classification; SUSAR, unknown suspected serious adverse reaction; Tmax, time to maximum observed concentration; UADR, unknown adverse drug reaction; UAE, unknown adverse event; ULN, upper limit of normal.

[0141] composition The compositions for use in the methods of this disclosure comprise cyticine, or its pharmaceutically acceptable derivatives, conjugates, or salts, or mixtures thereof, which are collectively referred to herein as “cyticine.” In this context, “pharmaceutically acceptable” means that the substance does not result in unacceptable toxicity to the subject or interaction with other components of the composition. Cyticine, (-)-cyticine, and cyticine are referred to interchangeably.

[0142] Any suitable cyticine pharmaceutical composition or formulation can be used in the manner described herein. In some embodiments, cyticine can be formulated in tablet form, for example, as a compressed film-coated tablet for oral administration.

[0143] Compositions for use in accordance with this disclosure can be formulated as one or more dose units. The terms “dose unit” and “administered dose unit” as used herein refer to a portion of a pharmaceutical composition containing an amount of therapeutic agent suitable for a single dose to provide a therapeutic effect. Such dose units may be administered once or multiple times per day (i.e., 1 to about 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 times), or as many times as necessary to induce a therapeutic response.

[0144] A unit dose may include a single tablet, such as a tablet containing 3.0 mg of cyticine, or it may include two or more tablets that together contain a unit dose (e.g., 3.0 mg of cyticine). For example, a unit dose of 3.0 mg may include two tablets, each containing 1.5 mg of cyticine, such as two Tabex® tablets. Each Tabex® tablet is typically formulated as a compressed film-coated tablet, containing 1.5 mg of cyticine in a single tablet along with a number of tablet-forming excipients (calcium sulfate, cellulose powder, colloidal silica, magnesium stearate), and coated with a colored film coating containing polyvinyl alcohol, titanium dioxide, and iron oxide. As another example, a unit dose of 3.0 mg may include three tablets, each containing 1.0 mg of cyticine, such as three tablets formulated similarly to Tabex® tablets.

[0145] Alternatively, cyticine may be formulated into capsules or another vehicle for oral administration, making it orally deliverable, or into a composition for nasal or topical administration. The terms “orally deliverable” or “oral administration” as used herein include any form of delivery of the therapeutic agent or composition to a subject, where the agent or composition is placed in the subject’s mouth, whether or not it is swallowed. Thus, “oral administration” includes buccal, sublingual, and esophageal administration.

[0146] Tablets and other dosage forms (hereinafter collectively referred to as "compositions") may contain one or more excipients, such as those common in the art. Excipients that may be used in compositions include, for example, fillers, disintegrants, preservatives, lubricants, and wetting agents.

[0147] Examples of fillers that can be used include lactose (e.g., either anhydrous or monohydrate), cellulose, starch (e.g., corn and / or wheat starch), calcium phosphate, calcium sulfate, and mannitol.

[0148] Preservatives prevent bacterial or fungal contamination of the formulation and include various antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid.

[0149] Suitable lubricants include stearic acid and its salts. An example of a lubricant for use in the compositions of this disclosure is magnesium stearate.

[0150] The pharmaceutical composition may further contain sweeteners, flavorings, or coloring agents.

[0151] In some embodiments, the placebo is a tablet containing the same, substantially the same, similar, or substantially similar inactive (e.g., cyticine) component as the test composition. In these embodiments, the placebo contains the same, substantially the same, similar, or substantially similar excipients, fillers, preservatives, lubricants, sweeteners, flavorings, and / or colorants as the test composition, as well as at least one inactive component, such as cellulose. In some embodiments, the placebo tablet and the test composition tablet are the same or substantially the same weight, size, shape, and color, and / or contained in the same or substantially the same package.

[0152] Those skilled in the art will be familiar with suitable fillers, preservatives, and lubricants other than those specifically mentioned above, as well as suitable sweeteners, flavorings, colorants, and other additives. Cyticine pharmaceutical compositions useful in the methods of this disclosure may include coatings, such as film coatings, which may be coated using, for example, coridone, shellac, gum arabic, talc, titanium dioxide, or sugar, according to any method known in the art.

[0153] Pharmaceutical compositions containing cyticine can be prepared by any preferred method. For example, capsules can be prepared by mixing cyticine with one or more inert carriers such as lactose or sorbitol and packing them into gelatin capsules. Tablets can be prepared by known compression methods.

[0154] In one embodiment, the compositions of the present disclosure, upon storage for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months in a sealed container maintained at room temperature, refrigerated (e.g., about 5 to about -10°C) temperature, or frozen, exhibit at least about 90%, at least about 95%, at least about 97.5%, or at least about 99% of the active ingredient(s) initially present therein.

[0155] method This disclosure provides a method for treating nicotine addiction or nicotine dependence in a subject who requires treatment, and includes administering an effective dose of cyticine to the subject. In some embodiments, a method for treating nicotine addiction or nicotine dependence includes preventing smoking relapse and / or promoting cessation or reduction of smoking in a subject who requires treatment.

[0156] In some embodiments, the Disclosure provides a method for treating nicotine addiction or nicotine dependence in a subject that requires treatment, comprising administering a therapeutically effective dose of cyticine to the subject. In some embodiments, the Disclosure relates to a method for preventing smoking relapse in a subject that requires treatment, comprising administering a therapeutically effective dose of cyticine to the subject. In another embodiment, the Disclosure provides a method for promoting smoking cessation in a subject that requires treatment, comprising administering a therapeutically effective dose of cyticine to the subject. In some embodiments, the Disclosure provides a method for promoting reduction in smoking in a subject that requires treatment, comprising administering an effective dose of cyticine to the subject. In some embodiments, the Disclosure provides a method for treating nicotine addiction or nicotine dependence in a subject that requires treatment, and nicotine addiction or nicotine dependence is in the form of cigarettes, smokeless tobacco, snus, e-cigarettes (e-cig), vaping using vaping devices, and / or hookah. In some embodiments, the vaping device contains a liquid containing nicotine, for example, nicotine at a concentration of about 1 mg / ml to about 12 mg / ml, or more than about 13 mg / ml. Any patient with nicotine addiction or nicotine dependence can be treated by the methods disclosed herein.

[0157] In additional embodiments, the Disclosure provides a method for treating and / or preventing addiction or dependence in subjects where such treatment and / or prevention is required, comprising administering a therapeutically effective dose of cyticine to the subject. Without being intended to be bound by any particular theory, cyticine interacts with the dopamine neurotransmitter release cycle as a partial agonist of nicotinic acetylcholine receptors (nAChRs) and is useful for treating and / or preventing multiple addictions or dependences in subjects where such treatment and / or prevention is required. Non-limiting examples of addictions and dependences that are thought to be treated and / or prevented by the administration of cyticine include addictions and / or dependences to substances, compounds, and / or behaviors that may involve the dopamine neurotransmitter release cycle. Exemplary substances, compounds, and / or actions include, but are not limited to, marijuana, cannabis, tetrahydrocannabinol (THC), cannabidiol (CBD), alcohol, opioids and other analgesics, cocaine, food, gambling, sexual activity, heroin, benzodiazepines, barbiturates, stimulants, and inhalants. In further embodiments, the Disclosure provides a method for promoting the cessation of addiction or dependence in a subject, comprising administering a therapeutically effective amount of cyticine to the subject. In some embodiments, the Disclosure provides a method for promoting reduction in addiction and / or dependence in a subject, comprising administering an effective amount of cyticine to the subject. Compositions and methods described herein in relation to smoking, vaping, and nicotine can be used to treat, prevent, and / or reduce addiction or dependence in a subject, such as any subject having addiction or dependence involving a dopamine neurotransmitter release cycle.

[0158] In further embodiments, a method for treating nicotine addiction or nicotine dependence includes doing so in subjects who require prevention of vaping relapse and / or promotion of cessation or reduction of vaping. In some embodiments, the Disclosure relates to a method for doing so in subjects who require prevention of vaping relapse, and includes administering a therapeutically effective dose of cyticine to the subject. In another embodiment, the Disclosure provides a method for doing so in subjects who require promotion of cessation of vaping, and includes administering a therapeutically effective dose of cyticine to the subject. In some embodiments, the Disclosure provides a method for doing so in subjects who require promotion of reduction of vaping, and includes administering a therapeutically effective dose of cyticine to the subject.

[0159] In some embodiments, provided herein are methods for treating nicotine addiction or nicotine dependence in a subject, comprising administering cyticine to the subject in need twice daily ("bid" or "BID") or three times daily ("tid" or "TID") in equal doses. In one embodiment, each of the two daily doses is administered in the morning and evening, respectively. In another embodiment, each of the two daily doses is administered at intervals of approximately 10 to 12 hours. In yet another embodiment, each of the three daily doses is administered in the morning, afternoon, and evening, respectively. In yet another embodiment, each of the three daily doses is administered at intervals of approximately 4 to 5 hours. In yet another embodiment, each of the three daily doses is administered at intervals of approximately 4, 5, 6, 7, 8, 9, 10 hours, or longer. In one embodiment, the administration is carried out for a period of at least about 6 weeks, at least about 12 weeks, at least about 24 weeks, or indefinitely. In this embodiment, the administration may include BID or TID for any day or week during the administration period. For example, in these embodiments, the entire duration of the administration may be a BID or TID. As another example, in these embodiments, at least a portion of the administration, for example, at least about 1 day, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 12 weeks, etc., may be a BID or TID. As yet another example, in these embodiments, the BID or TID administration may be in any order during the administration period, such as day 1 being a BID or TID, day 2 being a BID or TID, day 3 being a BID or TID, and so on.

[0160] In some embodiments, administration is carried out regardless of whether the subject is feeding or fasting. For example, administration can be carried out simultaneously with food, with food, at any time before the subject ingests food, or at any time after the subject ingests food. Without intending to limit ourselves to any particular theory, it is inconceivable that food (or feeding or fasting) would affect the bioavailability of cyticine or the overall bioavailability of cyticine, which may be determined by the systemic absorption of cyticine in the subject.

[0161] In some embodiments, the TID dose is 1 mg, 1.5 mg, 2 mg, 2.5 mg, or 3.0 mg of cyticine. In some embodiments, the TID dose is 1 mg, regardless of how the dose is divided. For example, each TID dose can be administered as two 0.5 mg strength tablets three times a day, or one 1 mg tablet three times a day, or any other possibility. In some embodiments, the TID dose is 1.0 mg, regardless of how the dose is divided among the dose units. In some embodiments, the TID dose is 1.5 mg, regardless of how the dose is divided among the dose units. In some embodiments, the TID dose is 2 mg, regardless of how the dose is divided among the dose units. In yet another embodiment, the TID dose is 2.5 mg, regardless of how the dose is divided among the dose units. In some embodiments, the TID dose is 3.0 mg, regardless of how the dose is divided among the dose units.

[0162] In some embodiments, subjects do not experience any adverse events associated with cyticine treatment. Adverse events may be mild (e.g., no interference with activity), moderate (interference with activity, but requiring little to no medical intervention), or severe (interfering with daily activities and requiring medical intervention). Non-limiting examples of adverse events include upper respiratory tract infections (URTIs), abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In other embodiments, subjects experience two or fewer adverse events associated with cyticine treatment, such as an increase of approximately 0% to approximately 10% in the subject's nausea, abnormal dreams, insomnia, headache, and / or URTI, e.g., approximately 0%, approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9%, or approximately 10%. In some embodiments, subjects do not experience adverse events compared to subjects administered nicotine replacement therapy (NRT), bupropion, varenicline, e-cigarettes, vaping, and / or combinations thereof.

[0163] In some embodiments, subjects experience nicotine addiction or nicotine dependence by smoking cigarettes, ingesting smokeless tobacco and / or snus, using e-cigarettes (e-cig) and / or vapes, and / or using hookah, on a daily basis, such as consuming units of nicotine per day. In some embodiments, subjects with nicotine addiction or nicotine dependence consume approximately 0 to approximately 100 units of nicotine per day.For example, one cigarette can be a unit of nicotine, and individuals with nicotine addiction or nicotine dependence are classified as follows: approximately 0 cigarettes per day to approximately 100 cigarettes per day, approximately 5 cigarettes per day to approximately 75 cigarettes per day, approximately 5 cigarettes per day to approximately 50 cigarettes per day, approximately 5 cigarettes per day to approximately 25 cigarettes per day, approximately 10 cigarettes per day to approximately 50 cigarettes per day, and approximately 20 cigarettes per day. Tobacco - approximately 50 cigarettes per day, approximately 25 cigarettes per day - approximately 75 cigarettes per day, approximately 25 cigarettes per day - approximately 50 cigarettes per day, for example, approximately 0 cigarettes per day, approximately 1 cigarette per day, approximately 2 cigarettes per day, approximately 3 cigarettes per day, approximately 4 cigarettes per day, approximately 5 cigarettes per day, approximately 6 cigarettes per day, approximately 7 cigarettes per day, approximately 8 cigarettes per day Approximately 9 cigarettes per day, approximately 10 cigarettes per day, approximately 11 cigarettes per day, approximately 12 cigarettes per day, approximately 13 cigarettes per day, approximately 14 cigarettes per day, approximately 15 cigarettes per day, approximately 16 cigarettes per day, approximately 17 cigarettes per day, approximately 18 cigarettes per day, approximately 19 cigarettes per day, approximately 20 cigarettes per day, approximately 25 cigarettes per day, approximately 30 cigarettes per day Smoking tobacco, approximately 35 cigarettes per day, approximately 40 cigarettes per day, approximately 45 cigarettes per day, approximately 50 cigarettes per day, approximately 55 cigarettes per day, approximately 60 cigarettes per day, approximately 65 cigarettes per day, approximately 70 cigarettes per day, approximately 75 cigarettes per day, approximately 80 cigarettes per day, approximately 85 cigarettes per day, approximately 90 cigarettes per day, or approximately 100 cigarettes per day.In other examples, units of nicotine also include the ingestion of smokeless tobacco and / or snus, the use of e-cigarettes (e-cig) and / or vapes (e.g., vaping), and / or the use of hookah in place of or in combination with daily cigarettes.

[0164] In some embodiments, administration of cyticine reduces the number of units of nicotine ingested by a subject per day, such as the number of cigarettes smoked per day. In some embodiments, the method of the present technology reduces the percentage of cigarettes smoked by a subject by at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% after treatment with cyticine at 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID, compared to a control subject, placebo control, and / or baseline.

[0165] In some embodiments, administration of cyticine increases withdrawal in subjects after treatment with cyticine at 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID. In these embodiments, subjects experience approximately 5% to approximately 30% withdrawal after cyticine treatment, compared to withdrawal achieved without cyticine treatment, for example, approximately 5% to approximately 15%, approximately 5% to approximately 10%, approximately 5% to approximately <10%, approximately 10% to approximately 25%, approximately 15% to approximately 20%, approximately 20% to approximately 30%, or approximately 25% to approximately <30%, approximately 5% to approximately 100%, approximately 5% to approximately 75%, approximately 5% to approximately 50%, approximately 25% to approximately 75%, approximately 25% to approximately The withdrawal increases by 50%, approximately 30% to approximately 50%, approximately 30% to approximately 50%, approximately 30% to approximately 75%, approximately 30% to approximately <100%, or approximately 30% to approximately 100%, for example, at least approximately 10%, at least approximately 15%, at least approximately 20%, at least approximately 25%, at least approximately 30%, at least approximately 35%, at least approximately 40%, at least approximately 45%, at least approximately 50%, or at least approximately 55%. In some embodiments, the withdrawal is a withdrawal period such as approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 12 weeks, approximately 16 weeks, approximately 20 weeks, approximately 24 weeks, approximately 28 weeks, or approximately 32 weeks. In a particular embodiment, the withdrawal period is approximately 1 day to 4 weeks, approximately 1 week to 8 weeks, approximately 2 weeks to 12 weeks, approximately 4 weeks to 24 weeks, or approximately 8 weeks to 32 weeks.

[0166] In some embodiments, administration of cyticine increases the smoking cessation rate in subjects after treatment with cyticine at 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID. In these embodiments, subjects have a smoking cessation rate of approximately 5% to approximately 30%, for example, approximately 5% to approximately 15%, approximately 5% to approximately 10%, approximately 5% to approximately <10%, approximately 10% to approximately 25%, approximately 15% to approximately 20%, approximately 20% to approximately 30%, or approximately 25% to approximately <30%, approximately 5% to approximately 100%, approximately 5% to approximately 75%, approximately 5% to approximately 50%, approximately 25% to approximately 75%, and approximately 25%. Having a smoking cessation rate of ~50%, approximately 30% to approximately 50%, approximately 30% to approximately 50%, approximately 30% to approximately 75%, approximately 30% to approximately <100%, or approximately 30% to approximately 100%, for example, at least approximately 10%, at least approximately 15%, at least approximately 20%, at least approximately 25%, at least approximately 30%, at least approximately 35%, at least approximately 40%, at least approximately 45%, at least approximately 50%, or at least approximately 55%. In some embodiments, the withdrawal period is determined after a withdrawal period such as about 1 day, about 3 days, about 7 days, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, or about 32 weeks. In a particular embodiment, the withdrawal period is about 1 day to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 2 weeks, about 3 weeks to about 6 weeks, about 2 weeks to about 12 weeks, about 9 weeks to about 12 weeks, about 4 weeks to about 24 weeks, or about 8 weeks to about 32 weeks.

[0167] In some embodiments, the subject has a cyticine level of approximately 0 ppm to approximately 50 ppm, for example, approximately 10 ppm to approximately 40 ppm, approximately 10 ppm to approximately 30 ppm, approximately 10 ppm to less than approximately 20 ppm, approximately 20 ppm to approximately 30 ppm, approximately 20 ppm to approximately 40 ppm, approximately 20 ppm to less than approximately 50 ppm, or approximately 20 ppm to approximately 50 ppm, for example, approximately 0 ppm, approximately 2 ppm, approximately 4 ppm, approximately 6 ppm The patient has exhaled carbon monoxide (CO) levels of approximately 8 ppm, 10 ppm, 12 ppm, 14 ppm, 16 ppm, 18 ppm, 20 ppm, 22 ppm, 24 ppm, 26 ppm, 28 ppm, 30 ppm, 32 ppm, 34 ppm, 36 ppm, 38 ppm, 40 ppm, 42 ppm, 44 ppm, 46 ppm, 48 ppm, or 50 ppm. In some embodiments, administration of cyticine in the form of 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID, or treatment with cyticine in the form of 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID, reduces the exhaled carbon monoxide (CO) levels of subjects by at least approximately 60%, at least approximately 65%, at least approximately 70%, at least approximately 75%, at least approximately 80%, at least approximately 85%, at least approximately 90%, at least approximately 95%, or at least approximately 100%, compared to control subjects, placebo controls, and / or baseline. In some embodiments, the subject has an exhaled carbon monoxide (CO) level of approximately 0 ppm to approximately 30 ppm after treatment with cyticine, for example, approximately 10 ppm to approximately 25 ppm, approximately 10 ppm to approximately 20 ppm, approximately 10 ppm to approximately 20 ppm, approximately 5 ppm to approximately 15 ppm, approximately 5 ppm to approximately 10 ppm, approximately 1 ppm to approximately 10 ppm, or approximately 10 ppm to approximately 5 ppm, for example, approximately 0 ppm, approximately 2 ppm, approximately 4 ppm, approximately 6 ppm, approximately 8 ppm, approximately 10 ppm, approximately 12 ppm, approximately 14 ppm, approximately 16 ppm, approximately 18 ppm, or approximately 20 ppm.

[0168] In some embodiments, the subjects were given a blood glucose level of approximately 5 ng / mL to 500 ng / mL, approximately 25 ng / mL to 400 ng / mL, approximately 25 ng / mL to 400 ng / mL, approximately 25 ng / mL to 300 ng / mL, approximately 50 ng / mL to 200 ng / mL, approximately 75 ng / mL to 150 ng / mL, approximately 85 ng / mL to 100 ng / mL, approximately 100 ng / mL to 400 ng / mL, approximately 100 ng / mL to 300 ng / mL, approximately 100 ng / mL to 200 ng / mL, approximately 200 ng / mL to 300 ng / mL, approximately 200 ng / mL to 400 ng / mL, approximately 200 ng / mL to <500 ng / mL, and approximately 200 ng / mL before treatment with cyticine. Having serum and / or plasma cotinine levels of approximately 500 ng / mL, for example, approximately 10 ng / mL, 20 ng / mL, 30 ng / mL, 40 ng / mL, 50 ng / mL, 60 ng / mL, 70 ng / mL, 80 ng / mL, 90 ng / mL, 100 ng / mL, 125 ng / mL, 150 ng / mL, 175 ng / mL, 200 ng / mL, 225 ng / mL, 250 ng / mL, 275 ng / mL, 300 ng / mL, 325 ng / mL, 350 ng / mL, 375 ng / mL, 400 ng / mL, 425 ng / mL, 450 ng / mL, 475 ng / mL, or approximately 500 ng / mL. In some embodiments, administration of cyticine in the form of 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID, or treatment with cyticine in the form of 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID, reduces serum and / or plasma cotinine levels in subjects by at least 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%, compared to control subjects, placebo controls, and / or baseline.In some embodiments, subjects have serum and / or plasma cotinine levels of approximately 0.1 ng / mL to approximately 20 ng / mL, approximately 0.1 ng / mL to approximately 15 ng / mL, approximately 0.5 ng / mL to approximately 10 ng / mL, approximately 1 ng / mL to approximately 10 ng / mL, approximately 0.5 ng / mL to approximately 5 ng / mL, or approximately 0.5 ng / mL to approximately 1 ng / mL, for example, approximately 0.1 ng / mL, approximately 0.5 ng / mL, approximately 1 ng / mL, approximately 1.5 ng / mL, approximately 3 ng / mL, approximately 5 ng / mL, approximately 7 ng / mL, approximately 8 ng / mL, approximately 9 ng / mL, approximately 10 ng / mL, approximately 15 ng / mL, or approximately 20 ng / mL after treatment with cyticine.

[0169] In some embodiments, administration of cyticine increases the odds ratio in subjects after 4 weeks of treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cyticine, after 8 weeks of treatment, and 4 weeks after the end of treatment. In these embodiments, subjects have odds ratios of about 1.1 to about 20, about 1.1 to about 15, about 1.1 to about 10, about 1.1 to about 5, about 5 to about 10, about 5 to about 15, about 10 to about 15, about 10 to about <20, or about 10 to about 20 compared to a control subject, placebo control, and / or baseline.

[0170] In some embodiments, the subject's vital signs, hematological and chemical levels, and ECG are measured before and / or after administration of cyticine. In some embodiments, the subject does not show clinically significant changes in vital signs, hematological and chemical levels, or ECG after administration of cyticine.

[0171] In some embodiments, subjects are heavy, moderate, or light nicotine users, e.g., smokers or vapers who use nicotine and can be classified as “heavy smokers” or “heavy vapers,” “moderate smokers” or “moderate vapers,” or “light smokers” or “light vapers.” For example, “heavy smokers” as provided herein refers to subjects who report consuming 20 or more cigarettes per day. “Moderate smokers” as provided herein refers to subjects who report consuming 11 to 19 cigarettes per day. “Light smokers” as provided herein refers to subjects who report consuming 1 to 10 cigarettes per day. As another example, “heavy vapers” as provided herein refers to subjects who report engaging in vaping activities 20 or more times per day, or consuming exhalations from a vaping device 20 or more times per day, or otherwise reporting using a vaping device 20 or more times per day. As provided herein, “moderate vapers” refers to subjects who report engaging in 11 to 19 vaping activities per day, or consuming 11 to 19 exhalations from a vaping device per day, or otherwise report using a vaping device 11 to 19 times per day. As provided herein, “mild vapers” refers to subjects who report engaging in 1 to 10 vaping activities per day, or consuming 1 to 10 exhalations from a vaping device per day, or otherwise report using a vaping device 1 to 10 times per day. In some embodiments, administration of cyticine reduces cotinine levels in subjects identified as heavy smokers or heavy vapers. In some embodiments, administration of cyticine reduces cotinine levels in subjects identified as moderate smokers or moderate vapers. In yet another embodiment, administration of cyticine reduces cotinine levels in subjects identified as light smokers or mild vapers.

[0172] In some embodiments, the subject has been smoking or vaping for at least about 1 year, at least about 5 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 35 years, at least about 40 years, at least about 45 years, at least about 50 years, or longer prior to the administration of cyticine.

[0173] In some embodiments, subjects began smoking or vaping in adolescence. In some embodiments, subjects began smoking or vaping cigarettes between the ages of 10 and 19. In some embodiments, prior to administration of cyticine, subjects had started smoking or vaping cigarettes in adolescence and had been smoking or vaping for at least about 20 years, at least about 25 years, at least about 30 years, at least about 35 years, at least about 40 years, at least about 45 years, at least about 50 years, or longer.

[0174] In some embodiments, the duration of administration is up to approximately 26 weeks. In certain embodiments, the duration of administration is approximately 6 to 12 weeks, and in some embodiments, cyticine is administered for approximately 6 weeks as described above.

[0175] Compared to commercially available 25-day dose-setting schedules with a unit dose of 1.5 mg of cyticine, the proportion of smokers experiencing continuous withdrawal is remarkably high in patients treated according to the methods disclosed herein, as shown, for example, in Figure 7.

[0176] In some embodiments, the subjects are smokers who smoke, for example, about three or more cigarettes per day. In some embodiments, the subjects are smokers who smoke about five or more or about ten or more cigarettes per day. In some embodiments, the subjects have a measurable exhaled carbon monoxide (CO) concentration of about 10 ppm or higher before administration of cyticine.

[0177] In some embodiments, the subjects are treatment-refractory patients. As used herein, “treatment-refractory patient” or “treatment-refractory subject” is a subject who has failed to respond to treatment with one or more nicotine addiction or nicotine dependence treatments. In some embodiments, nicotine addiction or nicotine dependence treatments include both regulatory-approved treatments and methods of quitting smoking, such as vaping and behavioral support. Non-limiting examples of behavioral support include behavioral support that is useful to reduce, prevent, or otherwise treat anxiety, depression, and / or withdrawal symptoms. In certain embodiments, behavioral support includes counseling, diaries, wearable devices, apps, web-based smoking quit programs, text message interventions, and combinations thereof. In further embodiments, behavioral support is provided to treatment-refractory patients, such as control patients (e.g., baseline, placebo administration, smoking without citicinicline, vaping, or administration of nicotine-quitting medication). In some embodiments, nicotine addiction or nicotine dependence treatments include FDA-approved first-line smoking quit medications such as NRT, bupropion, and varenicline. Nicotine replacement therapy can take the form of patches, gums, lozenges, sprays, and inhalers.

[0178] In some embodiments, the subjects are refractory patients who have failed treatment with one or more therapies for nicotine addiction or nicotine dependence. For example, the subjects have failed two or more treatments, three or more treatments, four or more treatments, five or more treatments, six or more treatments, seven or more treatments, eight or more treatments, nine or more treatments, or ten or more treatments. In some embodiments, the subjects are refractory patients who have failed treatment for nicotine addiction or nicotine dependence, including NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof.

[0179] In some embodiments, the subject has previously attempted to quit smoking or vaping at least once, at least twice, at least three times, at least four times, at least five times, at least six times, at least seven times, at least eight times, at least nine times, at least ten times, or more, prior to the administration of cyticine.

[0180] In some embodiments, refractory subjects have previously received treatment for nicotine addiction and / or nicotine dependence for at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks prior to the administration of cyticine.

[0181] In one embodiment, the method comprises administering cyticine to a subject, the cyticine being provided in unit doses ranging from approximately 1.0 mg to approximately 5.0 mg. In a particular embodiment, the unit dose of cyticine is approximately 1.0 mg. In a particular embodiment, the unit dose of cyticine is approximately 1.5 mg. In a particular embodiment, the unit dose of cyticine is approximately 3.0 mg. In some embodiments, the unit dose of cyticine is administered to the subject 3 to 6 times per day. In some embodiments, the unit dose of cyticine is administered to the subject 3 times per day. In some embodiments of the methods disclosed herein, the unit dose is one of the following, administered three times a day: about 1.0 mg, about 1.5 mg, or about 3.0 mg, for a period of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 4 months, about 1 year, about 1.25 years, about 1.5 years, about 1.75 years, about 2 years, or more than about 2 years: about 1.0 mg, about 1.5 mg, or about 3.0 mg, administered three times a day. In certain embodiments, the unit dose of cyticine is administered for a maximum of about 2 weeks, about 2 weeks to about 6 weeks, about 3 weeks to about 6 weeks, or about 9 weeks to about 12 weeks. In some embodiments, the relapse rate is lower in subjects administered the unit dose of cyticine for at least about 4 weeks compared to subjects administered the unit dose of cyticine for at least about 2 weeks. In other embodiments, the recurrence rate is lower in subjects administered a unit dose of cyticine for at least about 6 weeks compared to subjects administered a unit dose of cyticine for at least about 4 weeks. In further embodiments, the recurrence rate is lower in subjects administered a unit dose of cyticine for at least about 8 weeks compared to subjects administered a unit dose of cyticine for at least about 4 weeks. In even further embodiments, the recurrence rate is lower in subjects administered a unit dose of cyticine for at least about 12 weeks compared to subjects administered a unit dose of cyticine for at least about 4 weeks.

[0182] In some embodiments, administration of cyticine to subjects resulted in significantly better nicotine cessation rates (smoking cessation rates or vaping continuation rates) compared to subjects administered a commercially available 1.5 mg per unit dose setting schedule. In some embodiments, a unit dose of 3.0 mg of cyticine is administered three times daily for 6 weeks (e.g., the first 6 weeks), followed by a placebo for 6 weeks (e.g., the next 6 weeks). In certain embodiments, behavioral support is provided during at least part of the first 6 weeks, at least part of the next 6 weeks, at least part of the first 6 weeks, at least part of the next 6 weeks, or a combination thereof. In some embodiments, a unit dose of 3.0 mg of cyticine is administered three times daily for 12 weeks. In certain embodiments, behavioral support is provided to subjects during at least part of the 12 weeks, at least part of the 12 weeks, after the 12 weeks, or a combination thereof. Subsequently, in some embodiments, the subjects... (a) Reduction in the units of nicotine used per day, such as cigarettes smoked per day or vaping per day, compared to subjects receiving NRT, control subjects, placebo control, and / or baseline. (b) Reduction in exhaled carbon monoxide (CO) levels compared to subjects receiving NRT, control subjects, placebo control, and / or baseline. (c) Reduction in serum and / or plasma cotinine levels in subjects receiving NRT, control subjects, placebo control, and / or baseline. (d) Increase in smoking cessation rate compared to subjects receiving NRT, control subjects, placebo control, and / or baseline. (e) No change, no increase, or decrease in adverse events compared to subjects receiving NRT, control subjects, placebo control, and / or baseline. (f) Increase in the odds ratio of a subject compared to subjects receiving NRT, control subjects, placebo control, and / or baseline. (g) Compared to subjects receiving NRT, control subjects, placebo control, and / or baseline, the increase in withdrawals (h) Reduction of nicotine craving and / or tobacco craving in subjects receiving NRT, control subjects, placebo control, and / or baseline. (i) Reduction in the severity of nicotine withdrawal symptoms compared to subjects receiving NRT, control subjects, placebo control, and / or baseline. (j) Reduction in the severity of anxiety compared to subjects receiving NRT, control subjects, placebo control, and / or baseline, and / or (k) Demonstrate one or more of the following: a reduction in the severity of depression compared to a subject receiving NRT, a control subject, a placebo control, and / or baseline.

[0183] In one embodiment, the method of the Disclosure includes measuring the baseline level of one or more markers shown in (a) to (k) above before administering the drug to a subject or group of subjects. In another embodiment, the method includes administering the composition disclosed herein to a subject after the baseline level of one or more markers shown in (a) to (k) has been determined, followed by additional measurement of the one or more markers. In another embodiment, during treatment with the composition of the Disclosure, the subject, (a) A reduction of at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, or more in the units of nicotine used per day, such as cigarettes smoked per day or vaping per day, compared to subjects receiving NRT, control subjects, placebo control, and / or baseline. (b) A reduction in exhaled carbon monoxide (CO) levels of approximately 5% to 100%, for example, approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more, compared to baseline, control, or placebo levels, in subjects receiving NRT, control subjects, placebo control, and / or baseline. (c) A reduction in serum and / or plasma cotinine levels of at least approximately 5%, at least approximately 10%, at least approximately 15%, at least approximately 20%, at least approximately 25%, at least approximately 30%, at least approximately 35%, at least approximately 40%, at least approximately 45%, at least approximately 50%, or more, compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline. (d) An increase in smoking cessation rates of approximately 5% to 100%, 5% to 75%, 5% to 50%, 25% to 75%, 25% to 50%, 30% to 50%, 30% to 75%, 30% to <100%, or 30% to 100% compared to subjects receiving NRT, control subjects, placebo control, and / or baseline. (e) No change, no increase, or a decrease of approximately 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to subjects receiving NRT, control subjects, placebo control, and / or baseline in adverse events. (f) An increase in the odds ratio of approximately 0%, approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, or more in subjects receiving NRT, control subjects, placebo control, and / or baseline. (g) A withdrawal increase of approximately 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to subjects receiving NRT, control subjects, placebo control, and / or baseline. (h) A reduction in tobacco craving of approximately 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to subjects receiving NRT, control subjects, placebo control, and / or baseline. (i) A reduction in the severity of nicotine withdrawal symptoms by approximately 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more, compared to subjects receiving NRT, control subjects, placebo control, and / or baseline. (j) A reduction in anxiety severity of approximately 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more, compared to subjects receiving NRT, control subjects, placebo control, and / or baseline, and / or (k) One or more reductions in depression severity of approximately 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or greater, compared to subjects receiving NRT, control subjects, placebo control, and / or baseline.

[0184] In some embodiments, the methods of the present disclosure include doing so in subjects who require treatment of nicotine addiction, nicotine dependence, or cessation of smoking and / or vaping, and / or reduction in smoking and / or vaping, the method including administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, three times daily to a subject. In certain embodiments, subjects do not experience adverse events after cyticine treatment. In some embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, subjects do not experience nausea after cyticine treatment. In some embodiments, cyticine is administered for about 6 weeks or about 12 weeks. In some embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine. In some embodiments, the subjects are refractory patients who have failed to treat one or more nicotine addictions, nicotine dependences, or smoking cessation therapies. In some embodiments, nicotine addiction, nicotine dependence, or smoking cessation therapy is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. In some embodiments, the subject is either (a) smoked 10 or more cigarettes or used 10 or more vapes per day prior to administration of cyticine, (b) had an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to administration of cyticine, or (c) a combination of (a) and (b). In some embodiments, the method further includes providing the subject with behavioral support.

[0185] In some embodiments, the methods of the present disclosure include doing so in subjects who require treatment of nicotine addiction, nicotine dependence, or cessation of smoking and / or vaping, and / or reduction in smoking and / or vaping, wherein the methods include administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, three times daily to a subject, and the subject does not experience any adverse events after receiving cyticine treatment. In some embodiments, the adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0186] In some embodiments, the methods of the present disclosure include doing so in subjects who require treatment for nicotine addiction, nicotine dependence, or the cessation of smoking and / or vaping, and / or the reduction of smoking and / or vaping, wherein the methods include administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, three times daily to a subject, wherein the subject does not experience nausea after receiving cyticine.

[0187] In some embodiments, the methods of the present disclosure include, in subjects for whom it is necessary to treat nicotine addiction, nicotine dependence, to facilitate cessation of smoking and / or vaping, and / or to facilitate reduction in smoking and / or vaping, the methods including administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, to a subject three times a day for about six or twelve weeks. In some embodiments, the unit dose of cyticine includes (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine.

[0188] In some embodiments, the methods of the present disclosure include doing so in subjects who require treatment of nicotine addiction, nicotine dependence, or cessation of smoking and / or vaping, and / or reduction in smoking and / or vaping, wherein the methods include administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg, to subjects three times daily, the subjects being refractory patients who have failed to be treated with one or more nicotine addictions, nicotine dependence, or smoking cessation therapies. In some embodiments, the nicotine addiction, nicotine dependence, or smoking cessation therapy is selected from NRT, administration of bupropion, administration of varenicline, e-cigarettes, vaping, and combinations thereof.

[0189] In some embodiments, the methods of the present disclosure include treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction in smoking and / or vaping, the methods comprising administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, to a subject three times daily, the subject being (a) having smoked 10 or more cigarettes per day prior to administration of cyticine, (b) having an exhaled carbon monoxide (CO) concentration of about 10 ppm or more prior to administration of cyticine, or (c) a combination of (a) and (b).

[0190] In some embodiments, the methods of the present disclosure include doing so in subjects who require treatment of nicotine addiction, nicotine dependence, or the promotion of cessation of smoking and / or vaping, and / or reduction in smoking and / or vaping, the method including administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, three times daily to a subject and providing behavioral support to the subject.

[0191] The methods of the present disclosure further include the treatment of nicotine addiction or nicotine dependence in subjects requiring treatment for nicotine addiction or nicotine dependence, the methods comprising administering cyticine to a subject, the subject being a refractory patient who has failed to receive treatment with one or more treatments for nicotine addiction or nicotine dependence. In certain embodiments, the treatment for nicotine addiction or nicotine dependence includes NRT, administration of bupropion, administration of varenicline, e-cigarettes, vaping, or a combination thereof. In some embodiments, cyticine is provided in unit doses of about 1.0 mg to about 6.0 mg of cyticine three to six times daily to a subject requiring it. In certain embodiments, cyticine is provided in unit doses of 3.0 mg of cyticine three times daily to a subject requiring it. In some embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine. In some embodiments, cyticine is administered for about 6 weeks or about 12 weeks. In some embodiments, subjects do not experience adverse events after cyticine treatment. In certain embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, subjects either (a) smoked 10 or more cigarettes per day prior to cyticine administration, (b) had an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to cyticine administration, or (c) a combination of (a) and (b).

[0192] The methods of the present disclosure further provide a method for preventing smoking and / or vaping relapse in subjects requiring such prevention, comprising administering cyticine to a subject three times daily in unit doses of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine. In some embodiments, cyticine is administered for about 6 weeks or about 12 weeks. In some embodiments, subjects do not experience adverse events after receiving cyticine treatment. In certain embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subjects are (a) who smoked 10 or more cigarettes per day prior to administration of cyticine, (b) who have an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to administration of cyticine, or (c) a combination of (a) and (b). In some embodiments, the subjects are refractory patients who have failed to be treated with one or more smoking cessation therapies. In certain embodiments, smoking cessation therapy includes NRT, administration of bupropion, administration of varenicline, e-cigarettes, vaping, or a combination thereof.

[0193] The methods of the present disclosure further include doing so in subjects requiring prevention of smoking and / or vaping relapse, the methods comprising administering cyticine to a subject, the subject being a refractory patient who has failed to treat with one or more smoking cessation therapies selected from the group consisting of NRT, bupropion, varenicline, e-cigarettes, vaping, or a combination thereof. In some embodiments, the subject is (a) smoked 10 or more cigarettes per day prior to administration of cyticine, (b) had an exhaled carbon monoxide (CO) concentration of about 10 ppm or more prior to administration of cyticine, or (c) a combination of (a) and (b). In some embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine, administered three times daily to the subject, with cyticine administered for approximately 6 weeks or approximately 12 weeks. In some embodiments, the subject does not experience any adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after cyticine treatment.

[0194] This disclosure also provides pharmaceuticals, such as pharmaceuticals, containing a unit dose of cyticine of 3.0 mg, 1.5 mg, or 1.0 mg for subjects who require treatment of nicotine addiction, nicotine dependence, cessation of smoking and / or vaping, and / or reduction in smoking and / or vaping, the pharmaceuticals being for oral administration three times daily to the subject. In some embodiments, the subject does not experience adverse events after cyticine treatment. In certain embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after cyticine treatment. In some embodiments, cyticine is administered for about 6 weeks or about 12 weeks. In some embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine. In some embodiments, the subjects are refractory patients who have failed to treat one or more nicotine addictions, nicotine dependences, or smoking cessation therapies. In certain embodiments, nicotine addiction, nicotine dependence, or smoking cessation therapy is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. In some embodiments, the subjects are (a) who smoked 10 or more cigarettes per day prior to administration of cyticine; (b) who have an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to administration of cyticine; or (c) a combination of (a) and (b). In some embodiments, the method further includes providing action support to the subject.

[0195] This disclosure also provides pharmaceuticals, such as pharmaceuticals containing a unit dose of cyticine of 3.0 mg, 1.5 mg, or 1.0 mg, for subjects who require treatment of nicotine addiction, nicotine dependence, cessation of smoking and / or vaping, and / or reduction in smoking and / or vaping, wherein the pharmaceuticals are for oral administration to the subject three times a day, and the subject does not experience adverse events after receiving cyticine treatment. In certain embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cyticine treatment.

[0196] The Disclosure further provides pharmaceuticals, such as pharmaceuticals, to subjects who require treatment of nicotine addiction, nicotine dependence, cessation of smoking and / or vaping, and / or reduction in smoking and / or vaping, comprising a unit dose of cyticine of 3.0 mg, 1.5 mg, or 1.0 mg, to do so, wherein cyticine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine.

[0197] In some embodiments, the Disclosure further provides a pharmaceutical product comprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine to serve subjects who require treatment of nicotine addiction, nicotine dependence, or cessation of smoking and / or vaping, and / or reduction in smoking and / or vaping, and the subjects are refractory patients who have failed to be treated with one or more nicotine addiction or smoking cessation therapies. In certain embodiments, the nicotine addiction or smoking cessation therapy is selected from NRT, administration of bupropion, administration of varenicline, e-cigarettes, vaping, and combinations thereof.

[0198] In some embodiments, the Disclosure further provides a pharmaceutical comprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine for the treatment of nicotine addiction, nicotine dependence, promotion of cessation of smoking and / or vaping, and / or promotion of reduction in smoking and / or vaping, wherein the subject (a) smokes 10 or more cigarettes per day prior to administration of cyticine, (b) has an exhaled carbon monoxide (CO) concentration of about 10 ppm or more prior to administration of cyticine, or (c) a combination of (a) and (b).

[0199] This disclosure further provides pharmaceuticals, such as pharmaceuticals containing cyticine, for the treatment of nicotine addiction or nicotine dependence in subjects who are refractory patients who have failed to receive treatment with one or more nicotine addiction or nicotine dependence therapies, and the pharmaceuticals are for oral administration to the patient three times a day. In some embodiments, the treatment of nicotine addiction or nicotine dependence includes NRT, administration of bupropion, administration of varenicline, e-cigarettes, vaping, or a combination thereof. In some embodiments, cyticine is provided in unit doses of about 1.0 mg to about 6.0 mg of cyticine three to six times a day to subjects who require it. In a particular embodiment, cyticine is provided in unit doses of 3.0 mg of cyticine three times a day to subjects who require it. In some embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine. In some embodiments, cyticine is administered for about 6 weeks or about 12 weeks. In some embodiments, subjects do not experience adverse events after cyticine treatment. In certain embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, subjects either (a) smoked 10 or more cigarettes per day prior to cyticine administration, (b) had an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to cyticine administration, or (c) a combination of (a) and (b).

[0200] In some embodiments, the drug contains a unit dose of cyticine in (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine, for subjects requiring prevention of smoking and / or vaping relapse, and the drug is intended for oral administration three times daily to the subject. In certain embodiments, cyticine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience any adverse events after receiving cyticine treatment. In certain embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subjects are (a) who smoked 10 or more cigarettes per day prior to administration of cyticine, (b) who have an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to administration of cyticine, or (c) a combination of (a) and (b). In some embodiments, the subjects are refractory patients who have failed to be treated with one or more smoking cessation therapies. In certain embodiments, smoking cessation therapy includes NRT, administration of bupropion, administration of varenicline, e-cigarettes, vaping, or a combination thereof.

[0201] The disclosure further provides pharmaceuticals, such as a cyticine-containing pharmaceutical, for the prevention of smoking and / or vaping relapse in subjects who are refractory patients who have failed to receive treatment with one or more nicotine addiction or nicotine dependence treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, e-cigarettes, or vaping, the pharmaceutical being for oral administration three times daily to the subject. In some embodiments, the subject is (a) smoked 10 or more cigarettes per day prior to administration of cyticine, (b) had an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to administration of cyticine, or (c) a combination of (a) and (b). In some embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine, and the cyticine is administered for approximately 6 weeks or approximately 12 weeks. In some embodiments, subjects do not experience adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after cyticine treatment.

[0202] In some embodiments, this disclosure provides the use of cyticine in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg to subjects who require treatment of nicotine addiction, nicotine dependence, cessation of smoking and / or vaping, and / or reduction in smoking and / or vaping, wherein cyticine is for oral administration to the subject three times daily. In some embodiments, subjects do not experience adverse events after cyticine treatment. In certain embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, subjects do not experience nausea after cyticine treatment. In some embodiments, cyticine is administered for about 6 weeks or about 12 weeks. In some embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine. In some embodiments, the subjects are refractory patients who have failed to treat one or more nicotine addictions, nicotine dependences, or smoking cessation therapies. In certain embodiments, nicotine addiction, nicotine dependence, or smoking cessation therapy is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. In some embodiments, the subjects are (a) who smoked 10 or more cigarettes per day prior to administration of cyticine; (b) who have an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to administration of cyticine; or (c) a combination of (a) and (b). In some embodiments, use further includes providing action support to the subject.

[0203] This disclosure further provides the use of cyticine, for example, to treat nicotine addiction or nicotine dependence in subjects who are refractory patients who have failed to treat with one or more nicotine addiction or nicotine dependence therapies, and cyticine is intended for oral administration to the patient three times daily. In certain embodiments, the treatment of nicotine addiction or nicotine dependence includes NRT, administration of bupropion, administration of varenicline, e-cigarettes, vaping, or a combination thereof. In some embodiments, cyticine is provided in unit doses of approximately 1.0 mg to approximately 6.0 mg of cyticine three to six times daily to subjects who require it. In certain embodiments, cyticine is provided in unit doses of 3.0 mg of cyticine three times daily to subjects who require it. In certain embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine. In some embodiments, cyticine is administered for about 6 weeks or about 12 weeks. In some embodiments, subjects do not experience adverse events after cyticine treatment. In certain embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, subjects either (a) smoked 10 or more cigarettes per day prior to cyticine administration, (b) had an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to cyticine administration, or (c) a combination of (a) and (b).

[0204] In some embodiments, the use of a unit dose of cyticine in the form of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine, is used in subjects who require prevention of smoking relapse, and cyticine is intended for oral administration to the subject three times daily. In some embodiments, cyticine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience any adverse events after receiving cyticine treatment. In certain embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subjects are (a) who smoked 10 or more cigarettes per day prior to administration of cyticine, (b) who have an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to administration of cyticine, or (c) a combination of (a) and (b). In some embodiments, the subjects are refractory patients who have failed to be treated with one or more smoking cessation therapies. In certain embodiments, smoking cessation therapy includes NRT, administration of bupropion, administration of varenicline, e-cigarettes, vaping, or a combination thereof.

[0205] In some embodiments, the use of cyticine to prevent smoking relapse in subjects who are refractory patients who have failed to receive treatment with one or more nicotine addiction or nicotine dependence treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, e-cigarettes, or vaping, wherein cyticine is for oral administration to the subject three times a day. In some embodiments, the subject either (a) smoked 10 or more cigarettes per day prior to administration of cyticine, (b) had an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to administration of cyticine, or (c) a combination of (a) and (b). In certain embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine, and the cyticine is administered for approximately 6 weeks or approximately 12 weeks. In some embodiments, subjects do not experience adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after cyticine treatment.

[0206] This disclosure further provides the use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine for oral administration of approximately 3.0 mg of cyticine three times daily to a subject for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction in smoking and / or vaping. In some embodiments, subjects do not experience adverse events after cyticine treatment. In certain embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, subjects do not experience nausea after cyticine treatment. In some embodiments, cyticine is administered for approximately 6 weeks or approximately 12 weeks. In some embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine. In some embodiments, the subjects are refractory patients who have failed to treat one or more nicotine addictions, nicotine dependences, or smoking cessation therapies. In certain embodiments, nicotine addiction, nicotine dependence, or smoking cessation therapy is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. In some embodiments, the subjects are (a) who smoked 10 or more cigarettes per day prior to administration of cyticine; (b) who have an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to administration of cyticine; or (c) a combination of (a) and (b). In some embodiments, use further includes providing action support to the subject.

[0207] In some embodiments, the use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine is for the oral administration of approximately 3.0 mg of cyticine three times daily to subjects who are refractory patients who have failed to be treated with one or more nicotine addiction or nicotine dependence treatments for the treatment of nicotine addiction or nicotine dependence in subjects. In certain embodiments, the treatment of nicotine addiction or nicotine dependence includes NRT, administration of bupropion, administration of varenicline, e-cigarettes, vaping, or a combination thereof. In some embodiments, cyticine is provided in unit doses of approximately 1.0 mg to approximately 6.0 mg of cyticine three to six times daily to subjects who require it. In certain embodiments, cyticine is provided in unit doses of 3.0 mg of cyticine three times daily to subjects who require it. In some embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine. In some embodiments, cyticine is administered for about 6 weeks or about 12 weeks. In some embodiments, subjects do not experience adverse events after cyticine treatment. In certain embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, subjects either (a) smoked 10 or more cigarettes per day prior to cyticine administration, (b) had an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to cyticine administration, or (c) a combination of (a) and (b).

[0208] In some embodiments, the use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine is for oral administration of approximately 3.0 mg of cyticine three times daily to the subject to prevent smoking and / or vaping relapse in the subject. In certain embodiments, cyticine is administered for approximately 6 weeks or approximately 12 weeks. In some embodiments, the subject does not experience any adverse events after cyticine treatment. In certain embodiments, adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject is (a) smoked 10 or more cigarettes per day prior to cyticine administration, (b) had an exhaled carbon monoxide (CO) concentration of approximately 10 ppm or higher prior to cyticine administration, or (c) a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed to be treated with one or more smoking cessation therapies. In certain embodiments, smoking cessation therapy includes NRT, administration of bupropion, administration of varenicline, e-cigarettes, vaping, or a combination thereof.

[0209] In some embodiments, the use of tablets containing approximately 1.0 mg or approximately 1.5 mg of cyticine is for the oral administration of approximately 3.0 mg of cyticine three times daily to subjects who have failed to receive treatment with one or more nicotine addiction or nicotine dependence treatments selected from the group consisting of NRT, bupropion, varenicline, e-cigarettes, or vaping, in order to prevent smoking relapse in the subjects. In some embodiments, the subjects are (a) smoking 10 or more cigarettes per day prior to administration of cyticine, (b) having an exhaled carbon monoxide (CO) concentration of approximately 10 ppm or higher prior to administration of cyticine, or (c) a combination of (a) and (b). In some embodiments, a unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine, and the cyticine is administered for approximately 6 weeks or approximately 12 weeks. In some embodiments, subjects do not experience adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after cyticine treatment.

[0210] Accordingly, in yet another embodiment, provided herein is a method for treating nicotine addiction or nicotine dependence in a subject, comprising administering cyticine to a subject in need, the subject being a refractory patient who has failed to treat one or more nicotine addiction or nicotine dependence therapies. Preferred unit doses include doses of about 1.0 mg to about 6 mg, which can be administered 3 to 6 times a day, for example, at approximately equal intervals. For example, in some embodiments, the method comprises administering cyticine, provided in a unit dose of 3.0 mg of cyticine, three times a day to a refractory patient. Any preferred duration of administration can be used in the manner disclosed herein, for example, about 26 weeks, about 12 weeks, or about 6 weeks. In some embodiments, the treatment is administered for about 6 weeks.

[0211] The techniques described herein may further include methods for attenuating adverse events in subjects being treated for the prevention of smoking relapse and / or vaping relapse. In some embodiments, the techniques describe methods for attenuating adverse events in subjects being treated for nicotine addiction and / or nicotine dependence. In some embodiments, the methods include reducing or preventing adverse events, reducing the risk of adverse events occurring, or preventing the onset and / or progression of adverse events in subjects.

[0212] In some embodiments, the subjects are refractory patients who have failed to treat with one or more nicotine addiction treatments. In some embodiments, the subjects are refractory patients who have failed to treat with one or more smoking cessation treatments, one or more of which are selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping. In some embodiments, the method comprises administering cyticine to the subjects. In some embodiments, the subjects (a) smoke 10 or more cigarettes per day prior to administration of cyticine, (b) have an exhaled carbon monoxide (CO) concentration of about 10 ppm or more prior to administration of cyticine, or (c) a combination of (a) and (b). In some embodiments, cyticine is provided to the subjects three times a day in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg. In some embodiments, cyticine is provided to the subjects three times a day in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine. In some embodiments, cyticine is provided to a subject in a unit dose of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine, three times a day. In some embodiments, cyticine is provided in tablets containing about 1.0 mg or about 1.5 mg of cyticine for three oral doses of about 3.0 mg of cyticine per day. In some embodiments, cyticine is provided to a subject requiring it in a unit dose of about 1.0 mg to about 6.0 mg of cyticine three to six times a day, or to a subject in a unit dose of 3.0 mg of cyticine three times a day.

[0213] In some embodiments, subjects being treated for the prevention of smoking relapse and / or vaping relapse do not experience any adverse events selected from a group of adverse events consisting of upper respiratory tract infection, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after administration of cyticine. In some embodiments, the adverse events are selected from a group consisting of nausea, headache, anxiety, depression, and suicidal ideation. In some embodiments, the adverse events are nausea and headache. In some embodiments, the adverse event is nausea. In some embodiments, the adverse event is headache. In some embodiments, subjects experience reduced anxiety, reduced depression, and / or the same or less suicidal ideation compared to or with a control subject. In some embodiments, the control subject is administered a placebo.

[0214] In some embodiments, the technology describes the use of cyticine to attenuate adverse events in subjects being treated for the prevention of smoking relapse and / or vaping relapse. In some embodiments, the technology describes the use of cyticine to attenuate adverse events in subjects being treated for nicotine addiction and / or nicotine dependence. In some embodiments, the use is for the reduction or prevention of adverse events, a reduction in the risk of adverse events occurring, or the prevention of the onset and / or progression of adverse events in subjects. In some embodiments, subjects are refractory patients who have failed to treat one or more nicotine addictions or smoking cessation therapies. In some embodiments, one or more nicotine addiction treatments are selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping. In some embodiments, subjects either (a) smoke 10 or more cigarettes per day prior to administration of cytisine, (b) have an exhaled carbon monoxide (CO) concentration of about 10 ppm or higher prior to administration of cytisine, or (c) a combination of (a) and (b). In some embodiments, use is a unit dose of cytisine of 3.0 mg, 1.5 mg, or 1.0 mg. In some embodiments, cytisine is provided to subjects 3 to 6 times per day in unit doses of about 1.0 mg to about 6.0 mg of cytisine, or to subjects 3 times per day in unit doses of 3.0 mg of cytisine. In some embodiments, cyticine is provided in a unit dose comprising (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine. It is administered for about 6 weeks or about 12 weeks. In some embodiments, cyticine is provided in a unit dose comprising (a) two tablets, each containing 1.5 mg of cyticine; or (b) a single tablet containing 3.0 mg of cyticine.

[0215] In some embodiments, the adverse event is selected from a group of adverse events consisting of upper respiratory tract infection, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after administration of cyticine. In some embodiments, the adverse event is selected from a group consisting of nausea, headache, anxiety, depression, and suicidal ideation. In some embodiments, the adverse event is nausea and headache. In some embodiments, the adverse event is nausea, and in some embodiments, the adverse event is headache. In some embodiments, the subject experiences reduced anxiety, reduced depression, and / or the same or less suicidal ideation compared to or from a control subject. In some embodiments, the control subject is administered a placebo. In some embodiments, the use does not result in any adverse event selected from a group of adverse events consisting of upper respiratory tract infection, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after administration of cyticine. In some embodiments, the adverse event is selected from a group consisting of nausea, headache, anxiety, depression, and suicidal ideation. In some embodiments, the adverse event is nausea and headache. In some embodiments, the adverse event is nausea; in some embodiments, the adverse event is headache. In some embodiments, the subject is compared to a control subject. In some embodiments, the control subject is administered a placebo.

[0216] In some embodiments, the methods disclosed herein may further include providing behavioral support to subjects, for example, patients with treatment-resistant smoking. Behavioral support may include, but is not limited to, counseling on topics such as withdrawal, past smoking cessation experiences, predictions of motivation or challenges in future attempts, alcohol use, frequency of proximity to and approaching other nicotine users (e.g., smokers), awareness of risky situations, and improving coping abilities.

[0217] In some embodiments, the methods disclosed herein may further include providing a subject with one or more questionnaires. Non-limiting examples of one or more questionnaires include the E-cigarette Dependence Scale Questionnaire, the Marijuana Craving Questionnaire—Short Version, the Phagastrom Nicotine Dependence Test, the Smoking Self-Efficacy Questionnaire (SEQ-12), the Quick Smell-to-Smoking Brief Questionnaire (QSU-Brief), the Minnesota Nicotine Withdrawal Symptoms Scale (MNWS) Questionnaire, the "Since Last Visit" C-SSRS Questionnaire, and the HADS Questionnaire. In certain embodiments, the questionnaire(s) may be provided to the subject at any time during administration of the composition, before administration of the composition, or after administration of the composition. In some embodiments, one or more questionnaires may be provided to the subject once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, fifteen times, twenty times, or thirty times.

[0218] The patents, patent applications, and scientific documents referenced herein are incorporated herein by whole as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference. Any inconsistency between any reference cited herein and any particular teaching herein shall be resolved for the sake of the latter. Similarly, any inconsistency between the technical definition of a word or phrase specifically taught herein and the definition of that word or phrase shall be resolved for the sake of the latter.

[0219] As can be understood from the above disclosure, the technology has a wide variety of applications. The technology is further demonstrated by the following examples, which are illustrative only and are not intended to limit the definition and scope of the technology. [Examples]

[0220] Example 1: Effects of cyticine on the treatment of nicotine addiction This was a six-arm, multicenter, double-blind, randomized, placebo-controlled study conducted in male or female adults, who were 18 years of age or older, smoked 10 or more cigarettes daily, and were willing to have their smoking cessation day set 5–7 days after randomization. The study was designed to evaluate the efficacy of 1.5 mg cyticine versus placebo using a commercially available dose-setting schedule approved in Central and Eastern Europe. This study also evaluated the efficacy of a simplified TID dosing schedule of 1.5 mg and an increased dose of 3.0 mg (using both the commercially available dose-setting (COM) and the simplified TID dosing schedule). The overall goal of this study was to obtain effect size estimates at efficacy and safety endpoints that could be used to inform the design of future Phase 3 trials.

[0221] The study's medication schedule is shown in Figure 1. The study was double-blinded to the dose rather than the administration schedule, and the study arms are shown in Figure 2. As shown in Figure 3, the study treatment was initiated the day after randomization so that the study treatment would begin before the cessation day.

[0222] The primary efficacy endpoint in this study was the reduction in the number of cigarettes smoked during treatment, which was calculated as follows:

number

[0223] The secondary efficacy endpoint was the smoking cessation rate (confirmed by CO < 10 ppm), analyzed at week 4 (i.e., end of treatment) and sustained (4 weeks) withdrawal from week 5 to week 8 (i.e., end of treatment).

[0224] The population statistics for the target population are summarized in Figure 4. The types of cigarettes smoked by the subjects before and after treatment are shown in Figure 5.

[0225] 1.1 Results Table 1 summarizes the population statistics of the study. In total, 254 male or female adults aged 18 years or older, who smoked 10 or more cigarettes daily and were willing to set a smoking cessation day 5 to 7 days after randomization, were enrolled in the study. Population statistics and baseline characteristics were well balanced across both the schedule and treatment arms. [Table 1]

[0226] Of the study population, 53% were female and 47% were male. 79% of the study population were white, 18% black, and 3% of other races. Smoking diary adherence, on which the primary analysis was partially based, was high in all treatment arms. Study drug adherence was >94% in all treatment arms, and slightly higher (>98%) in the TID schedule. The mean duration of treatment was 23.4 days, and 96.6% of subjects received the average dose of cyticine.

[0227] Table 2 summarizes the smoking history of subjects across all treatment arms. Overall, the study population averaged 48.4 years of age and represented highly addicted smokers who had smoked for 32 years, most of whom started smoking in adolescence. Furthermore, the subjects had previously attempted to quit smoking an average of 4.5 times, with their last attempt approximately 3.7 years prior to entering the study, and were currently smoking an average of one pack of cigarettes per day. Of the subjects who had previously attempted to quit smoking, 35% had received varenicline, 16% received bupropion, and 48% received NRT. [Table 2]

[0228] Analysis of the international EAGLES trial provided clear evidence that smoking at a young age and being born in the United States were associated with a lower success rate of quitting smoking. The low success rate of smokers in the United States may indicate that smokers in the United States have reached the epidemic point of tobacco, and thus those who continue to smoke have special characteristics that make it more difficult to quit smoking despite the negative cultural pressure.

[0229] Overall, study drug compliance was high in all treatment arms, and the TID schedule (98.18%) was better than the commercial schedule (94.90%). More specifically, Table 3 summarizes the study drug compliance in all treatment arms. The study drug compliance ranged from 96.7% to 99.5% in the TID arm, while the study drug compliance ranged from 94.2% to 96.4% in the COM arm.

Table 3

[0230] The reduction in smoked cigarettes in all treatment arms is shown in Figure 6 and summarized in Table 4. The results from the primary analysis showed a significant reduction in the predicted percentage of smoked cigarettes (cigarette score) in both COM arms. Pooling the placebo arms, the cigarette score was significantly reduced in both COM arms and the 1.5mg TID arm, and significantly approached in the 3.0mg TID arm. Using the COM schedule, subjects treated with 1.5mg or 3.0mg of cytisine smoked approximately 14% - 16% fewer cigarettes than expected compared to the placebo. Using the TID schedule, subjects treated with 1.5mg or 3.0mg of cytisine smoked approximately 9% - 12% fewer cigarettes than expected compared to the placebo arm.

Table 4

[0231] While the reduction in the TID schedule was not as high as that shown in the COM schedule, it should be noted that the TID schedule placebo group reported a higher reduction in cigarettes smoked than the COM schedule placebo group. The TID placebo group smoked only one-third of the cigarettes they normally smoke (LS mean: 35.30%), compared to half the number of cigarettes smoked by the COM placebo group (LS mean: 47.10%), which may have masked the effect of cyticine therapy on the TID schedule.

[0232] Furthermore, exhaled carbon monoxide (CO) levels were measured during this study as an objective biochemical marker of reduction in smoking. The reduction in carbon monoxide (CO) in all treatment arms is shown in Figure 6 and summarized in Table 4. In all cyticine treatment arms, the reduction in carbon monoxide (CO) (55%–62% reduction) was consistent with the reported reduction in cigarettes smoked (e.g., a range of 25%–32% as a cigarette score represents a 75%–68% reduction in cigarette smoking). Conversely, in the placebo treatment arm, the reported reduction in cigarettes smoked (e.g., 41% as a cigarette score represents a 59% reduction in cigarettes smoked) did not parallel with the corresponding reduction in carbon monoxide (CO) at only 29%. A similar pattern in plasma cotinine levels was observed in the cyticine arms, with a much larger reduction in cotinine levels compared to the placebo arms.

[0233] These changes in objective markers generally suggest that subjects treated with placebo overreported the reduction in cigarettes smoked. They also suggest that the true difference in cigarette smoking scores between subjects treated with cyticine and those treated with placebo was greater than actually observed.

[0234] The smoking cessation rates for the TID schedule arms versus placebo are shown in Figures 7 and 8, and summarized in Table 5. The results for the initial smoking cessation rate at week 4 demonstrated that both arms of the TID schedule had higher odds of success in quitting smoking compared to placebo. Subjects in the 3.0 mg cyticine arm had the best odds of success in quitting smoking, with an OR of 6.31 (95% CI: 2.28, 18.45). The OR for the 1.5 mg cyticine arm in the TID schedule was 5.81 (95% CI: 2.12, 16.87). In the COM schedule, the ORs for the 1.5 mg cyticine arms were 5.59 (95% CI: 2.03, 16.29) and 5.38 (95% CI: 1.95, 15.72), respectively. [Table 5]

[0235] Referring to Figures 7 and 8, and Table 5, for the long-term withdrawal endpoint at weeks 5–8, both arms of the TID schedule had higher odds of success for withdrawal compared to placebo, with subjects in the 3.0 mg cyticine arm having the best odds of success for withdrawal at weeks 5–8, with an OR of 5.04 (95% CI: 1.42, 22.32). The OR for the 1.5 mg cyticine arm in the TID schedule was 4.33 (95% CI: 1.21, 19.30). In the COM schedule, the ORs for the 1.5 mg cyticine and 3.0 mg arms were 3.23 (95% CI: 0.86, 14.85) and 2.24 (95% CI: 0.55, 10.82), respectively.

[0236] Table 6 summarizes the comparison of exhaled carbon monoxide (CO) levels and the reduction in smoking cessation rates at weeks 4 and 5-8 for 3.0 mg of cyticene arm versus placebo. [Table 6]

[0237] The cytosis arm subjects in the TID schedule also had higher odds of smoking withdrawal at weeks 6, 7, and 8 compared to subjects in the corresponding group of the COM schedule to placebo, as indicated by the high OR at each time point.

[0238] 1.2 Purpose and general methods of sensitivity The primary outcome (cigarette score) and the primary secondary withdrawal outcome were subjected to sensitivity analysis. The primary secondary withdrawal outcome was the initial abstinence rate at week 4 and the sustained 4 weeks of abstinence from weeks 5 to 8, which were confirmed by exhaled carbon monoxide (CO) levels below 10 ppm, and this was referred to as Cess / W5~8 / CO success. The objective was to assess the robustness of the results from the trial and to conduct any alternative analyses that could confirm the observed results or challenge the conclusions of the trial.

[0239] Other outcomes related to objective biochemical assessments were also analyzed. The relationships between these biochemical assessments are particularly important when used as part of the definition of cessation and withdrawal from smoking, and are also important because they are free from evaluative subjectivity.

[0240] The focus of these sensitivity analyses in this report is on comparing the 3.0 mg cyticine TID arm with the pooled placebo (0 mg cyticine) arm. Some analyses present other comparisons for contrast.

[0241] The effectiveness of the revised analysis methodology A common method for evaluating the robustness, consistency, and significance of results from clinical trials is to perform an effect-modified analysis (EMA). The goal of an EMA is to assess the degree to which the estimated effects of arms differ for discrete values ​​of a baseline attribute. For example, an EMA for sex estimates the effects of sex-specific arms and assesses whether these estimates differ. If the baseline attribute being evaluated using an EMA is not discrete, the attribute is discretized by identifying cut points based on external criteria or by using percentiles (median, quartile, or quartile) calculated from pooled data. For example, baseline carbon monoxide (CO) levels can be divided into those below 10 ppm and those above, or by using pooled quartiles.

[0242] EMA fits a statistical model to data. An EMA model includes an interaction term to detect differences in arm effects across discrete factor values. Heterogeneity in effect estimation is detected when the interaction term significantly improves the model's fit compared to a model without it. The improvement in fitting due to the interaction term is measured by the interaction p-value; a small p-value, typically less than 0.10, indicates improved fitting.

[0243] There are two types of interactions: qualitative and quantitative. A quantitative interaction exists when the direction of the effect estimate of the arm is the same for all discrete values ​​of the factor. A qualitative interaction exists when the direction of the effect is mixed across the values ​​of the factor.

[0244] The results from multiple EMAs conducted in this study are presented compactly as a forest plot, showing, for each factor value, the subset-related frequency (distribution across arms), the estimated effect, and the applicable confidence interval. The graph of the EMA forest provides a gestalt regarding the stability of the estimated overall effect in the factors included in the graph. The complete EMA forest graph also shows, for each factor, a quantitative assessment of heterogeneity from the EMA model, e.g., the interaction P-value. Also, the estimated effect and confidence interval of the arm effect at each value of the factor are presented in the forest plot. (Such a forest plot will be shown later.)

[0245] Justification in the pooled control arm The comparison between arms was a pairwise comparison of each active arm with the pooled placebo arm. The justification for comparing with the pooled placebo was ● The absence of evidence that the two placebo arms differed with respect to the primary or two secondary outcomes, and that the primary or two secondary outcomes had P-values of 0.1197, 0.9963, and 0.9996, respectively, for the stratified control arm comparison of the cigarette score, initial smoking cessation success at week 4, and Cess / W5~8 / CO success outcome. ● The absence of evidence that randomization between the placebo arms differed with respect to any of the baseline attributes used as factors in the subsequent EMA presented, including clinical sites.

[0246] For the purpose of sensitivity assessment, the absence of evidence of a difference between placebo arms is considered a justification for pooling, with the advantage of increased statistical sensitivity.

[0247] Descriptive graph of the mean number of cigarettes smoked daily The following is a longitudinal graph of the average number of cigarettes smoked as reported in the diary for each study treatment day (days 1-25 after randomization). Each arm and the pooled placebo arm are shown in different colors or as a solid versus dashed line. Figure 5 shows that each day, participants attempted to quit smoking until the planned abstinence interval (days 5-7) with abstinence up to day 8, reducing the number of cigarettes smoked per day.

[0248] 1.3 Biochemical Verification Analysis The following are two longitudinal graphs of the visit-mean carbon monoxide (CO) and the 95% confidence interval for cotinine, respectively, using a pooled placebo arm and a cyticine-treated arm.

[0249] Carbon monoxide (CO) levels (ppm) were assessed during the study at screening, baseline, and at the end of the study treatment intervention (week 4), and weekly over 8 weeks (Figure 9). Mean carbon monoxide (CO) levels at screening and baseline visits were approximately the same across all arms. At week 4, a significant reduction in carbon monoxide (CO) levels was observed in all subjects treated in the cyticine treatment arm, regardless of schedule. During the follow-up period from weeks 4 to 8 (with behavioral support only), mean carbon monoxide (CO) levels in the pooled placebo arm remained approximately constant, but somewhat lower than the mean before the start of the study treatment intervention. Mean levels in the active treatment arm remained significantly lower than the pooled placebo arm at all follow-up visits, although the mean showed a slight upward trend.

[0250] Serum cotinine levels were exploratory and assessed only at screening, week 4, and week 8. Results reported with cotinine <10 ng / mL were converted to 0 ng / mL before statistical analysis. The cotinine graph in Figure 10 showed the same pattern as observed for carbon monoxide (CO). All subjects in the cyticine treatment arm had a significant decrease in cotinine levels at week 4 and showed a slight upward trend until week 8.

[0251] 1.4 Cigarette Score Analysis First-order model stratification and covariate assumptions The first-order model for cigarette smoking scores included BMI stratification (3 levels) as a covariate and the mean number of cigarettes smoked as reported by screening diaries. The validity of the conclusions drawn from the first-order model results depended on the absence of interactions between each of these covariates and the arm variables. If one or both of these interactions are required in the statistical model, the magnitude of the estimated arm effect will be a function of the BMI class and / or the mean number of cigarettes smoked as reported by screening diaries.

[0252] Planned statistical analyses of the primary endpoint were performed, and as part of these analyses, each cyticine treatment arm was compared to a pooled placebo arm at the primary efficacy endpoint (cigarette score). These analyses included the analysis of variable models with fixed effects of the treatment arms, as well as BMI (18.5 to <25 kg / m²). 2 , 25~<30kg / m 2 , 30~<35kg / m 2 The analysis was conducted using the covariates of body weight (BMI) and baseline number of cigarettes. The analysis used the BMI variable derived from the subjects' actual BMI, with one subject (104-144) being compared to the subject's BMI (39.9 kg / m²). 2 ) is the upper limit of the higher BMI classification (30~<35 kg / m²). 2 It was omitted because it was more expensive than ).

[0253] Two variables in this analysis were used as part of the sensitivity analysis. These were: ●The BMI variable was derived from the actual BMI of the subjects, but the model included all 254 subjects in all randomized sets. The BMI classification used in this analysis was 18.5–25 kg / m². 2 Less than 25-30 kg / m 2 Less than, less than 30-35 kg / m2, and 35 kg / m 2 That was all. ● A model using the BMI stratification variable in randomization. Subjects 104 - 144 were within the BMI strata (30 - <35 kg / m 2 ) reported for that subject by randomization and were included in this analysis. As a result, this analysis included all 254 subjects in the entire randomized set. The BMI classifications used in this analysis were 18.5 - <25 kg / m 2 , 25 - <30 kg / m 2 , and 30 - <35 kg / m 2 .

[0254] Figures 11A - 11B show the comparison between the homogeneity of each group (COM 0 mg and TID 0 mg, and between TID 0 mg and TID 3.0) as a factor of the predicted percentage of smokers of combustible cigarettes (combustible cigarette score).

[0255] Figures 16 and 17 are additional evaluations regarding the interaction number between BMI and the baseline mean of combustible cigarettes, especially in the 3.0 mg TID arm, compared to the pooled placebo arm.

[0256] For BMI, this evaluation regarding the presence of an interaction between the arms was evaluated as an EMA using BMI as a factor, and the size of the interaction P indicates the information about the presence of this interaction (Figure 16). The EMA interaction P value for BMI is <0.1303>, which is not small enough to raise concerns, but based on the estimation of the layer-specific effect size, it was suggested that patients with high BMI may have higher efficacy compared to subjects with low BMI.

[0257] Evidence of an interaction between the arm and the baseline mean of combustible cigarettes (model covariate) was evaluated by the parallelism between the arms of the linear correlation between the combustible cigarette score and the baseline mean of combustible cigarettes. The P value for this evaluation of parallelism shown in the scatter plot (Figure 17) is <0.2754>, providing evidence of non - parallelism.

[0258] Alternative combustible cigarette score analysis The primary outcome was based on the number of cigarettes smoked daily from diaries. Cigarette scores were calculated using diary data from the planned 25-day period during the study treatment. Sensitivity analyses are presented for comparison between the 3.0 mg TID arm and the pooled placebo arm, which are associated with variability in the primary analysis of cigarette scores. An alternative definition of cigarette score is characterized by cigarettes recorded in the diary from day 8 onwards, rather than from day 1 onwards, after a planned abstinence period of 5–7 days.

[0259] Another alternative analysis was based on a reanalysis of the primary cigarette score and the alternative cigarette score described above, with weighting related to the standard error of the mean number of cigarettes estimated from the log entries. The weighting used for each subject was 1 / (SE) 2 SE is the standard error of the mean estimate, and this type of weighting is called inverse variance weighting and is commonly used. This weighting gives a larger weight to the mean estimated with a smaller SE. However, the definition of this weighting needed to be slightly modified. 1 / (SE) 2 When calculating SE=0, a specific rule was used, especially when all log entries were equal. In these cases, SE was calculated as if only one of the recorded values ​​was greater than 1. When this correction is made to the data, SE can be expressed as SE=1 / N, where N is the number of entries per day.

[0260] Table 7 shows the p-values ​​and effect estimates with 95% confidence intervals for four analyses describing the comparison between the 3.0 mg TID arm and the pooled placebo arm. The effect estimates were somewhat more favorable when the diary data start was on day 8 instead of day 1 (-11.8 vs. -9.5, respectively, for the primary cigarette score), because smoking data before the planned quit day was excluded. When weighting was applied to the primary cigarette score for the analysis, the effect estimate p-value was 0.0466 compared to 0.0675 in the unweighted analysis of the primary cigarette score. This was because diary data prior to the planned quit day (before day 8) and subsequent quitting resulted in a larger SE, thereby reducing the weighting of the quitters. This reduction in weighting did not apply to the redefined cigarette score using log data starting on day 8, and therefore the weighted effect size of the redefined cigarette score was clearly more favorable compared to the unweighted primary cigarette score starting on day 1 (-15.0 vs. -9.5, respectively). [Table 7]

[0261] An analysis of whether evidence of heterogeneity of effects exists across eight clinical sites (subject sources) was performed using an EMA with interaction p-values ​​as a measure of heterogeneity of effects. This analysis was performed for both the primary outcome variable of cigarette score and Cess / W5-8 / CO success. For cigarette score, the EMA model has additional covariates for BMI stratification and the mean number of cigarettes reported by screening diaries. For Cess / W5-8 / CO success, no covariates were added to the EMA model because of the possibility of empty cells in cross-classification across the binary outcome, arm, and clinical site discrete variables. For example, there were situations where a particular clinical site did not have any successful subjects in one or both arms.

[0262] Figures 18–25 provide EMA analysis results for each of the four comparisons of the active cyticine arm to the pooled placebo arm, and for both outcome variables. No evidence of heterogeneity of effects attributable to clinical sites was found in any of these EMAs; i.e., the interaction p-values ​​were not small enough to raise concerns about clinical site heterogeneity.

[0263] 1.5 Comparison of smoking cessation rates for citicinicline and Chantix® Figure 12 and Table 8 show the study design for comparing citicinicline (cyticine) and Chantix®. The duration of treatment with Chantix® (12 weeks) was approximately 3.5 times longer than the duration of treatment with citicinicline (25 days). The sustained withdrawal time for Chantix® (12 weeks measured beyond the last 4 weeks of treatment) was longer than that for citicinicline (8 weeks measured beyond 4 weeks after the end of treatment). Table 8 contains additional details regarding clinical trials using citicinicline and Chantix®. [Table 8]

[0264] Figure 13 shows the carbon monoxide (CO)-confirmed smoking cessation rates between 3.0 mg of citicinicline and 3.0 mg of Chantix® at weeks 4 and 12 of treatment. The Chantix® data represents the prevalence at day 7, while the citicinicline data represents the prevalence at day 1. The CO-confirmed smoking cessation rate at the end of treatment for subjects treated with 3.0 mg of citicinicline was higher than that for subjects treated with 3.0 mg of Chantix® at both weeks 4 and 12 (end of Chantix® treatment). Citicinicline demonstrated higher efficacy compared to Chantix®.

[0265] Figure 14 and Tables 9-11 show the odds ratios for citicinicline and Chantix® at 4 weeks, at the end of treatment, and 4 weeks after the end of treatment. Citicinicline and Chantix® have similar odds ratios and efficacy. Although the 95% confidence intervals (CIs) for both treatments overlap, the odds ratio for citicinicline treatment is consistently superior to that of Chantix®. [Table 9] [Table 10] [Table 11]

[0266] Table 12 shows the latest EAGLES trial, published in 2018, comparing smoking cessation rates in the United States with those in non-US regions. This trial shows significantly lower smoking cessation rates in the US compared to non-US regions. The overall smoking cessation rate of 22% over 24 weeks for those treated with Chantix® was only 16% for patients in the US (N=1065). The smoking cessation rate was significantly lower than in previous nationwide trials of Chantix®. The 24-week smoking cessation rate in the EAGLES trial was lower than the 52-week smoking cessation rate in the primary trial. There were few withdrawal outcomes associated with early age of first smoking and being born in the US. [Table 12]

[0267] Figure 15 shows the odds ratios for citicinicline at 4 weeks, at the end of treatment, and 4 weeks after the end of treatment, compared to current products. Although there is some overlap in the 94% confidence intervals for treatment, the odds ratios for citicinicline treatment are consistently superior to those for NRT, Zyban®, and Chantix®.

[0268] 1.6 Analysis of baseline attributes and smoking status Baseline patient attribute effect adjustment analysis A summary of baseline attributes, including age, race, sex, duration of smoking, and number of smoking cessation attempts, was analyzed for both the primary outcome variable of the cigarette score and Cess / W5-8 / CO success (Figures 26 and 27). Only comparisons between the cyticine 3.0 mg TID arm and the pooled placebo arm are shown. The same EMA model used to analyze clinical sites was employed. The forest graphs for these analyses are shown below. (Note: In these forest graphs, (M), (T), or (Q) at the end of the factor labels indicate that the pooled data were segmented by median, tertile, or quartile, respectively. Hx indicates “history.”)

[0269] The only interaction p-value of note was for the duration of smoking history divided by quartiles for cigarette score ("Smoking Hx Dur(y)(Q)"), with p=0.0800. Since other smoking history duration variables did not have significant p-values ​​(p≧0.2566), this finding was considered unimportant. None of the other factors raised concerns regarding heterogeneity of effects.

[0270] Historical effect adjustment analysis of anti-smoking interventions Factors of past anti-smoking interventions were analyzed for the primary outcome variable of cigarette score and Cess / W5-8 / CO success, comparing the cyticine 3.0 mg TID arm with a pooled placebo arm (Figures 28 and 29). Factors analyzed included whether there were two or more attempts at anti-smoking intervention and whether the participant had previously or recently been treated with Chantix®, Zyban®, vaping, or nicotine replacement therapy. The same EMA model used to analyze clinical sites was implemented. The forest graphs of these analyses are shown below.

[0271] The only interaction p-value of note was related to the history of past use of Chantix® ("Chantix® Hx") for cigarette scores, with a p-value of 0.0508. However, the interaction p-value for the factor variable indicating Chantix® as a recent intervention ("Chantix® Recent") did not indicate concern (p-value of 0.3179). The interaction appeared to be quantitative, and the results for recent use were inconsistent, thus reducing concerns that Chantix® was an effect modifier.

[0272] Effectiveness-adjusted analysis of baseline test markers related to smoking Baseline test factors were analyzed for the primary outcome variable of cigarette score and Cess / W5~8 / CO success, comparing the cyticine 3.0 mg TID arm with a pooled placebo arm (Figures 30 and 31). These factors included nicotine metabolic ratio (NMR), exhaled carbon monoxide (CO), and serum cotinine, and these factors were analyzed by median, tertile, and quartile. The same EMA model used to analyze clinical sites was implemented. Forest graphs of these analyses are shown in Figures 30 and 31. (Note: In these forest graphs, (M), (T), or (Q) at the end of the factor label indicates that the pooled data were split by median, tertile, or quartile, respectively.)

[0273] In the cigarette score, only the interaction p-values ​​of 0.0434 and 0.0652 at the median and tertile divisions of baseline cotinine, respectively, met the criteria suggesting an effect modification. However, the interaction p-values ​​for the secondary outcome of continued withdrawal were 0.2925, 0.3738, and 0.9732 at the median, tertile, and quartile divisions, respectively, and did not indicate an effect modification with respect to baseline cotinine levels. Since 4 weeks of withdrawal is planned to be the primary outcome in future phase 3 trials, the concern regarding baseline cotinine as an effect modifier is a lesser concern.

[0274] 1.7 Analysis of turning points 5-8 weeks after quitting smoking A turning point analysis was performed for Cess / W5~8 / CO success in the comparison of cyticine 3.0 mg TID arms versus pooled placebo arms, and is shown in Figure 32. The purpose of the turning point analysis was to assess the extent to which reassignment of cases, defined as failures due to insufficient evaluation data, affected the outcome. The evaluation of turning points involved reanalyzing data for all possible reversals of failed assignments to successes, accompanied by graphs showing which reassignments met the statistical criteria. The horizontal axis represents the number of possible control arm reassignments, and the vertical axis represents the number of possible experimental arm reassignments. Each combination of reassignments was reanalyzed to assess whether the statistical criteria were met. The point in the lower left represents cases without reassignment (i.e., planned analysis). Areas where reassignments meet the statistical criteria are patterned, while areas where reassignments do not meet the statistical criteria are grayed out.

[0275] There were six control arm cases and three experimental arm cases eligible for reallocation. The most important result from this graph is that if there are 0 or 1 reallocations in the experimental arm, the statistical criteria are not met if there are 3 or more reallocations in the control arm. Similarly, if there are 2 or 3 reallocations in the experimental arm, the statistical criteria are not met if there are 5 or more reallocations in the control arm. Therefore, the persistent forbidden secondary outcome was robust to reallocation.

[0276] In summary, the initial smoking cessation rates at week 4 across all cyticine treatment arms showed a significantly increased initial rate (50%–54%) compared to the pooled placebo (16%), with an OR ranging from 5.38 to 6.31. Long-term withdrawal from weeks 5 to 8 (i.e., 4 weeks after the end of treatment) also showed a significantly increased long-term smoking cessation rate of 16–30% compared to the pooled placebo (8%) in the cyticine treatment arms, with an OR of 3.23–5.04. Overall, the initial and long-term smoking cessation rates were highest in the 3.0 mg TID arms at 54% and 30%, respectively, with the highest ORs of 6.31 and 5.04, respectively.

[0277] Safety analysis Overall, there were no post-dosing safety concerns in either the 1.5 mg or 3.0 mg treatment arm, and no new or unexpected adverse events were identified during the study period.

[0278] Table 13 summarizes the treatment-related critical adverse events (TEAEs). TEAEs were experienced by approximately half of the study population in all treatment arms. The TID dosing schedule had slightly fewer TEAEs overall. Across both schedules, the SOCs with the highest incidence of TEAEs in any treatment arm were infections and parasitic infections, psychiatric disorders, and gastrointestinal disorders. Common TEAEs were those already reported in other studies or within the investigational drug brochure. All TEAEs were mild or moderate in severity according to the market schedule, and all but two events were mild or moderate in the TID schedule. One patient experienced a severe head injury, and another experienced a severe case of influenza. Neither event was considered to be related to the study drug. [Table 13]

[0279] There were no significant mean changes or shifts from baseline in laboratory parameters or 12-lead ECG results over time. The overall incidence of potentially clinically significant changes in vital sign measurements was low, with the lowest incidence observed on the TID schedule.

[0280] Table 14 summarizes the TEAEs of citicinicline compared to Chantix® in a previous 2016 study. TEAEs were experienced by less than 30% of the study population treated with either citicinicline, Chantix®, or placebo. Subjects treated with Chantix® experienced the highest incidence of TEAEs compared to citicinicline and placebo. The incidence of most TEAEs with citicinicline treatment was only slightly higher than with placebo. [Table 14]

[0281] In summary, there were no serious or severe adverse events, and the overall incidence of adverse events was low. The results from the study indicate no clinically significant changes in vital signs, typical hematology, and / or chemistry, and no changes in ECG. Overall, no new safety signals were observed during the duration of this study.

[0282] conclusion The results from the study showed that the benefits of cyticine occurred across all baseline characteristics and attributes. Specifically, the benefits of cyticine occurred across population statistics, baseline CO levels, and the number of cigarettes smoked daily, as well as based on smoking history. Regarding population statistics, the benefits were consistent across the target population regardless of race, sex, age, and BMI. Furthermore, regarding smoking history, subjects showed the same benefits from cyticine administration regardless of duration of smoking, attempts to quit, and past use of smoking cessation medications (e.g., Chantix®, Zyban®, NRT, vaping).

[0283] The results further demonstrated that cyticine administration provided similar benefits regardless of the subjects' ability to metabolize nicotine. In particular, no therapeutic relationship was observed based on the subjects' baseline nicotine metabolite ratios, and similar benefits of cyticine were observed for both rapid and delayed nicotine metabolites.

[0284] Results from the primary analysis showed a reduction in the predicted percentage of cigarettes smoked in both schedules compared to a pooled placebo. Results at the initial smoking cessation endpoint showed that both cyticine arms in the TID schedule had higher odds of success compared to placebo, with subjects on the 3.0 mg cyticine arm having the best odds of success to quit smoking at week 4.

[0285] For long-term withdrawal from weeks 5 to 8, both arms of the TID schedule had higher odds of success compared to placebo, with the 3.0 mg cyticine arm having the best odds of success for withdrawal from weeks 5 to 8. This study demonstrated that cyticine is an effective aid for smoking cessation with a favorable adverse event profile, and that 3.0 mg TID dosing is more effective overall without increased adverse events.

[0286] Overall, there were no post-dosing safety concerns in either the 1.5 mg cyticine or 3.0 mg arm under either schedule.

[0287] Example 2: Effects of continuous treatment with cyticine on smoking cessation This example describes a Phase 3, multicenter, double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of cyticine in adult smokers. The study is designed to determine whether efficacy outcomes can be improved and whether continued treatment can prevent early smoking relapse. The study is designed to evaluate treatment across three treatment arms: placebo (A), 6 weeks of treatment with cyticine (e.g., citicinicline) (B), and 12 weeks of treatment with cyticine (C), as shown in the schematic diagram in Figure 33. Participants are randomized to one of the three arms: A, B, or C. In arm A, participants receive 12 weeks of placebo plus behavioral support. In arm B, participants receive 6 weeks of 3.0 mg citicinicline TID, followed by 6 weeks of placebo plus behavioral support. In Arm C, subjects will be treated with 3.0 mg citicinicline TID for 12 weeks in addition to behavioral support. Citicinicline treatment will be evaluated in study populations for 6 or 12 weeks, with a primary efficacy endpoint at 4 weeks of continuous withdrawal during treatment, and a 6-month follow-up period.

[0288] 2.1 Research purpose 2.1.1 Primary Efficacy Purpose The primary efficacy objective of the study is based on two comparisons, and the success of the study can depend on the success of either comparison. ● To evaluate whether subjects randomized to Arm B have a higher probability of withdrawal during weeks 3-6 after randomization compared to subjects randomized to Arm A, and ● Evaluate whether subjects randomized to Arm C have a higher probability of withdrawal between weeks 9 and 12 after randomization compared to subjects randomized to Arm A.

[0289] 2.1.2 Secondary efficacy purposes If the corresponding primary comparison meets the statistical criteria, the analysis of the secondary objective is then carried out. The secondary efficacy objective of this study is: ● To evaluate whether subjects randomized to Arm B have a higher probability of continued withdrawal from week 6 to week 24 after randomization compared to subjects randomized to Arm A, and ● Evaluate whether subjects randomized to Arm C have a higher probability of continued withdrawal between weeks 12 and 24 after randomization compared to subjects randomized to Arm A.

[0290] If the bilinear comparison meets the statistical criteria, an analysis will be conducted for the subsequent additional secondary objectives. The additional secondary efficacy objectives of this study are: ●Evaluate the reduction in the risk of relapse between weeks 6 and 24 in subjects who received 3.0 mg of citicinicline for 6 weeks, followed by either continuing 3.0 mg of citicinicline from weeks 6 to 12 (Arm C) or switching to placebo from weeks 6 to 12 (Arm B).

[0291] Those who did not abstain from the drug in the sixth week are likely to have relapsed.

[0292] 2.1.3 Other purposes Other objectives of this study are: ● The arms (arm B vs. arm A, arm C vs. arm A) will be compared weekly from week 2 to week 12 regarding the 7-day prevalence, and then compared between weeks 16, 20, and 24. ● The arms (arm B vs. arm A, arm C vs. arm A) will be compared every other week from week 2 to week 12 for serum cotinine levels, and then again at weeks 16, 20, and 24. ● The arms (arm B vs. arm A, arm C vs. arm A) will be compared weekly from week 2 to week 12 in terms of exhaled carbon monoxide (CO) levels, and then again at weeks 16, 20, and 24. ● The arms (Arm B vs. Arm A, Arm C vs. Arm A) will be compared for the use of any non-cigarette nicotine product, including vaping, from weeks 2 to 12 during the study treatment, and again from weeks 16 to 24 during the study follow-up. ● To evaluate whether subjects randomized to Arm B have a higher probability of withdrawal between weeks 9 and 12 compared to subjects randomized to Arm A (placebo). ● Evaluate whether the subset of subjects who achieve abstinence from weeks 3 to 6, randomized to arm B, has a higher probability of continuing abstinence from weeks 3 to 24 after randomization, compared to subjects randomized to arm A. ● Evaluate whether subjects randomized to Arm C have a higher probability of continuing abstinence from weeks 9 to 24 after randomization compared to subjects randomized to Arm A, within the subset of subjects who achieve abstinence between weeks 9 and 12. ● For those who achieve abstinence between weeks 3 and 6, compare the time it takes to fail to maintain abstinence between arms (arm B vs. arm A, arm C vs. arm A) up to week 24. ● To explore the extent of treatment effects across arms in various subgroups defined by population statistics and baseline characteristics for primary and secondary outcomes, and ● Explore potential relationships between outcomes reported by participants (e.g., anxiety, depression, withdrawal symptoms, and tobacco craving) and primary and secondary outcomes.

[0293] 2.1.4 Safety objectives The safety objective of the research is, ● Evaluate the safety profile of 3.0 mg TID citicinicline compared to placebo (e.g., arm B vs. arm A and arm C vs. arm A). ● Compare the safety profiles of Arm B subjects versus Arm C subjects in terms of adverse events occurring after 6 weeks in the study.

[0294] 2.2 Research design The study population consists of adult men or women who smoke cigarettes daily, intend to quit smoking, and intend to set a discontinuation date within 5-7 days of starting treatment. Study treatment will begin the day after randomization.

[0295] Participants met all requirements outlined in the inclusion and exclusion criteria. A total of approximately 750 participants were randomly assigned with equal probability to one of three arms, as shown in Figure 33 (Arm A, 12 weeks of placebo: N=250; Arm B, 6 weeks of citicinicline followed by 6 weeks of placebo: N=250; Arm C, 12 weeks of citicinicline: N=250).

[0296] Each randomized participant will receive 12 weeks of treatment using the TID medication schedule. Smoking cessation assessment will begin at week 2 (14 ± 1 days after randomization) and will be continued weekly during follow-up visits at weeks 16, 20, and 24 of the treatment period, based on self-reported and carbon monoxide (CO) biochemical verification from participants who have stopped smoking.

[0297] All participants will receive simultaneous smoking cessation behavioral support during the study treatment period (weeks 1-12). Additional behavioral support will be provided during the follow-up period based on issues, concerns, and / or questions raised by the participants.

[0298] Safety assessments at follow-up visits will be performed on days 2 and 7 of week 1, and then weekly throughout the treatment period. Laboratory hematological and chemical assessments will be performed on days 7, 6, and 12 (end of treatment "EOT") during the treatment period. Adverse events ongoing at week 12 will be followed up until they are resolved or determined to be chronic. The end of the study will be defined as the final follow-up visit (by week 24) for the last subject.

[0299] 2.3 Treatment period The treatment period begins the day after randomization. The study treatment is blinded, and participants take one study tablet three times a day, approximately 5 hours apart. Participants randomly assigned to Arm A will take one placebo tablet per day for 12 weeks. Participants in Arm B will take one citicinicline tablet per day for the first 6 weeks, followed by one placebo tablet per day for the last 6 weeks. Participants in Arm C will take one citicinicline tablet per day for 12 weeks.

[0300] 2.4 Inclusion Criteria Individuals who meet all of the following criteria are eligible to participate in the study. ● Open to men or women aged 18 or older. ● Smokers who currently smoke cigarettes daily (at least 10 cigarettes per day on average upon completion of a 7-day screening smoking diary) and who intend to quit smoking. ● Exhaled carbon monoxide (CO) levels of 10 ppm or higher. ● At least one previous attempt to quit smoking, with or without therapeutic support, has failed. ● You are willing to start the research treatment the day after randomization and to set your smoking cessation date within 5-7 days of starting treatment. ●I am willing to actively participate in supporting smoking cessation behaviors provided throughout the research. ● You must fully understand the research requirements, be willing to participate, and adhere to the medication schedule. ● Sign the informed consent form.

[0301] 2.5 Exclusion criteria Participants will be excluded from the study if they meet any of the following criteria. ● Two or more research participants from the same household. ● Previous citicine treatment in any other clinical study or citicine use. ● Known hypersensitivity to citicinicline or any of the excipients. ● Positive urine-dependent drug screening determined within 28 days prior to the first dose of citicinicline. ● Clinically significant abnormal serological or hematological values ​​(i.e., requiring treatment or monitoring) within 28 days of randomization. ● Clinically significant abnormalities in a 12-lead ECG (i.e., requiring treatment or further evaluation) determined at least 5 minutes after the patient is placed in the supine position within 28 days of randomization. ●BMI classification indicating either underweight (less than 18.5 kg / m2) or obesity of class 2 or higher (35 kg / m2 or more). ● Recent (within the last 3 months) hospitalization for acute myocardial infarction, unstable angina, stroke, cerebrovascular disease, or congestive heart failure. ●Current uncontrolled hypertension (blood pressure of 160 / 100 mmHg or higher). ● A documented diagnosis of schizophrenia or bipolar disorder; current mental disorder; suicidal ideation / risk (answering "yes" to question 4 or 5 on the C-SSRS, or "yes" to any suicidal behavior question); or current moderate to severe depressive symptoms (HADS score of 11 or higher). ● Renal dysfunction defined as creatinine clearance (CrCl) of less than 60 mL / min (estimated by the Cockroft-Gault formula). ● Liver dysfunction defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 2.0 times the upper limit of normal (ULN). ●Pregnant or breastfeeding women. ● This study is for men or women of childbearing potential who do not consent to using an acceptable method of contraception during the research treatment period. ● Participation in a clinical study with the investigational drug during the 4 weeks prior to randomization. ● Treatment with other smoking cessation medications (bupropion, varenicline, nortriptyline, or any of the nicotine replacement therapies [NRT]) during the four weeks prior to randomization, or plans for the use of these other smoking cessation medications during the study. ●Plans for use of non-cigarette and / or non-combustible nicotine products (pipe tobacco, cigars, snuff, smokeless tobacco, hookah, e-cigarettes / vaping), or marijuana smoking or vaping within two weeks prior to randomization or during the study. ● Any other reason that the researcher believes the subject should not participate or cannot meet the requirements for the study.

[0302] 2.6 Prior and combination drug therapies All participants will continue receiving their existing prescription medications. Efforts will be made to ensure that their existing medication regimens remain stable throughout the study period.

[0303] At the discretion of the principal investigator, if clinically indicated during the study period, the use of other medications (prescription or over-the-counter) may be permitted. All new medications will be fully documented in the relevant case report form (CRF).

[0304] All concomitant medications (multiple medications allowed) taken during the clinical trial, as well as any changes (additions, deletions, or dose changes), are recorded in the CRF.

[0305] 2.7 Treatment Compliance Treatment adherence will be monitored throughout the 84-day (12-week) treatment period through reviews of administration timing and study drug management. Participants will maintain a daily treatment diary recording the number of tablets taken and the time of administration. Participants will be instructed to bring their medication pack (blister pack) to each visit so that clinic staff can cross-reference it with the treatment diary and record the number of tablets taken and any missed. In addition, an optional text messaging system will be implemented to provide each participant with reminder texts corresponding to the approximate time of medication administration.

[0306] 2.8 Research Procedure After providing signed informed consent, all subjects will be evaluated for inclusion in the study during a 28-day screening period. Subjects meeting the selection criteria must provide a deferral date that must be within 5–7 days of treatment initiation and agree to begin study treatment the day after randomization. Both the planned deferral date and treatment initiation date will be documented to confirm inclusion. Once all eligibility criteria are confirmed, randomization may be performed. Study day 1 is defined as the first day of treatment. Subjects will complete visits on days 2, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, and 86. Follow-up visits are scheduled for weeks 16, 20, and 24.

[0307] 2.8.1 Procedure Schedule Table 15 provides a summary of the required study evaluation. The screening evaluation will be conducted within 28 days between the start of the screening evaluation and randomization. Participants will begin the study treatment the day after randomization, so that the study treatment will begin one day before the discontinuation day and within 5-7 days from day 1. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 16]

[0308] 2.8.2 Target Log A 7-day smoking diary is collected during the screening period to obtain the number of cigarettes smoked each day for seven consecutive days. This data is used to calculate the average number of cigarettes smoked per day to support the second selection criterion.

[0309] Furthermore, a research treatment diary will be maintained by each subject, recording the date and timing of administration of the research drug during the treatment period. The diary will be organized into specific sections to support the subject's reporting.

[0310] 2.9 Efficacy Criteria This study follows general criteria applicable to past and present clinical trials of withdrawal assistance, with participants having a predetermined target withdrawal date and direct contact with investigators or clinic staff. Endpoint analyses for withdrawal (four weeks of withdrawal recorded in the last four weeks of treatment) and continuous withdrawal (continuously recorded up to 24 weeks after randomization) include the following criteria: ●Self-reported smoking abstinence since the last visit in each clinic's evaluation. ●The forbidden biochemical verification using exhaled carbon monoxide (CO) at each patient visit. ● Use of a “treatment intent” methodology, which includes data from all randomized smokers in the analysis. ● Subjects who have an unknown smoking status at the 6th, 12th, and 24th week assessments, or who have lost their ability to follow up, will be classified as having failed to quit smoking. ●Self-reporting of smoking abstinence during the follow-up period (weeks 12 to 24) should follow the Russell criteria. ●Treatment assignments will remain blinded during the collection of follow-up data up to week 24.

[0311] 2.9.1 Safety Assessment All participants are monitored for adverse events starting with a preliminary screening, followed by a phone call on day 1, visits on days 2 and 7 of week 1, weekly throughout the treatment period (weeks 2 to 12 / EOT), and monthly during the follow-up period (see Tables 15 and 16). Laboratory (hematological and chemistry) evaluations are performed using the central laboratory during visits at weeks 1, 6, and 12.

[0312] Safety is assessed considering all adverse events reported or elicited from subjects, as well as abnormalities detected in hematological and serological tests. Exacerbations of other pre-existing conditions and any changes in concomitant medications / treatments are also considered in this assessment.

[0313] 2.9.2 Laboratory Standard laboratory evaluation Standard laboratory safety samples are analyzed by the central laboratory for each subject during screening and visits as identified in Table 15. Whether out-of-range results are clinically significant or not is determined by the principal investigator, and the report is annotated accordingly. Clinically significant abnormalities occurring during the study are recorded on the AE page. Reference ranges for laboratory parameters are also entered into the database and filed in the principal investigator's site file.

[0314] Hematology: Hemoglobin, red blood cells, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelets.

[0315] Chemistry: Total protein, albumin, total bilirubin, SGPT (ALT), SGOT (AST), alkaline phosphatase, glucose, sodium, potassium, calcium, creatinine, and urea.

[0316] Exhaled CO Exhaled carbon monoxide (CO) is obtained using calibrated equipment provided and maintained by the clinical facility (e.g., Bedfont Micro+ Smokerlyzer®). Each clinical facility has documentation of the equipment used and current calibration. Carbon monoxide (CO) levels are reported weekly in parts per million (ppm) from weeks 2 to 12, and again at weeks 16, 20, and 24.

[0317] Serum cotinine levels Serum samples are collected at weeks 2, 4, 6, 8, 10, 12, 16, 20, and 24 to determine cotinine levels. For baseline cotinine testing, frozen serum collected at the SV1 visit is used for randomized subjects. Cotinine levels are determined in the central laboratory.

[0318] 2.9.3 Vital Signs Systolic / diastolic blood pressure, pulse rate, and oral temperature are recorded while the patient is seated. Weight is also recorded. Height is recorded during the first screening visit for BMI calculation.

[0319] 2.9.4 Physical Examination A physical examination will be conducted by an investigator. The examination will include a general appearance, head, ears, eyes, nose, throat, neck, skin, cardiovascular system, respiratory system, gastrointestinal system, central nervous system, lymph nodes, and musculoskeletal system. The investigator may examine other body systems at their discretion, if necessary.

[0320] 2.10 Primary outcome for the target group The primary efficacy outcome for each group (biochemically validated withdrawal during the last four weeks of citicinicline treatment) is a success-versus-failure binary. Success is defined as a group reporting smoking withdrawal (no cigarettes since the last visit) at each clinic assessment from weeks 3 to 6 (Arm B) and weeks 9 to 12 (Arm C), with biochemical validation at each assessment. Biochemical validation is defined as an exhaled carbon monoxide concentration of less than 10 ppm. A similar timeframe and analysis are performed for the placebo group in Arm A.

[0321] 2.11 Secondary outcomes regarding the subjects Secondary efficacy outcomes 1 and 2 (continued abstinence biochemically validated up to week 24) in each subject are a success-versus-failure binary. Success is defined as a subject reporting smoking abstinence since the last visit at each clinic assessment from week 6 (arm B) or week 12 (arm C) to week 24, with biochemical validation at each assessment. Biochemical validation is defined as an exhaled carbon monoxide concentration of less than 10 ppm. During the follow-up smoking cessation assessment period from week 12 to week 24, self-reported smoking abstinence follows the Russell criteria.

[0322] Secondary efficacy outcome 3 is success in terms of no relapse at week 24. Secondary efficacy outcome 3 (reduction of relapse risk from week 6 to week 24 in arm C versus arm B) is evaluated for each subject (both arm C and arm B). Subjects who did not abstain at week 6 are considered to have relapsed.

[0323] 2.12 Safety objectives Safety assessments include reported adverse events, laboratory findings, and vital signs. Safety variables are summarized for a Safety Analysis Set (SAS), defined as all randomized subjects receiving at least one dose of the study drug.

[0324] Adverse events (AEs) are coded using the MedDRA dictionary. The coding includes system organ classes (SOCs) and basic terms (PTs). All verbatim descriptions and coded terms are listed for every AE.

[0325] 2.13 Early withdrawal from treatment 124 participants (15.7%) withdrew from the study treatment early, and 72 participants (9.1%) withdrew before week 6. Of the 792 participants, 61 (7.7%) withdrew before week 6 for reasons other than adverse events or death. Of these withdrawals, there were 10 adverse events (AEs) (pregnancy, depression, anxiety, chest discomfort / tachycardia, nightmares, chest pain / nausea / headache, abnormal dreams / dizziness / acid reflux / nausea, analgesia, suicidal ideation, abdominal pain / anxiety / disordered appetite / chest pain / diarrhea / dry mouth / dyspnea / fatigue / flatulence / headache / hyperhidrosis / insomnia / irritability / muscle pain / nausea / oral pain / palpitations / peripheral swelling / somnolence / tachycardia / vertigo / vomiting), 1 death (drug overdose - heroin), 35 withdrawals by subject, 3 withdrawals by physician decision (non-adherence to study visits and journals, inability to assess subject safety, failure to follow up on rescheduled visits), 5 other withdrawals (meeting exclusion #10, which is uncontrolled blood pressure; exceeding the 28-day screening window; all subjects were randomized / withdrawn due to error), and 18 loss of follow-up.

[0326] Fifty-two subjects (6.6%) discontinued treatment after 6 weeks and before 12 weeks. Of these, two were due to adverse events (coronary artery disease, suicidal ideation), 16 were lost to follow-up, 29 were due to subject-specific reasons, one was due to physician-initiated non-compliance, two were due to other reasons (imprisonment and inability to attend appointments), and two were due to death (hemorrhagic stroke, postoperative complications).

[0327] 2.14 Withdrawal during the follow-up period Thirty-four participants (4.3%) dropped out of the study during the follow-up period (weeks 12–24). This included one death (stab wound), 16 participant-initiated dropouts, one physician-initiated dropout (participant was disrespectful and uncooperative towards staff), one other dropout (participant was unable to attend appointments at weeks 16, 20, and 24 due to a medical condition reported to the sponsor), and 14 loss of follow-up.

[0328] 2.15 Major Protocol Deviations 136 major protocol deviations (PDs) were identified among 117 participants (14.8%) across 20 facilities. These are summarized in Table 17. [Table 17]

[0329] In a previous meeting, 116 major pathological progressions (PDs) occurred among 99 participants across 20 facilities (12.5%). In ORCA-2, 13% of participants had a major PD at the end of the study, and 6.4% of the PDs were due to absences from appointments. [Table 18]

[0330] 2.16 COVID-19 Cases 73 adverse events (AEs) occurring during COVID-19 treatment have been reported since the start of the study. All were mild or moderate in severity. Four are ongoing and none are SAEs, and one was a dose discontinuation. Similar to ORCA-2, iCO devices used by individuals are distributed to facilities. Nineteen participants have been established from facilities 121, 123, 130, 135, 137, and 139. Ten participants have reads. Nine participants do not have reads reported in the database. To date, COVID-19 cases are not considered a significant problem.

[0331] 2.17 Population statistics and medical history Table 19 outlines the population statistics of the study participants, and Table 20 outlines the comparison of psychiatric histories. [Table 19] [Table 20] TIFF2026516432000026.tif90170 2.18 Adverse Events [Table 21] [Table 22] [Table 23-1] [Table 23-2] [Table 23-3] [Table 24] [Table 25] [Table 26] [Table 27]

[0332] 2.18 Potentially clinically significant vital signs (N=768) The summary of vital signs parameters included 4 cases (0.5%) of systolic BP <85 mmHg (and a decrease from baseline of ≥20 mmHg), 31 cases (3.9%) of systolic BP >160 mmHg (and an increase from baseline of ≥20 mmHg), 151 cases (19.2%) of diastolic BP >90 mmHg (and an increase from baseline of ≥10 mmHg), and 55 of the 151 patients who had DBP >90 and an increase from baseline of ≥10 over two or more visits (of which 31 met the criteria in consecutive visits, and 16 of the 31 had a history of hypertension), as well as 42 cases (5.3%) of HR >100 bpm (and an increase from baseline of ≥15 bpm).

[0333] 2.19 Dose reduction The total dose reductions in the study included nine subjects. These dose reductions are summarized in Table 28. [Table 28] 2.20 Adverse events related to research drugs [Table 29] 2.21 Reported psychiatric adverse events [Table 30]

[0334] Example 3: A randomized, placebo-controlled clinical study to promote the benefits of e-cigarette cessation in pharmacological treatment. This example describes the Phase 2 ORCA-V1 trial, which evaluated 160 adult e-cigarette users at five clinical trial sites in the United States. The trial completed enrollment in approximately four months. ORCA-V1 participants were randomized to receive either 3 mg of citicinicline three times daily for 12 weeks or placebo, in combination with standard cessation behavior support. The dose and administration of citicinicline in the ORCA-V1 study were identical to those used in the Phase 3 enrollment trial for smoking cessation.

[0335] Tobacco use remains a major health concern, with over 50 million adults in the United States using tobacco in any form. An estimated 9 million adults and over 2 million high school students use e-cigarettes to vape nicotine. Many users become dependent on nicotine and want to quit but find it difficult. No FDA-approved treatments have been specifically evaluated in this population, and the ORCA-V1 trial is the first randomized, placebo-controlled clinical study to demonstrate the success of e-cigarette cessation.

[0336] ORCA-V1 evaluated the efficacy and safety of 3 mg of citicinicline, administered three times daily for 12 weeks, compared to placebo in 160 adult e-cigarette or nicotine vape users. All participants received behavioral support for nicotine withdrawal.

[0337] The primary endpoint for ORCA-V1 was biochemically validated continuous withdrawal from nicotine e-cigarette use, which was measured during the last four weeks of treatment. Subjects receiving 12 weeks of citicinicline treatment had a 2.6-fold higher odds or likelihood of quitting vaping during the last four weeks of treatment compared to subjects receiving placebo (p=0.035) (Figures 58A and B). The vaping cessation rate during weeks 9–12 was 31.8% for citicinicline compared to 15.1% for placebo. The benefits supporting citicinicline were consistently observed across secondary endpoints. Additionally, the cessation benefit for citicinicline was observed across clinical trial sites and population statistics, e.g., age, sex, race, or whether the patient was a past smoker.

[0338] Citicinicline was well-tolerated, and no serious adverse events were reported. Similar rates of adverse events (AEs) were observed between the treatment arms (54.7% in the placebo arm vs. 50.9% in the citicinicline arm). The most frequently reported (≥5%) AEs in the placebo arm were anxiety, headache, upper respiratory tract infection, nausea, and Covid-19 infection. In the citicinicline arm, the ≥5% AEs reported were sleep disturbance, anxiety, headache, fatigue, and upper respiratory tract infection.

[0339] ORCA-V1 participants had a mean age of 34 years, were current daily users of nicotine-containing e-cigarettes, and had a median of two previous attempts to quit vaping, primarily without support, prior to joining the study. Participants were stratified based on their past smoking history. Approximately 72% were former cigarette smokers, and 28% were non-cigarette smokers. Efficacy outcomes were similar in both groups.

[0340] Settings and Targets The clinical trial was conducted at 17 US sites. Adults aged 18 years or older were eligible if they currently smoked 10 or more cigarettes per day, had a breath carbon monoxide (CO) level of 10 ppm or higher, and intended to quit smoking. Individuals who had used or planned to use any non-cigarette tobacco product (pipe tobacco, cigars, smokeless tobacco, hookah), e-cigarettes, smoking cessation medications (bupropion, varenicline, nortriptyline, nicotine replacement products), or marijuana (smoking or vaping) in the 28 days prior to randomization were excluded. Other exclusion criteria included uncontrolled hypertension, hepatic or renal impairment, hospitalization for acute myocardial infarction, unstable angina, cerebrovascular disease, or congestive heart failure within the past three months, a diagnosis of schizophrenia or bipolar disorder, current mental illness, suicidal ideation or suicide risk (Columbia Suicide Severity Rating Scale), (1) moderate to severe depressive symptoms (Hospital Anxiety and Depression Scale score of 11 or higher), or (2) positive urine screening for illegal drugs. (See full criteria in the trial protocol).

[0341] Recruitment and assignment to criteria At the screening visit, individuals provided written informed consent, completed a medical history, brief physical examination, electrocardiogram, and clinical laboratory tests, agreed to a smoking cessation date 5–7 days after the start of the study drug, and recorded the number of cigarettes smoked daily for 7 days. At the second visit, participants who met the inclusion and exclusion criteria were randomly assigned to a study arm, received brief smoking cessation counseling, set a smoking cessation date within 5–7 days, and began the study drug therapy the following day. Using a predetermined central computer-generated randomization sequence, participants (1:1:1) stratified by the research site were assigned to receive either a 12-week placebo TID (Arm A), a 6-week 3 mg citicinicline TID, followed by a 6-week placebo TID (Arm B), or a 12-week 3 mg citicinicline TID (Arm C).

[0342] intervention The research drug therapy consisted of tablets of identical appearance, each containing either 3 mg of citicinicline or placebo, administered orally for 12 weeks on the TID. Participants were followed up for an additional 12 weeks after the completion of treatment. All participants received 10-minute brief smoking cessation behavior support provided by a trained counselor at each visit from randomization to 24 weeks.

[0343] evaluation Post-randomization assessments were conducted in person on day 2, weekly from weeks 1 to 12, and at weeks 16, 20, and 24. Participants who discontinued the study drug early were encouraged to remain in the study and complete all assessment visits. Smoking status was assessed by self-reported cigarette abstinence since the last visit, measured weekly from weeks 2 to 12. Self-reported abstinence at weeks 16, 20, and 24 was defined as not smoking more than 5 cigarettes since the last visit, using the Russell criterion (3). Respiratory carbon monoxide (CO) levels were measured at each visit. Verification of abstinence required self-reported non-smoking and respiratory carbon monoxide (CO) levels below 10 ppm. Participants who did not meet these criteria or had missing data were classified as smokers.

[0344] In total, 231 individuals were screened, and 71 failed screening. 160 were randomized, and 159 received treatment. 53 were randomized to placebo, and 106 to 12 weeks of treatment (Figures 56 and 57). In the placebo group, 79% completed the study (N=42), 21% discontinued (N=11), 1 was due to an adverse event, 5 were dropped out for follow-up, 4 were dropped out due to subject-specific reasons, and 1 was classified as other. In the treatment group, 83% completed the study (N=89), 17% discontinued (N-18), 4 were dropped out due to subject-specific reasons, 1 was dropped out due to physician-specific reasons, 9 were dropped out for follow-up, and 4 were classified as other.

[0345] Safety was assessed on day 2 by measuring vital signs and by participant self-reporting of adverse events and concomitant medication therapies, and at weekly visits during treatment weeks 1–12 and an additional 12 weeks of follow-up. Hematological and chemocytological tests were performed at weeks 1, 6, and 12. Electrocardiograms were performed at weeks 6 and 12. Clinically significant adverse events or abnormalities were followed up until resolution or termination of the study.

[0346] Outcome indicators The study had two primary endpoints. These two primary endpoints assessed whether citicinicline resulted in greater biochemically confirmed continuous smoking abstinence compared to placebo during the last four weeks of the six-week treatment (weeks 3–6 for arm B vs. A) and during the twelve-week treatment (weeks 9–12 for arm C vs. A). Study success was defined as both primary endpoints meeting statistical criteria. A secondary outcome measure examined continuous cigarette abstinence up to week 24 (weeks 3–24 for arm B vs. A, and weeks 9–24 for arm C vs. A). A third secondary outcome measure compared the risk of smoking relapse between weeks 6–24 among participants assigned to citicinicline who achieved abstinence by week 6. These individuals either switched to placebo at week 6 (arm B) or continued citicinicline until week 12 (arm C). Other pre-specified endpoints included comparisons of arm-to-arm differences in validated 7-day prevalence withdrawal at each visit from weeks 2 to 24, and assessments of evidence for effect modification for subsets defined by baseline attributes. To assess cigarette craving between groups, the Quick Squeeze Questionnaire (QSU-brief) was administered at visits on day 0 and from weeks 1 to 6 (4, 5). Safety outcomes included the incidence of serious and non-serious adverse events occurring under treatment with citicinicline or placebo, as well as clinically significant changes in vital signs, laboratory tests, or electrocardiograms.

[0347] statistical analysis Analysis of binary primary and secondary outcomes was based on direct analysis 2x2 tables stratified by clinical site. Missing assessments of primary and secondary endpoints were imputed as failures, thereby enabling analyses that adhered to the intention-to-treat principle. Multiplicity was controlled using the Hochberg procedure (6). Target samples of 750 participants (n=250 per arm) were validated using computer calculations and simulations, yielding a 96% power for overall one-sided 0.025 type I error probability and specificity for success probability, with 7% for placebo and 19% for citicinicline. Sensitivity analysis included assessment of effect modifications related to subsets defined by baseline attributes, using logistic and cumulative logit models. Longitudinal analysis used repeated measures mixed model methodology (7). Safety analysis included all randomized participants who received at least one dose of the study drug. Analysis was performed by BB.

[0348] Additional research outcomes and measurements A multicenter, double-blind, randomized, placebo-controlled study was conducted to evaluate citicinicline as an aid in vaping cessation in adult nicotine e-cigarette users intending to quit smoking. Participants were randomized in a 2:1 ratio (100 receiving citicinicline: 50 receiving placebo), totaling 160 participants (Figure 56). Participants were stratified based on whether they had smoked more than 100 cigarettes in their lifetime (yes vs. no) (Figure 57). The study size had 95% power to detect approximately a 19% reduction in cotinine levels from baseline. Odds ratios (95% confidence intervals) exclude cases where citicinicline withdrawal success was ≥18%. For example, a 6% placebo rate versus an 18% outcome, or an odds ratio of 3.44, is significant. Missing data can be assumed to represent reported vaping. The smoking cessation rate for 3 mg of citicinicline versus placebo yielded an odds ratio of 2.64 (P=0.036) (Figures 58A and B).

[0349] Key inclusion criteria included daily e-cigarette use (age 18 or older), willingness to bring the e-cigarette or nicotine device used to the clinical site, and willingness to document the specific product type, flavor, and nicotine level. Individuals were required to have a positive cotinine test (positive test at cotinine levels of 30 ng / mL or higher) using the Alere iScreen® oral fluid screening device. Individuals were required to set a smoking cessation day within 7–14 days after randomization and willingness to participate in vaping cessation behavior support provided throughout the study.

[0350] Key exclusion criteria included current smokers, those who had smoked within the four weeks prior to study randomization, and those with exhaled carbon monoxide (CO) levels of 10 ppm or higher indicating recent combustible tobacco use (i.e., not being a dual user). Individuals with clinically abnormal laboratory values ​​were also excluded, as were those with positive urine screening for illegal drugs (THC was not included in the screening). Uncontrolled hypertension (BP ≥ 160 / 100 mmHg), abnormal ECGs, or recent acute myocardial infarction, stroke, or heart failure hospitalization within the past three months were excluded. Psychiatric exclusions included (1) schizophrenia or bipolar disorder, (2) current moderate to severe depressive symptoms, and (3) a high risk of suicidal ideation. Pregnant or breastfeeding women, or women unwilling to use acceptable contraception during the study, were also excluded.

[0351] The first measurement consisted of biochemically validated continuous vaping withdrawal during the last four weeks of treatment following 12 weeks of citicinicline treatment versus placebo. Vaping withdrawal during weeks 9–12 was validated, and no vaping with weekly salivary cotinine levels below 10 ng / mL was reported. The primary analysis with prospective stratification factor odds ratios was 2.64 (p=0.035), the primary analysis with facility as the stratification factor odds ratio was 3.03 (p=0.017), and the primary analysis without any stratification factor odds ratios was 2.62 (p=0.035) (Figure 59). Similar trends were observed for the beneficial effect of citicinicline regardless of sex or race and age or body mass (Figures 60 and 61).

[0352] A second measurement consisted of biochemically validated continuous vaping withdrawal at any point during treatment, with vaping withdrawal at weeks 3–6 or 6–9 for citicinicline treatment versus placebo. Prevalence at day 7 was compared for vaping withdrawal (weeks 2–12) (Figure 62). Additional measurements included reductions in daily vaping as measured by cotinine, with citicinicline treatment versus placebo measured for reductions in nicotine vaping using weekly quantitative cotinine levels from weeks 2–12. Safety was assessed by adverse and serious adverse events, taking into account the number, severity, and attributes of the study drugs. Early beneficial effects were observed, persisted over 12 weeks, and were statistically significant or near-statistically significant in several weeks (weeks 4, 6, 7, 8, 9, and 12) (Figures 63–65). Cotinine values ​​less than 1 were converted to 1 due to extreme asymmetry (Figure 65).

[0353] Top line and exploratory analysis Arm effect measurements are primarily expressed as estimates of odds ratios, and in some cases, they are estimations of inter-arm probability differences. The same p-value is applied when both of these two types of estimations are presented. The definitions of these two types of arm effects are as follows:

[0354] Odds Ratio (OR): An OR estimate that is substantially greater than 1 indicates a profit. The OR is the ratio of the odds of success in the citicinicline arm divided by the odds of success in the placebo arm. The odds for each arm are the ratio of the probability of success divided by the probability of failure (Figures 58A and B).

[0355] Probability difference: A probability difference estimate that is substantially greater than zero indicates a profit. The probability difference is the probability of success in the citicinicline arm minus the probability of success in the placebo arm.

[0356] Three statistical methods were used, depending on the data structure. Direct computer calculations were used where appropriate.

[0357] In a stratified 2x2 frequency table, the 2x2 structure is an arm × binary outcome.

[0358] General Linear Model (GLM): GLM provides linear regression modeling for measured and binary outcomes. Binary outcomes were modeled using logits.

[0359] Log(odds): Logit models are the basis of logistic regression. GLM models can include repeated measures, whether using measured or binary outcomes, in which case the mixed-models repeated measures (MMRM) methodology is applicable.

[0360] Primary analysis: Analysis of the primary response outcome (whether or not a person smokes fewer than 100 cigarettes in their lifetime) using a stratified 2x2 direct methodology. Variability results from the Cochran-Mantel-Haenszel analysis are shown (Figures 39 and 40). The effect size of interest is the estimate of the common odds ratio.

[0361] Primary response effect modifier analysis (EMA): Analysis of specified stratifiers (whether or not a patient smokes fewer than 100 cigarettes in their lifetime) and clinical sites as potential effect modifiers for the primary response outcome arm effect. The statistical model for each EMA is logistic regression of the primary response with terms for the arm, <effect modifier>, and arm × <effect modifier> interaction. This model is not stratified. Small effect modifier p-values ​​are evidence of effect modification (heterogeneity of effects associated with effect modifier classification) (Figures 41 and 42).

[0362] Primary and Secondary Outcomes: Primary outcome analysis (unstratified) and secondary outcomes are analyzed using Fisher's exact test. A forest graph compares the effects of primary and secondary outcomes (Figure 43).

[0363] Point-time prevalence: Data were analyzed at each visit, and then analyzed using a repeated measures model. Two longitudinal sections of the results from the repeated measures model are shown (Figures 44-46).

[0364] Primary Response EMA: Analysis of additional effect modifiers for the primary response outcome arm effect. The statistical model for each EMA is logistic regression of the primary response with terms for the arm, <effect modifier>, and the arm × <effect modifier> interaction. This model is not stratified. Small effect modifier p-values ​​are evidence of effect modification (heterogeneity of effects related to effect modifier classification) (Figures 47-50).

[0365] Cotinine: Data were analyzed at each visit and also using a repeated measures model. There are two longitudinal sections of the results from the repeated measures model, the two longitudinal sections being arm-specific stochastic model estimates and arm-effect odds ratio model estimates (Figures 51-55). Cotinine values ​​less than 1 were converted to 1 due to asymmetry.

[0366] Participants: Results Of the 1345 individuals screened, 810 were eligible and randomized to one of three arms: placebo (Arm A, n=271), 6 weeks of citicinicline plus 6 weeks of placebo (Arm B, n=269), or 12 weeks of citicinicline (Arm C, n=270) from October 2020 to June 2021 (Figure 34). Population statistical features did not differ between randomized and unrandomized screened individuals. The primary efficacy analysis included all 810 randomized participants. The safety analysis (n=809) excluded one Arm A participant who did not receive the study drug. Follow-up visits were completed in December 2021.

[0367] Individuals across all arms were similar in baseline characteristics, including age, sex, race, ethnicity, smoking and quitting history, nicotine dependence, and anxiety and depressive symptoms (Table 31). Participants smoked an average of 20 cigarettes per day. Overall, 663 participants (81.9%) completed 12 weeks of study drug treatment [Arm A: 214 (79.0%), Arm B: 217 (80.7%), Arm C: 232 (85.9%)]. Study drug adherence was high, with 69.3% of participants in Arm A, 76.6% in Arm B, and 79.3% in Arm C taking 90% or more of the study drug dose. Adherence to behavioral support was also high, with 86.8% of planned sessions completed in Arm A, 89.5% in Arm B, and 92.8% in Arm C. Follow-up evaluations were completed over 24 weeks by 618 participants (76.2%) [Arm A: 194 (71.6%), Arm B: 199 (74.0%), Arm C: 225 (83.3%)]. Participants who completed follow-up and those who did not were substantially different in age, sex, or the number of cigarettes smoked per day at baseline.

[0368] Effectiveness: Results The primary outcome measure, biochemically confirmed continuous smoking abstinence during the last four weeks of treatment, was significantly higher for citicinicline compared to placebo across both treatment durations (Table 32). For 6 weeks of treatment (arm B vs. A), 25.3% vs. 4.4% of participants abstained between weeks 3 and 6 (OR 8.0, 95% CI 3.9–16.3, p<0.0001). For 12 weeks of treatment (arm C vs. A), the difference was 32.6% vs. 7.0% between weeks 9 and 12 (OR 6.3, 95% CI 3.7–11.6, p<0.0001).

[0369] Continuous withdrawal for 6 months after the end of treatment (a secondary outcome measure compared to placebo) was significantly higher in both citicinicline treatment durations (Table 32). For 6 weeks of treatment (arm B vs. A), 8.9% vs. 2.6% of participants experienced withdrawal between weeks 3 and 24 (OR 3.7, 95% CI, 1.5–10.2, p=0.0016). For 12 weeks of treatment (arm C vs. A), 21.1% vs. 4.8% experienced withdrawal between weeks 9 and 24 (OR 5.3, 95% CI, 2.8–11.1, p<0.0001). Table 33 provides the risks and numbers required to handle estimates based on direct analysis of 2x2 tables of arm × treatment intention binary outcomes (not stratified due to lack of evidence suggesting clinical site effect modification). The confidence interval was calculated algebraically using a computer from the 95% confidence interval of the direct odds ratio (8).

[0370] Among participants assigned to citicinicline (arms B and C) who achieved continuous withdrawal during weeks 3–6, those who continued citicinicline for an additional 6 weeks (arm C) did not have a significantly different relapse-free withdrawal rate from weeks 6–24 compared to those who switched to placebo at week 6 (arm B) (arm B vs. arm C: 10.4% vs. 13.3%; OR 1.31, 95% CI, 0.75–2.33, p=0.35). For this analysis, individuals who did not withdraw at weeks 3–6, 12, 16, 20, and 24 were considered to have relapsed under the intention-to-treat principle.

[0371] Figure 35 shows the measurement of the point prevalence withdrawal outcome. Both citicinicline arms showed a progressive increase in point prevalence withdrawal over the first 6 weeks of treatment and had a clinically significantly higher, biochemically confirmed 7-day point prevalence withdrawal probability than placebo throughout active treatment. The 95% confidence intervals of the estimated odds ratios for both comparisons at all time points during active treatment (weeks 2–12) and post-treatment follow-up did not include 1 (Figure 35). All randomized participants were included, and missing assessments were imputed as non-withdrawal. The estimated probabilities at each post-randomization time point for each arm at 6 and 12 weeks versus the placebo arm were statistically compared based on the odds ratio and 95% confidence interval. All comparisons at all time points excluded 1 (not shown). This suggests an immediate long-term benefit to point prevalence.

[0372] Figures 36 and 37 compare the efficacy of citicinicline versus placebo for two primary outcomes in subgroups defined by baseline characteristics. For both the citicinicline arm and placebo, significant differences in continuous withdrawal during the last four weeks of treatment were observed in subgroups defined by age, sex, ethnicity, and cigarettes smoked per day. Citicinicline appeared to be less effective in non-white participants during both treatment durations. These EMAs (and EMAs for other baseline attributes not shown) failed to find any indication of qualitative heterogeneity. These EMAs were exploratory and unadjusted for multiplicity.

[0373] The mean total cigarette craving score, using the QSU-brief, decreased more rapidly from baseline to week 6 in participants who received citicinicline for 6 or 12 weeks compared to placebo (Figure 38). During the first 6 weeks of treatment, the mean cigarette craving score, as measured by the Quick Smoking Impulse Questionnaire (QSU-brief), decreased more in patients randomized to 6 and 12 weeks of citicinicline than in patients randomized to placebo. The effect estimate of interest at each post-randomization time point is a comparison of the estimated means of each arm at week 6 and week 12 against the placebo arm. Arm effects were estimated using a cLDA MMRM model with unstructured covariance (7). 95% confidence intervals for effect estimates at all time points excluded zero (not shown). Confidence intervals for effect estimates at weeks 1–6 excluded zero and provided evidence of rapid and sustained effects.

[0374] Safety: Results Adverse events occurring during treatment were reported by 166 participants (61.5%) in the placebo arm, 172 participants (63.9%) in the 6-week citicinicline arm, and 184 participants (68.2%) in the 12-week citicinicline arm (Table 34). The majority of adverse events were non-serious and mild to moderate in severity. Across all three arms, nausea, headache, abnormal dreams, and insomnia were the most frequent (over 5%) adverse events, except for abnormal dreams and insomnia, which were more prevalent in the citicinicline arm compared to placebo. Discontinuation of the study drug due to adverse events occurred in 17 participants (3.2%) of 539 who received citicinicline (Arm B: 2.6%, Arm C: 3.7%) and 4 participants (1.5%) of 270 who received placebo (Figure 34). Serious adverse events (SAEs) occurred in 18 out of 539 participants (3.3%) in the citicinicline group and in 3 out of 270 participants (1.1%) in the placebo group (OR=3.08, direct 95% CI, 0.98–13.18). None of the SAEs, including one death in Arm B, were determined to be treatment-related.

[0375] Detailed data from ORCA-V1 is presented in Tables 31-109 below. [Table 31] [Table 32] [Table 33] [Table 34] [Table 35] [Table 36] [Table 37] [Table 38] [Table 39] [Table 40] [Table 41] [Table 42] TIFF2026516432000051.tif88170 [Table 43] TIFF2026516432000053.tif214170 [Table 44] TIFF2026516432000055.tif248170TIFF2026516432000056.tif254170TIFF2026516432000057.tif119170 [Table 45] TIFF2026516432000059.tif157170 [Table 46]

[0376] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 47] [Table 48] Warning: 25% of cells have an expected count of less than 5. Chi-squared is valid. It might not be an exam. Note: Vaping stop is expressed as a success vs. failure binary for each target. Success is defined as being documented in weeks 9, 10, 11, and 12. This is a biochemically verified vaping contraindication. At each visit, success For each individual patient, vaping withdrawal has been reported (since the last visit). (Nicotine-free vaping) Salivary cotinine levels less than 10 ng / mL It is defined as possessing. [Table 49]

[0377] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 50]

[0378] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 51]

[0379] Sample size N=45. Vaping cessation was defined as a success vs. failure binary for each subject. Success was defined as biochemically validated vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success was defined as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine <10 ng / mL for each individual subject. [Table 52]

[0380] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 53]

[0381] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 54]

[0382] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 55]

[0383] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 56]

[0384] Sample size N=115. Vaping cessation was defined as a success vs. failure binary for each subject. Success was defined as biochemically validated vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success was defined as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine <10 ng / mL for each individual subject. [Table 57] [Table 58]

[0385] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 59]

[0386] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 60]

[0387] Sample size N=160. Vaping cessation was defined as a success vs. failure binary for each subject. Success was defined as biochemically validated vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success was defined as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine <10 ng / mL for each individual subject. [Table 61]

[0388] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 62]

[0389] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 63] [Table 64]

[0390] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 65] [Table 66]

[0391] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 67] [Table 68]

[0392] Sample size N=160. Vaping cessation was defined as a success vs. failure binary for each subject. Success was defined as biochemically validated vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success was defined as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine <10 ng / mL for each individual subject. [Table 69] [Table 70]

[0393] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 71]

[0394] Vaping cessation is defined for each subject as a success-versus-failure binary. Success is biochemically verified vaping withdrawal documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping withdrawal (nicotine-free vaping since the last visit) and having salivary cotinine levels less than 10 ng / mL. [Table 72]

[0395] Total sample size = 160. Vaping cessation is defined for each subject as a success vs. failure binary. Success is biochemically verified vaping cessation documented at weeks 9, 10, 11, and 12. At each visit, success is defined for each subject as reporting vaping cessation (nicotine-free vaping since the last visit) and having salivary cotinine < 10 ng / mL. [Table 73] [Table 74] [Table 75] TIFF2026516432000090.tif220170 [Table 76] [Table 77] Table 78 Table 79 Table 80 Table 81 Table 82 Table 83 Table 84 Table 85 Table 86 Table 87 Table 88 Table 89 TIFF2026516432000105.tif132170 [Table 90] [Table 91] TIFF2026516432000108.tif177170 [Table 92]

[0396] These results from ORCA-V1 suggest that citicinicline may be a safe and effective treatment for nicotine dependence, including in cigarette smokers, e-cigarette users, and users of other nicotine-containing products.

[0397] Various embodiments of this technology are described herein in the following paragraphs 0398 to 0448.

[0398] A method for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction in smoking and / or vaping, wherein the method comprises administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, to the subject three times a day.

[0399] A method for preventing smoking and / or vaping relapse in a subject, the method comprising administering to the subject three times a day cyticine provided in a unit dose of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine.

[0400] A method for treating nicotine addiction and / or nicotine dependence in a subject who requires treatment, wherein the method comprises administering cyticine to the subject, the subject being a refractory patient who has failed to treat one or more nicotine addiction treatments.

[0401] A method for preventing smoking relapse and / or vaping relapse in a subject requiring such prevention, the method comprising administering cyticine to the subject, wherein the subject is a refractory patient who has failed to receive treatment with one or more smoking cessation therapies selected from the group consisting of nicotine replacement therapy, bupropion administration, varenicline administration, e-cigarettes, and vaping.

[0402] A method for preventing the onset and / or progression of an adverse event in a subject who is being treated for nicotine addiction and / or nicotine dependence, is being treated to facilitate cessation of smoking and / or vaping, and / or is being treated to facilitate reduction in smoking and / or vaping, the method comprising administering cyticine, provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, three times daily to the subject in need.

[0403] A method for preventing the onset and / or progression of an adverse event in a subject being treated for the prevention of smoking and / or vaping relapse, the method comprising administering cyticine to the subject in need three times a day, provided in a unit dose of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine.

[0404] A method for preventing the onset and / or progression of an adverse event in a subject being treated for nicotine addiction and / or nicotine dependence, wherein the method comprises administering cyticine to the subject in need, the subject being a refractory patient who has failed to treat with one or more nicotine addiction therapies.

[0405] A method for preventing the onset and / or progression of an adverse event in a subject being treated for the prevention of smoking relapse and / or vaping relapse, wherein the method comprises administering cyticine to the subject in need, the subject being a refractory patient who has failed to receive treatment with one or more smoking cessation therapies, the one or more smoking cessation therapies being selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping.

[0406] A method for reducing the risk of adverse events occurring in a subject being treated for nicotine addiction and / or nicotine dependence, being treated to facilitate cessation of smoking and / or vaping, and / or being treated to facilitate reduction in smoking and / or vaping, wherein the method comprises administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, three times daily to the subject in need.

[0407] A method for reducing the risk of adverse events occurring in a subject being treated for the prevention of smoking and / or vaping relapse, wherein the method comprises administering cyticine to the subject in need three times a day, provided in a unit dose of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine.

[0408] A method for reducing the risk of adverse events occurring in a subject being treated for nicotine addiction and / or nicotine dependence compared to a control subject, wherein the method comprises administering cyticine to the subject in need, the subject being a refractory patient who has failed to treat with one or more nicotine addiction treatments.

[0409] A method for reducing the risk of adverse events occurring in a subject being treated for the prevention of smoking relapse and / or vaping relapse, wherein the method comprises administering cyticine to the subject in need, the subject being a refractory patient who has failed to receive treatment with one or more smoking cessation therapies, the one or more smoking cessation therapies being selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping.

[0410] The method according to paragraphs 0400, 0401, 0403, 0404, 0408, or 0409, wherein cyticine is provided to the subject in a unit dose of approximately 1.0 mg to approximately 6.0 mg of cyticine 3 to 6 times per day, or to the subject in a unit dose of 3.0 mg of cyticine 3 times per day.

[0411] The method according to any one of paragraphs 0398, 0400-0405, and 0407-0409, wherein the cyticine is provided in a unit dose comprising (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine.

[0412] The method according to any one of paragraphs 0398, 0399, 0402, 0403, 0406, 0407, and 0410, wherein the subject is a refractory patient who has failed to be treated with one or more nicotine addictions or smoking cessation therapies.

[0413] The method according to any one of paragraphs 0400, 0404, 0407, or 0411, wherein the nicotine addiction or smoking cessation treatment is selected from nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, vaping, and combinations thereof.

[0414] The method according to any one of paragraphs 04398 to 0412, wherein the subject does not experience any adverse events selected from the group of adverse events consisting of upper respiratory tract infection, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after administration of cyticine.

[0415] The method according to any one of paragraphs 0398-0413, wherein the cyticine is administered for approximately 6 weeks or approximately 12 weeks.

[0416] One method according to any one of paragraphs 0398 to 0414, wherein the subject (a) smokes 10 or more cigarettes per day before administration of cytisine, (b) has an exhaled CO concentration of about 10 ppm or more before administration of cytisine, or (c) a combination of (a) and (b).

[0417] The method according to any one of paragraphs 0402 to 0409, wherein the adverse event is selected from the group consisting of nausea, headache, anxiety, depression, and suicidal ideation.

[0418] The method according to paragraph 0416, wherein the adverse events are nausea and headache.

[0419] The method according to paragraph 0416, wherein the adverse event is nausea.

[0420] The method according to paragraph 0416, wherein the adverse event is headache.

[0421] The method according to any one of paragraphs 0398-0419, wherein the subject requiring it experiences reduced anxiety, reduced depression, and / or the same or less suicidal ideation compared to or with a control subject.

[0422] The method according to any one of paragraphs 0398 to 0420, wherein the control subject is administered a placebo.

[0423] Use of a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine in a subject being treated for nicotine addiction and / or nicotine dependence, being treated to facilitate cessation of smoking and / or vaping, and / or being treated to facilitate reduction in smoking and / or vaping, wherein the cyticine is for oral administration three times daily to the subject in need.

[0424] Use of a unit dose of cyticine in the form of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine, for the prevention of the onset and / or progression of adverse events in a subject being treated for the prevention of smoking and / or vaping relapse.

[0425] Use of cyticine for the purpose of preventing the onset and / or progression of adverse events in a subject being treated for nicotine addiction or nicotine dependence, wherein the subject is a refractory patient who has failed to treat one or more nicotine addiction treatments, and the cyticine is for oral administration to the subject three times a day.

[0426] Use of cyticine to prevent the onset and / or progression of adverse events in a subject being treated for the prevention of smoking relapse and / or vaping relapse, wherein the subject is a refractory patient who has failed to treat one or more nicotine addiction treatments, the one or more nicotine addiction treatments being selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping, and the cyticine is for oral administration to the subject three times a day.

[0427] Use of a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine to reduce the risk of adverse events occurring in subjects being treated for nicotine addiction and / or nicotine dependence, being treated to facilitate cessation of smoking and / or vaping, and / or being treated to facilitate reduction in smoking and / or vaping, wherein the cyticine is for oral administration three times daily to the subjects in need.

[0428] Use of a unit dose of cyticine in the form of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine, for reducing the risk of adverse events occurring in a subject being treated for the prevention of smoking and / or vaping relapse compared to a control subject.

[0429] The use of cyticine to reduce the risk of adverse events compared to a control group, in a subject being treated for nicotine addiction and / or nicotine dependence, wherein the subject is a refractory patient who has failed to treat one or more nicotine addiction treatments, and the cyticine is for oral administration to the subject three times daily.

[0430] Use of cyticine to reduce the risk of adverse events occurring in a subject being treated for the prevention of smoking relapse and / or vaping relapse, wherein the subject is a refractory patient who has failed to treat one or more nicotine addiction treatments, the one or more nicotine addiction treatments being selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping, and the cyticine is for oral administration to the subject three times a day.

[0431] The use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine in subjects who are being treated for nicotine addiction or nicotine dependence, who are being treated to promote the cessation of smoking and / or vaping, and / or who are being treated to promote the reduction of smoking and / or vaping, in order to prevent the onset and / or progression of adverse events in said subjects.

[0432] The use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine to treat nicotine addiction and / or nicotine dependence in subjects who are refractory patients who have failed to treat one or more nicotine addiction therapies, by orally administering approximately 3.0 mg of cyticine three times a day.

[0433] The use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine to prevent the onset and / or progression of adverse events in subjects being treated for nicotine addiction or nicotine dependence, or to prevent smoking and / or vaping relapse in said subjects.

[0434] The use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine to prevent the onset and / or progression of adverse events and prevent smoking relapse in subjects who have failed to receive treatment with one or more nicotine addiction therapies selected from the group consisting of nicotine replacement therapy, bupropion administration, varenicline administration, e-cigarettes, and vaping, by orally administering approximately 3.0 mg of cyticine three times a day.

[0435] The use of cyticine as described in any one of paragraphs 0422 to 0433, wherein the cyticine is provided to a subject requiring it in a unit dose of approximately 1.0 mg to approximately 6.0 mg of cyticine three to six times a day, or to a subject requiring it in a unit dose of 3.0 mg of cyticine three times a day.

[0436] The use of cyticine as described in any one of paragraphs 0422 to 0433, wherein the unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine.

[0437] The use described in any one of paragraphs 0422, 0423, 0426, 0427, 0430, 0432, or 0433, wherein the subject is a refractory patient who has failed to be treated with one or more nicotine addictions or smoking cessation therapies.

[0438] The use described in any one of paragraphs 0422 to 0436, wherein the nicotine addiction or smoking cessation treatment is selected from nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, vaping, and combinations thereof.

[0439] The use described in any one of paragraphs 0422 to 0437, wherein the subject does not experience any adverse events selected from the group of adverse events consisting of upper respiratory tract infection, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after administration of cyticine.

[0440] Cytisine is administered for approximately 6 weeks or approximately 12 weeks, as described in any one of paragraphs 0422-0438.

[0441] The use described in any one of paragraphs 0422 to 0439, wherein the subject (a) smokes 10 or more cigarettes per day prior to administration of cyticine, (b) has an exhaled carbon monoxide (CO) concentration of approximately 10 ppm or more prior to administration of cyticine, or (c) a combination of (a) and (b).

[0442] The use described in any one of paragraphs 0422 to 0440, wherein the unit dose of cyticine comprises either (a) two tablets, each containing 1.5 mg of cyticine, or (b) a single tablet containing 3.0 mg of cyticine.

[0443] The use described in any one of paragraphs 0422 to 0441, wherein the adverse event is selected from the group consisting of nausea, headache, anxiety, depression, and suicidal ideation.

[0444] The use described in paragraph 0442, wherein the adverse events are nausea and headache.

[0445] The use described in paragraph 044, wherein the adverse event is nausea.

[0446] The use described in paragraph 0443, wherein the adverse event is headache.

[0447] The use described in any one of paragraphs 0422 to 0445, wherein the subject requiring it experiences reduced anxiety, reduced depression, and / or the same or less suicidal ideation compared to or with a control subject.

[0448] The use described in any one of paragraphs 0422 to 0446, wherein the control subject is administered a placebo.

[0449] References 1.Posner K,Brown GK,Stanley B,et al.The Columbia-Suicide Severity Rating Scale:initial validity and internal consistency findings from three multisite studies with adolescents and adults.Am J Psychiatry.2011;168:1266-1277. 2.Stern AF.The Hospital Anxiety and Depression Scale.Occupational Medicine.2014;64:393-4. 3.West R,Hajek P,Stead L,StapletonJ.Outcome criteria in smoking cessation trials:proposal for a common standard.Addiction(Abingdon,England)2005;100:299-303. 4.West R,Ussher M.Is the ten-item Questionnaire of Smoking Urges(QSU-brief)more sensitive to abstinence than shorter craving measures? Psychopharmacology 2010;208(3):427-32. 5.Cox LS,Tiffany ST,Christen AG.Evaluation of the brief questionnaire of smoking urges(QSU-brief)in laboratory and clinical settings.Nicotine & tobacco research:2001;3(1):7-16.DOI:10.1080 / 14622200020032051. 6.Benjamini Y,Hochberg Y.Controlling the false discovery rate:a practical and powerful approach to multiple testing.J Royal Statistical Society,Series B.1995;57:289-300. 7.Liu GF,Lu K,Mogg R,Mallick M,Mehrotra DV.Should baseline be a covariate or dependent variable in analyses of change from baseline in clinical trials? Stat Med.2009;28(20):2509-2530. 8.Thomas DG,Gart JJ.A table of exact confidence limits for differences and ratios of two proportions and their odds ratio.J.Am.Stat.Assoc.1977;72:73-76. 9.Heatherton TF,Kozlowski LT,Frecker RC,Fagerstrom KO.The Fagerstrom Test for Nicotine Dependence:a revision of the Fagerstrom Tolerance Questionnaire.British J Addiction.1991;86:1119-27.

Claims

1. A method for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction in smoking and / or vaping, wherein the method comprises administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, to the subject three times a day.

2. A method for preventing smoking and / or vaping relapse in a subject, the method comprising administering to the subject three times a day cyticine provided in a unit dose of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine.

3. A method for treating nicotine addiction and / or nicotine dependence in a subject who requires treatment, wherein the method comprises administering cyticine to the subject, the subject being a refractory patient who has failed to treat one or more nicotine addiction treatments.

4. A method for preventing smoking relapse and / or vaping relapse in a subject requiring such prevention, the method comprising administering cyticine to the subject, wherein the subject is a refractory patient who has failed to receive treatment with one or more smoking cessation therapies selected from the group consisting of nicotine replacement therapy, bupropion administration, varenicline administration, e-cigarettes, and vaping.

5. A method for preventing the onset and / or progression of adverse events in a subject who is being treated for nicotine addiction and / or nicotine dependence, is being treated to facilitate cessation of smoking and / or vaping, and / or is being treated to facilitate reduction in smoking and / or vaping, the method comprising administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, three times daily to the subject in need.

6. A method for preventing the onset and / or progression of an adverse event in a subject being treated for the prevention of smoking and / or vaping relapse, the method comprising administering cyticine to the subject in need three times a day, provided in a unit dose of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine.

7. A method for preventing the onset and / or progression of an adverse event in a subject being treated for nicotine addiction and / or nicotine dependence, wherein the method comprises administering cyticine to the subject in need, the subject being a refractory patient who has failed to treat one or more nicotine addiction therapies.

8. A method for preventing the onset and / or progression of an adverse event in a subject being treated for the prevention of smoking relapse and / or vaping relapse, wherein the method comprises administering cyticine to the subject in need, the subject being a refractory patient who has failed to receive treatment with one or more smoking cessation therapies, the one or more smoking cessation therapies being selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping.

9. A method for reducing the risk of adverse events occurring in a subject being treated for nicotine addiction and / or nicotine dependence, being treated to facilitate cessation of smoking and / or vaping, and / or being treated to facilitate reduction in smoking and / or vaping, wherein the method comprises administering cyticine, provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine, three times daily to the subject in need.

10. A method for reducing the risk of adverse events occurring in a subject being treated for the prevention of smoking and / or vaping relapse compared to a control subject, the method comprising administering cyticine to the subject in need three times a day, provided in a unit dose of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine.

11. A method for reducing the risk of adverse events occurring in a subject being treated for nicotine addiction and / or nicotine dependence compared to a control subject, wherein the method comprises administering cyticine to the subject in need, the subject being a refractory patient who has failed to treat one or more nicotine addiction therapies.

12. A method for reducing the risk of adverse events occurring in a subject being treated for the prevention of smoking relapse and / or vaping relapse, wherein the method comprises administering cyticine to the subject in need, the subject being a refractory patient who has failed to receive treatment with one or more smoking cessation therapies, the one or more smoking cessation therapies being selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping.

13. The method according to claim 3, 4, 7, 8, 11, or 12, wherein cyticine is provided to the subject in a unit dose of approximately 1.0 mg to approximately 6.0 mg of cyticine three to six times a day, or to the subject in a unit dose of 3.0 mg of cyticine three times a day.

14. The method according to any one of claims 1, 3-5, 6-8, and 10-13, wherein the cyticine is provided in a unit dose comprising (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine.

15. The method according to any one of claims 1, 2, 5, 6, 9, 10, 13, and 14, wherein the subject is a refractory patient who has failed to be treated with one or more nicotine addictions or smoking cessation therapies.

16. The method according to any one of claims 3, 7, 10, or 15, wherein the nicotine addiction or smoking cessation treatment is selected from nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, vaping, and combinations thereof.

17. The method according to any one of claims 1 to 16, wherein the subject does not experience any adverse events selected from the group of adverse events consisting of upper respiratory tract infection, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after administration of cyticine.

18. The method according to any one of claims 1 to 17, wherein the cyticine is administered for about six weeks or about twelve weeks.

19. The method according to any one of claims 1 to 18, wherein the subject (a) smokes 10 or more cigarettes per day before administration of cytisine, (b) has an exhaled carbon monoxide (CO) concentration of about 10 ppm or more before administration of cytisine, or (c) a combination of (a) and (b).

20. The method according to any one of claims 5 to 12, wherein the adverse event is selected from the group consisting of nausea, headache, anxiety, depression, and suicidal ideation.

21. The method according to claim 20, wherein the adverse events are nausea and headache.

22. The method according to claim 20, wherein the adverse event is nausea.

23. The method according to claim 20, wherein the adverse event is a headache.

24. The method according to any one of the prior claims, wherein the subject requiring it experiences reduced anxiety, reduced depression, and / or the same or less suicidal ideation compared to a control subject or the control subject.

25. The method according to any one of the prior claims, wherein the control subject is administered a placebo.

26. Use of a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cyticine in a subject being treated for nicotine addiction and / or nicotine dependence, being treated to facilitate cessation of smoking and / or vaping, and / or being treated to facilitate reduction in smoking and / or vaping, wherein the cyticine is for oral administration three times daily to the subject in need.

27. Use of a unit dose of cyticine in the form of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine, or (c) three tablets, each containing 1.0 mg of cyticine, for the prevention of the onset and / or progression of adverse events in a subject being treated for the prevention of smoking and / or vaping relapse.

28. Use of cyticine for the purpose of preventing the onset and / or progression of adverse events in a subject being treated for nicotine addiction or nicotine dependence, wherein the subject is a refractory patient who has failed to treat one or more nicotine addiction treatments, and the cyticine is for oral administration to the subject three times a day.

29. Use of cyticine to prevent the onset and / or progression of adverse events in a subject being treated for the prevention of smoking relapse and / or vaping relapse, wherein the subject is a refractory patient who has failed to treat one or more nicotine addiction treatments, the one or more nicotine addiction treatments being selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping, and the cyticine is for oral administration to the subject three times a day.

30. Use of a unit dose of cyticine of 3.0 mg, 1.5 mg, or 1.0 mg in subjects being treated for nicotine addiction and / or nicotine dependence, being treated to facilitate cessation of smoking and / or vaping, and / or being treated to facilitate reduction in smoking and / or vaping, wherein the cyticine is for oral administration three times daily to the subjects in need.

31. Use of a unit dose of cyticine in the form of three tablets, each containing either 1.5 mg or 3.0 mg of cyticine, for reducing the risk of adverse events occurring in a subject being treated for the prevention of smoking and / or vaping relapse compared to a control subject, wherein the cyticine is intended for oral administration three times daily to the subject in need.

32. The use of cyticine for the purpose of reducing the risk of adverse events compared to a control group, in a subject being treated for nicotine addiction and / or nicotine dependence, wherein the subject is a refractory patient who has failed to treat one or more nicotine addiction treatments, and the cyticine is for oral administration to the subject three times a day.

33. Use of cyticine to reduce the risk of adverse events occurring in a subject being treated for the prevention of smoking relapse and / or vaping relapse, wherein the subject is a refractory patient who has failed to treat one or more nicotine addiction treatments, the one or more nicotine addiction treatments being selected from the group consisting of nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, and vaping, and the cyticine is for oral administration to the subject three times a day.

34. The use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine in subjects who are being treated for nicotine addiction or nicotine dependence, who are being treated to promote the cessation of smoking and / or vaping, and / or who are being treated to promote the reduction of smoking and / or vaping, in order to prevent the onset and / or progression of adverse events in said subjects.

35. The use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine to treat nicotine addiction and / or nicotine dependence in subjects who are refractory patients who have failed to treat one or more nicotine addiction therapies, by orally administering approximately 3.0 mg of cyticine three times a day.

36. The use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine to prevent the onset and / or progression of adverse events in subjects being treated for nicotine addiction or nicotine dependence, and to prevent smoking and / or vaping relapse in said subjects.

37. The use of tablets containing approximately 1.0 mg or 1.5 mg of cyticine to prevent the onset and / or progression of adverse events and prevent smoking relapse in subjects who have failed to receive treatment with one or more nicotine addiction therapies selected from the group consisting of nicotine replacement therapy, bupropion administration, varenicline administration, e-cigarettes, and vaping, by orally administering approximately 3.0 mg of cyticine three times a day.

38. The use according to any one of claims 26 to 37, wherein the cyticine is provided to a subject requiring it in a unit dose of about 1.0 mg to about 6.0 mg of cyticine three to six times a day, or to a subject requiring it in a unit dose of 3.0 mg of cyticine three times a day.

39. The use according to any one of claims 26 to 37, wherein the unit dose of cyticine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cyticine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cyticine; or (c) three tablets, each containing 1.0 mg of cyticine.

40. The use according to any one of claims 26, 27, 30, 31, 34, 36, and 37, wherein the subject is a refractory patient who has failed to be treated with one or more nicotine addictions or smoking cessation therapies.

41. The use according to any one of claims 26 to 40, wherein the nicotine addiction or smoking cessation treatment is selected from nicotine replacement therapy, administration of bupropion, administration of varenicline, e-cigarettes, vaping, and combinations thereof.

42. The use according to any one of claims 26 to 41, wherein the subject does not experience any adverse events selected from the group of adverse events consisting of upper respiratory tract infection, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after administration of cyticine.

43. The use according to any one of claims 26 to 42, wherein cyticine is administered for approximately 6 weeks or approximately 12 weeks.

44. The use according to any one of claims 26 to 43, wherein the subject (a) smokes 10 or more cigarettes per day before administration of cytisine, (b) has an exhaled carbon monoxide (CO) concentration of about 10 ppm or more before administration of cytisine, or (c) a combination of (a) and (b).

45. The use according to any one of claims 26 to 44, wherein the unit dose of cyticine comprises either (a) two tablets, each containing 1.5 mg of cyticine, or (b) a single tablet containing 3.0 mg of cyticine.

46. The use according to any one of claims 26 to 45, wherein the adverse event is selected from the group consisting of nausea, headache, anxiety, depression, and suicidal ideation.

47. The use according to claim 46, wherein the adverse events are nausea and headache.

48. The use according to claim 47, wherein the adverse event is nausea.

49. The use according to claim 47, wherein the adverse event is headache.

50. The use according to any one of claims 26 to 49, wherein the subject requiring it experiences reduced anxiety, reduced depression, and / or the same or less suicidal ideation compared to a control subject or the control subject.

51. The use according to any one of claims 26 to 50, wherein the control subject is administered a placebo.

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