Compositions comprising cytisine for treating and / or preventing addiction in subjects in need thereof

Abstract

Methods of treating addictions and / or dependencies, methods of promoting abstraction of various addictions, such as smoking and / or vaporizing, and methods of promoting reduction of various addictions, such as smoking and / or vaporizing, the use of cytisine as an addiction abstraction treatment and dosage regimens therefor are provided.

Description

[0001] This case is a divisional application of the patent application with application number 202080064060.3 filed by the present applicant on August 14, 2020, entitled “Compositions including cytisine for treating and / or preventing addiction in subjects in need thereof”. The entire contents of the parent case are incorporated into this divisional by reference.

[0002] Priority claim

[0003] This application claims priority to U.S. Provisional Application No. 62 / 988,890, filed on March 12, 2020, and U.S. Provisional Application No. 62 / 899,637, filed on September 12, 2019, the entire contents of each of which are incorporated herein by reference and relied upon. Background Art

[0004] Nicotine is an addictive substance that is rapidly absorbed during the cigarette smoking process. The drug is distributed quickly and is considered to interact with the neuronal nicotinic acetylcholine receptors (nAChRs) in the central nervous system (CNS). Nicotine addiction is caused at least in part by this interaction. Although many smokers try to stop smoking, few succeed without drug-supported treatment.

[0005] Tobacco smoking causes about 7 million premature deaths worldwide each year. Smoking is highly addictive, with more than 95% of people unable to quit for six months without assistance. It is estimated that for every year a person delays stopping smoking after his or her mid-life of 30 years, he or she loses three months of life expectancy. The World Health Organization's Framework Convention on Tobacco Control identifies evidence-based methods for promoting smoking cessation, including mass media campaigns, increasing tobacco taxes, and helping smokers who want to quit.

[0006] Currently available pharmacological therapies to help smokers quit in the United States and Western Europe include nicotine replacement therapy (NRT) and two nicotine-free drugs: bupropion (Glaxo-SmithKline's ) and varenicline (Pfizer's ). NRT and bupropion appear to have approximately the same efficacy. Varenicline is more effective than single NRT and bupropion, but combination NRT is comparable in efficacy.

[0007] (-)-cytisine (cytisinicline; often referred to as cytisine) is a plant-based alkaloid isolated from the seeds of Cytisus laburnum L. (gold chain). References to cytisine herein refer to (-)-cytisine, cytisinicline.

[0008] Cytisine's mechanism of action helps basic pharmacologists understand the complex pharmacology of the various subtypes of nicotinic acetylcholine receptors. These studies show that both nicotine and cytisine strongly and preferentially bind to the α4β2 receptor, which mediates the release of dopamine in the shell of the nucleus accumbens and elsewhere. This receptor subtype is associated with the development and maintenance of nicotine dependence and is the primary target of the above-mentioned drug varenicline.

[0009] Contains the active ingredient cytisine It has been licensed and marketed in Central and Eastern Europe for decades by Sopharma PLC (Sophia, Bulgaria).

[0010] There is a need for nicotine addiction treatment utilizing patient-friendly regimens that are less costly, more effective, have an improved safety profile, and / or can more successfully treat individuals who have failed to abstain from nicotine using known treatments. Summary of the invention

[0011] In one aspect, provided herein is a method of treating nicotine addiction in a subject, the method comprising administering cytisine to the subject in need thereof twice a day ("bid" or "BID") or three times a day ("tid" or "TID") in equal doses.

[0012] In another aspect, provided herein is a method for treating nicotine addiction in a subject in need thereof, promoting a subject in need thereof to quit smoking, and / or promoting a subject in need thereof to reduce smoking, the method comprising administering to the subject cytisine provided at a unit dose of 3.0 mg or 1.5 mg cytisine three times daily.

[0013] In still another aspect, provided herein is a method of treating nicotine addiction in a subject, the method comprising administering cytisine to the subject in need thereof at a dose of 1.5 mg or 3.0 mg cytisine three times daily.

[0014] In still another aspect, provided herein is a method of treating nicotine dependence in a subject, the method comprising administering cytisine to the subject in need thereof at a dose of 1.5 mg or 3.0 mg cytisine three times daily.

[0015] In still yet another aspect, provided herein is a method of treating nicotine addiction in a subject, the method comprising administering cytisine to a subject in need thereof, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments.

[0016] In yet another aspect, the present invention provides a method for preventing smoking relapse in a subject in need thereof, the method comprising administering to the subject three times daily cytisine provided in the following unit doses: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0017] In another aspect, provided herein is a method for preventing relapse of smoking in a subject in need thereof, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies, the one or more smoking cessation therapies being selected from the group consisting of: NRT, administration of bupropion, administration of varenicline, electronic cigarettes (e-cigarettes), and vaping.

[0018] In one embodiment, each of the three daily administrations occurs in the morning, noon and evening, respectively, or occurs at intervals of about 4-5 hours. In one embodiment, the administration occurs for a period of at least about 6 weeks, at least about 12 weeks, at least about 24 weeks, or indefinitely. In another embodiment, the administration occurs for at least about 6 weeks or at least about 12 weeks, or is repeated indefinitely for 6-12 weeks.

[0019] In some embodiments, cytisine is provided to a subject in need at a unit dose of about 1.0 mg to about 6.0 mg cytisine once to six times a day. In some embodiments, cytisine is provided to a subject in need at a unit dose of about 1.0 mg to about 6.0 mg cytisine three to six times a day. In some embodiments, cytisine is provided to a subject in need at a unit dose of 1.5 mg cytisine three times a day. In some embodiments, cytisine is provided to a subject in need at a unit dose of 1.5 mg cytisine six times a day. In some embodiments, cytisine is provided to a subject in need at a unit dose of 3.0 mg cytisine three times a day. In some embodiments, cytisine is provided to a subject in need at a unit dose of 3.0 mg cytisine six times a day.

[0020] In some embodiments, cytisine is administered in one or more unit doses. In some embodiments, each unit dose (e.g., tablet or capsule) of cytisine includes 1.0 mg of cytisine. In some embodiments, each unit dose (e.g., tablet or capsule) of cytisine includes 1.5 mg of cytisine. In some embodiments, the unit dose of cytisine includes 3.0 mg of cytisine. In some embodiments, each unit dose is a tablet, such as a compressed film-coated tablet.

[0021] In some embodiments, the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments. In some embodiments, the subject is a refractory patient who has failed treatment with two or more nicotine addiction treatments. In some embodiments, the nicotine addiction treatment is selected from NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and combinations thereof.

[0022] In some embodiments, the subject smoked ten or more cigarettes per day prior to the administration of cytisine. In some embodiments, the subject had a carbon monoxide (CO) concentration of about 10 parts per million (ppm) or higher in the air exhaled prior to the administration of cytisine. In some embodiments, the subject (a) smoked ten or more cigarettes per day prior to the administration of cytisine, (b) had a CO concentration of about 10 ppm or higher in the air exhaled prior to the administration of cytisine, or (c) a combination of (a) and (b).

[0023] In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In some embodiments, the adverse events are selected from the group consisting of upper respiratory tract infection (URTI), abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0024] In some embodiments, the method further comprises providing behavioral support to the subject.

[0025] The present invention also includes the following items:

[0026] 1. A method for treating nicotine addiction, nicotine dependence, promoting abstinence from smoking and / or vaping in a subject in need thereof, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, the method comprising administering cytisine provided in a unit dose of 3.0 mg, 1.5 mg or 1.0 mg cytisine to the subject three times daily.

[0027] 2. A method for preventing relapse to smoking and / or vaping in a subject in need thereof, the method comprising administering to the subject three times daily cytisine provided in the following unit doses: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0028] 3. A method of treating nicotine addiction and / or nicotine dependence in a subject in need thereof, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction therapies.

[0029] 4. A method of preventing a subject in need thereof from relapsing to smoking and / or relapsing to vaping, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed 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, electronic cigarettes, and vaping.

[0030] 5. The method according to item 3 or item 4, wherein cytisine is provided to the subject at a unit dose of about 1.0 mg to about 6.0 mg cytisine three to six times a day or at a unit dose of 3.0 mg cytisine three times a day.

[0031] 6. A method according to any one of items 1 and 3 to 5, wherein the cytisine is provided in a unit dose comprising: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0032] 7. A method according to any one of items 1, 2, 5 and 6, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation therapies.

[0033] 8. The method of any one of item 3 or item 7, wherein the nicotine addiction or smoking cessation treatment is selected from nicotine replacement therapy, administration of bupropion, administration of varenicline, electronic cigarettes, steam smoking, and combinations thereof.

[0034] 9. The method according to any one of the preceding items, wherein the subject does not experience adverse events after administration of cytisine, the adverse events being selected from the group of adverse events consisting of upper respiratory tract infection, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0035] 10. The method according to any one of the preceding items, wherein the cytisine is administered for about 6 weeks or for about 12 weeks.

[0036] 11. A method according to any of the preceding items, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has a CO concentration of about 10 ppm or greater in exhaled air prior to administration of cytisine, or (c) a combination of (a) and (b).

[0037] 12. A use of cytisine at a unit dose of 3.0 mg, 1.5 mg or 1.0 mg for treating nicotine addiction, nicotine dependence, promoting a subject in need to quit smoking and / or vaping, and / or promoting a subject in need to reduce smoking and / or vaping, wherein the cytisine is for oral administration to the subject three times a day.

[0038] 13. A use of a unit dose of cytisine in the form of: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine, for preventing relapse to smoking and / or vaping in a subject in need thereof, wherein the cytisine is for oral administration to the subject three times daily.

[0039] 14. A use of cytisine for treating nicotine addiction or nicotine dependence in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments, wherein the cytisine is for oral administration to the subject three times daily.

[0040] 15. A use of cytisine for preventing a subject from relapsing to smoking and / or vaping, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments, wherein the one or more nicotine addiction treatments are selected from the group consisting of: nicotine replacement therapy, administration of bupropion, administration of varenicline, electronic cigarettes, and vaping, wherein the cytisine is for oral administration to the subject three times a day.

[0041] 16. Use of a tablet comprising about 1.0 mg or about 1.5 mg of cytisine for orally administering about 3.0 mg of cytisine to a subject three times daily to treat nicotine addiction, nicotine dependence, promote the subject to quit smoking and / or vaping, and / or promote the subject to reduce smoking and / or vaping.

[0042] 17. Use of a tablet comprising about 1.0 mg or about 1.5 mg of cytisine for oral administration of about 3.0 mg of cytisine three times daily to a subject for treating nicotine addiction and / or nicotine dependence in the subject, the subject being a refractory patient who has failed treatment with one or more nicotine addiction therapies.

[0043] 18. Use of a tablet comprising about 1.0 mg or about 1.5 mg of cytisine for orally administering about 3.0 mg of cytisine to a subject three times daily to prevent the subject from relapsing to smoking and / or vaping.

[0044] 19. Use of a tablet comprising about 1.0 mg or about 1.5 mg of cytisine for orally administering about 3.0 mg of cytisine three times daily to a subject who has failed treatment with one or more nicotine addiction treatments to prevent the subject from relapsing to smoking, wherein the one or more nicotine addiction treatments are selected from the group consisting of: nicotine replacement therapy, administration of bupropion, administration of varenicline, electronic cigarettes, and smoking vaping.

[0045] 20. The use according to any one of items 12, 14 and 15, wherein cytisine is provided to a subject in need thereof at a unit dose of about 1.0 mg to about 6.0 mg cytisine three to six times a day or at a unit dose of 3.0 mg cytisine three times a day.

[0046] 21. The use according to any one of items 14 to 20, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0047] 22. The use according to any one of items 12, 13, 16, 18, 20 and 21, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation therapies.

[0048] 23. The use according to any one of items 12 to 14, 16 to 18 and 20 to 22, wherein 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.

[0049] 24. The use according to any one of items 12 to 23, wherein the subject does not experience adverse events after administration of cytisine, the adverse events being selected from the group of adverse events consisting of upper respiratory tract infection, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0050] 25. The use according to any one of items 12 to 24, wherein cytisine is administered for about 6 weeks or for about 12 weeks.

[0051] 26. The use according to any one of items 12 to 25, wherein the subject (a) smokes ten or more cigarettes per day before the administration of cytisine, (b) has a CO concentration of about 10 ppm or more in exhaled air before the administration of cytisine, or (c) a combination of (a) and (b).

[0052] 27. The use according to any one of items 12, 13 and 20 to 26, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg of cytisine; or (b) a single tablet, the single tablet containing 3.0 mg of cytisine. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 It is a schematic diagram of the dosing regimen designed according to the study of Example 1 of the present technology.

[0054] Figure 2 It is a schematic diagram of the research design according to Example 1 of the present technology.

[0055] Figure 3 is a schematic diagram of dosing intensity, schedule and duration according to the study design of Example 1 of the present technology.

[0056] Figure 4 is a schematic diagram showing the distribution of the subject population according to the study of Example 1 according to the present technology.

[0057] Figure 5 is a representative graph depicting the number of cigarettes smoked per day by each treatment group according to the study of Example 1 in accordance with the present technology.

[0058] Figure 6 is a representative graph depicting the reduction in exhaled CO from a smoked cigarette in a population of subjects of Example 1 in accordance with the present technology.

[0059] Figure 7is a representative graph depicting a comparison between the quit rates after 4 weeks of abstinence and the quit rates during the ongoing abstinence period (weeks 5-8) in the subject population of Example 1 in accordance with the present technology.

[0060] Figure 8 is a representative graph depicting a comparison of abstinence rates between 3.0 mg three times daily (TID) and placebo after 4 weeks of abstinence and during sustained abstinence (weeks 5-8).

[0061] Fig. 9 ] is a representative graph depicting exhaled CO levels in parts per million at the screening visit, at week 4, and at week 8 combined for the treatment groups of placebo, TID 1.5 mg, TID 3.0 mg, 1.5 mg commercial dosing titration schedule (COM), and 3.0 mg COM according to the present technology.

[0062] Fig.10 is a representative graph depicting serum cotinine levels at the screening visit, at week 4, and at week 8 combined for placebo, TID 1.5 mg, TID 3.0 mg, COM 1.5 mg, and COM 3.0 mg according to the present technology.

[0063] Figures 11A-11B are representative plots comparing between groups homogeneity depicting the percentage of cigarettes intended to be smoked (cigarette score) compared between COM 0 mg and TID 0 mg and between TID 0 mg and TID 3.0 mg in accordance with the present technology.

[0064] Fig.12 According to the present technology, cytisine (cytisine) and Schematic representation of the study design for comparison.

[0065] Fig.13 According to the present invention, 3.0 mg of cytisine and 3.0 mg of Representative graph of smoking cessation rates among CO-confirmed smokers.

[0066] Fig.14 According to the present invention, cytisine and Representative plots comparing odds ratios.

[0067] Fig.15 is a representative plot comparing the odds ratios of cytisine to the current product at 4 weeks, end of treatment, and 4 weeks off treatment according to the present technology.

[0068] Fig.16is a representative plot depicting the interaction between the 3.0 mg TID group and the BMI stratifier in accordance with the present technology.

[0069] Fig.17 is a representative plot depicting the assessment of parallelism between groups using a linear relationship between cigarette score and baseline average number of cigarettes according to the present technique.

[0070] Fig.18 is a representative plot of the Effect Modifier Analysis (EMA) depicting cigarette scores across clinical sites for cytisine 1.5 mg TID compared to pooled placebo in accordance with the present technology.

[0071] Fig.19 is a representative plot of the EMA depicting cigarette scores across clinical sites for cytisine 3.0 mg TID compared to pooled placebo in accordance with the present technology.

[0072] Fig. 20 is a representative plot depicting the EMA of cigarette scores across clinical sites for cytisine 1.5 mg COM compared to pooled placebo in accordance with the present technology.

[0073] Fig.21 is a representative plot depicting the EMA of cigarette scores across clinical sites for cytisine 3.0 mg COM compared to pooled placebo in accordance with the present technology.

[0074] Fig. 22 is a representative plot depicting the EMA for cytisine 1.5 mg TID versus pooled placebo across clinical sites for 4 weeks of abstinence confirmed by <10 ppm exhaled CO (Cess / W5-8 / CO success) from Week 5 to Week 8 in accordance with the present technology.

[0075] Fig.23 is a representative graph depicting EMA of cytisine 3.0 mg TID versus pooled placebo across clinical sites for 4 weeks of abstinence confirmed by <10 ppm exhaled CO (Cess / W5-8 / CO success) from Week 5 to Week 8 in accordance with the present technology.

[0076] Fig.24 is a representative plot depicting EMA of cytisine 1.5 mg COM versus pooled placebo for 4 weeks of abstinence confirmed by <10 ppm exhaled CO (Cess / W5-8 / CO success) from Week 5 to Week 8 across clinical sites in accordance with the present technology.

[0077] Fig.25is a representative plot depicting EMA of cytisine 3.0 mg COM versus pooled placebo for 4 weeks of abstinence confirmed by <10 ppm exhaled CO (Cess / W5-8 / CO success) from Week 5 to Week 8 across clinical sites in accordance with the present technology.

[0078] Fig.26 Representative plots of the EMA of cigarette scores for attributes across baseline (race, Hispanic ethnicity, sex, age (M), age (T), stratified BMI, smoking Hx Dur(y) (M), smoking Hx Dur(y) (T), smoking HxDur(y) (Q), >2 quit Hx, screening average number of cigarettes / day (M)) for cytisine 3.0 mg TID compared to pooled placebo according to the present technology.

[0079] Fig. 27 Representative plots depicting the EMA of 4 weeks of abstinence confirmed by <10 ppm exhaled CO (Cess / W5-8 / CO Success) from Week 5 to Week 8 for cytisine 3.0 mg TID versus pooled placebo across baseline attributes (race, Hispanic ethnicity, sex, age (M), age (T), stratified BMI, Smoking Hx Dur(y)(M), Smoking Hx Dur(y)(T), Smoking Hx Dur(y)(Q), >2 Quit Hx, Screening Avg. number of cigarettes / day (M)) in accordance with the present technology.

[0080] Fig.28 The present invention describes the efficacy of cytisine 3.0 mg TID compared with placebo across prior anti-smoking interventions (>2 smoking cessation Tx, Hx, Hx, steam Hx, NRT Hx, (recent), Representative plots of EMA for cigarette scores for (recent), vapor (recent), and NRT (recent).

[0081] Fig.29 The present invention describes the efficacy of cytisine 3.0 mg TID compared with placebo across prior anti-smoking interventions (>2 smoking cessation Tx, Hx, Hx, steam Hx, NRT Hx, (recent), Representative plots of EMAs for 4 weeks of abstinence from week 5 to week 8 confirmed by <10 ppm exhaled CO (Cess / W5-8 / CO success) for EDTA (recent), Vapor (recent), and NRT (recent).

[0082] Fig.30is a representative plot depicting the EMA of cigarette scores across baseline laboratory markers (NMR, CO, cotinine) for cytisine 3.0 mg TID compared to pooled placebo in accordance with the present technology.

[0083] Fig.31 is a representative plot depicting EMAs for cytisine 3.0 mg TID versus pooled placebo across baseline laboratory markers (NMR, CO, cotinine) for 4 weeks of abstinence confirmed by <10 ppm exhaled CO (Cess / W5-8 / CO success) from Week 5 to Week 8 in accordance with the present technology.

[0084] Fig.32 is a representative plot depicting the critical point analysis of the cytisine 3.0 mg TID group versus the pooled placebo groups for 4 weeks of abstinence confirmed by <10 ppm exhaled CO (Cess / W5-8 / CO success) from week 5 to week 8 according to the present technology.

[0085] Fig.33 is a schematic diagram of the research design according to Example 2 of the present technology. DETAILED DESCRIPTION

[0086] Although the present disclosure can be embodied in various forms, the following description of several embodiments is made with the understanding that the present disclosure is to be regarded as an illustration of the present invention and is not intended to limit the present invention to the specific embodiments shown. Titles are provided only for convenience and should not be construed as limiting the present invention in any way. The embodiments shown under any title may be combined with the embodiments shown under any other title.

[0087] Unless otherwise expressly stated, the numerical values ​​used in the various quantitative values ​​specified in this application are all expressed as approximate values, as if the minimum and maximum values ​​in the range all begin with the word "about". It should be understood that, although not always expressly stated, all digital names are preceded by the term "about". It should be understood that the use of this range format is for convenience and simplicity, and should be flexibly understood to include the numerical values ​​clearly specified as range limits, and also include all individual numerical values ​​or sub-ranges covered within the range, as if each numerical value and sub-range is clearly specified. For example, a ratio ranging from about 1 to about 200 should be understood to include the clearly listed restrictions of about 1 and about 200, but also includes individual ratios such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100. It should also be understood that, although not always expressly stated, the agents described herein are merely exemplary, and their equivalents are known in the art.

[0088] As used herein, the term "about" when referring to a measurable value such as an amount or concentration, is intended to encompass variations of 20%, 10%, 5%, 1%, 0.5% or even 0.1% of the specified amount.

[0089] Likewise, the disclosure of ranges is intended as a continuous range, including every value between the recited minimum and maximum values, and any ranges that may be formed from these values. Also disclosed herein are any and all ratios (and ranges of any such ratios) that may be formed by dividing a disclosed numerical value by any other disclosed numerical value. Thus, those skilled in the art will recognize that many such ratios, ranges, and ranges of ratios may be clearly derived from the numerical values ​​presented herein, and in all cases, such ratios, ranges, and ranges of ratios represent various embodiments of the present disclosure.

[0090] As used herein, the phrase "statistically significant" means that a result from data generated by a test or experiment is unlikely to occur by chance or by chance and is instead attributable to a specific cause. Statistical significance is evaluated based on a calculated probability (p-value), where the p-value is a function of the mean and standard deviation of a sample of data and represents the probability that a statistical result occurs by chance or through sampling error. A result is considered statistically significant if the p-value is 0.05 or less, which corresponds to a 95% confidence level.

[0091] "Comprising" or "comprise" is intended to mean that compositions and methods contain the recited elements, but do not exclude other elements. When used to define compositions and methods, "consisting essentially of" shall mean excluding other elements that have any substantial significance for the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein will not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" shall mean excluding other ingredients and substantial method steps that exceed trace elements. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0092] As used herein, the phrase "control subject" refers to any subject used as a basis for comparison with a test subject. Control subjects include, but are not limited to, any subject to whom no composition is administered, to whom a composition other than the test composition is administered (e.g., 1.5 mg of cytisine three times a day or 3.0 mg of cytisine three times a day), or to whom a placebo is administered.

[0093] The term "treat" in relation to a given disease or condition includes, but is not limited to, inhibiting the disease or condition, e.g., arresting the development of the disease or condition; alleviating the disease or condition, e.g., causing regression of the disease or condition; or relieving the condition caused by the disease or condition or e.g., alleviating or treating the symptoms of the disease or condition. The term "prevent" in relation to a given disease or condition means: preventing the onset of the disease if disease development has not already occurred; preventing the onset of the disease or condition in a subject who may be susceptible to the condition or disease but has not yet been diagnosed as having the condition or disease, and / or preventing further disease / condition development if already present.

[0094] "Steaming" refers to the behavior of a subject inhaling the vapor of a solution carried in a box or chamber produced by a device. In some embodiments, the device is electronic and simulates smoking. A steaming device may include, but is not limited to, a power source, an atomizer, and a box or chamber. In some embodiments, steaming refers to consuming oil or steaming activities, such as drawing from a steaming device or consuming multiple steams, performing a steaming period with a steaming device, or using a steaming device to ingest steam. In another embodiment, steaming refers to consuming oil. In an alternative embodiment, steaming refers to consuming oil or drawing from a steaming device or consuming multiple steams. In yet another embodiment, steaming refers to steaming activities. In other embodiments, steaming refers to drawing from a steaming device or consuming multiple steams, performing a steaming period with a steaming device, or using a steaming device to ingest steam. In other embodiments, steaming refers to drawing from a steaming device or consuming multiple steams, or using a steaming device to ingest steam. In still further embodiments, vaporizing refers to using a vaporizing device to ingest vapor.

[0095] As used herein, the terms "reduction in vaping," "reduction in vaping," and "reduces vaping" refer to a decrease in the frequency or amount of vaping per hour, day, week, month, or year, such as a decrease in the amount of liquid consumed, a decrease in the number or frequency of puffs of vapor drawn or otherwise consumed from a vaping device, a decrease in the number or frequency of vaping sessions performed with a vaping device, or a decrease in the use of a vaping device to ingest vapor.

[0096] As used herein, the term "adverse event" (AE) refers to any unfavorable medical occurrence in a subject to which a composition is administered and not necessarily related to the treatment. Thus, an AE can be any unfavorable and unexpected sign (including abnormal laboratory findings), symptom or disease temporally associated with the use of the composition, whether or not it is considered to be related to the composition.

[0097] As used herein, the term "adverse drug reaction" refers to any undesirable and unexpected response to an administered composition. The term "response to a composition" means that attribution is at least reasonably possible (i.e., such a relationship cannot be ruled out and the relationship is judged by the investigator to be at least possible) (see definition below).

[0098] The terms "serious adverse event" (SAE) and "serious adverse reaction" (SAR) refer to an AE that results in at least one of the following AEs: death, is life-threatening, requires hospitalization or prolongs an existing hospitalization of a subject, results in persistent or significant disability or incapacity, results in a congenital anomaly or birth defect, or is a medically important event that requires medical intervention to prevent any of the foregoing outcomes.

[0099] As used herein, the term "suspected unexpected serious adverse reaction" (SUSAR) is an AE that is serious, unexpected, and has at least a reasonable probability of attribution between the event and the composition. Important medical events are those that may not be immediately life-threatening but may endanger the subject and may require intervention to prevent one of the serious consequences listed above. Examples of such events are intensive treatment of allergic bronchospasm in the emergency room or at home, or blood disorders or convulsions that do not lead to hospitalization. The term "life-threatening" refers to an event in which the subject is at risk of death at the time of the event; it does not refer to an event that is assumed to cause death if it is more serious. For example, drug-induced hepatitis that resolves without evidence of liver failure will not be considered life-threatening, even though drug-induced hepatitis may be fatal. Inpatient hospitalization or extension of existing hospital stay refers to hospital inpatient admission and / or hospital stay extension is necessary for the treatment of the AE, or occurs due to the event. It does not involve pre-planned elective hospital admissions or diagnostic procedures for the treatment of pre-existing conditions that have not yet significantly worsened.

[0100] The terms "cytisine-treated group," "active group," "treatment group," "active treatment group," and "study group" are used interchangeably throughout this document and refer to subjects to whom a composition comprising cytisine is administered.

[0101] 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 monitoring; ECG, electrocardiogram; GCP, good clinical practice; ICH, International Conference on Harmonization; IMP, investigational medicinal product (for this protocol, cytisine 3.0 mg film-coated tablets); MedDRA, Medical Dictionary of Regulatory Activities; SAE, serious adverse event; SAR, serious adverse reaction; SmPC, summary of product characteristics; SOC, MedDRA system organ class; SUSAR, suspected unexpected serious adverse reaction; Tmax, time to maximum observed concentration; UADR, unexpected adverse drug reaction; UAE, unexpected adverse event; ULN, upper limit of normal.

[0102] Composition

[0103] The compositions used in the methods of the present disclosure include cytisine or a pharmaceutically acceptable derivative, conjugate or salt thereof, or a mixture of any of the foregoing, which are collectively referred to herein as "cytisine". In this context, the term "pharmaceutically acceptable" means that the substance in question does not produce unacceptable toxicity to a subject or does not produce interactions with other components of the composition. Cytisine, (-)-cytisine and cytisine are referenced interchangeably.

[0104] Any suitable cytisine pharmaceutical composition or formulation can be used in the methods described herein.In some embodiments, cytisine can be formulated in tablet form, for example as a compressed film-coated tablet for oral administration.

[0105] Compositions used according to the present disclosure can be formulated into one or more dosage units. The terms "dose unit" and "dosage unit" herein refer to a portion of a pharmaceutical composition that contains a certain amount of therapeutic agent suitable for single administration to provide a therapeutic effect. Such dosage units can be administered once to multiple times (i.e., 1 to about 10 times, 1 to about 8 times, 1 to 6 times, 1 to 4 times, 1 to 3 times, or 1 to 2 times) per day or most likely multiple times according to the need to elicit a therapeutic response.

[0106] A unit dose may include a single tablet, such as a tablet containing 3.0 mg of cytisine, or it may include two or more tablets that together contain a unit dose (e.g., 3.0 mg of cytisine). For example, a unit dose of 3.0 mg may include two tablets, each containing 1.5 mg of cytisine, such as two Tablet. Each Tablets are typically formulated as compressed film-coated tablets containing 1.5 mg of cytisine in a single tablet along with various tablet forming excipients (calcium sulfate, cellulose powder, colloidal silicon dioxide, magnesium stearate) and coated with a colored film coating comprising polyvinyl alcohol, titanium dioxide and iron oxide. As another example, a 3.0 mg unit dose may include three tablets, each containing 1.0 mg of cytisine, such as Tablets At least three tablets formulated similarly.

[0107] Alternatively, cytisine can be formulated in the form of a capsule or another carrier for oral administration and orally deliverable; or can be administered in the form of a composition for nasal or topical administration. The term "orally deliverable" or "oral administration" herein includes any form of delivery of a therapeutic agent or composition thereof to a subject, wherein the agent or composition is placed in the subject's mouth, whether or not the agent or composition is swallowed. Therefore, "oral administration" includes buccal and sublingual as well as esophageal administration.

[0108] Tablets and other dosage forms (hereinafter referred to as "compositions") may contain one or more excipients, such as those commonly used in the art. Excipients that may be used in the composition include, for example, fillers, disintegrants, preservatives, lubricants and wetting agents.

[0109] Examples of fillers that may be used include lactose (eg, anhydrous or monohydrate), cellulose, starch (eg, corn and / or wheat starch), calcium phosphate, calcium sulfate, and mannitol.

[0110] Preservatives prevent bacterial or fungal contamination of the formulation, and include various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid.

[0111] Suitable lubricants include stearic acid and its salts.An example of a lubricant for use in the compositions of the present disclosure is magnesium stearate.

[0112] The pharmaceutical composition may further include sweetening, flavoring or coloring agents.

[0113] In some embodiments, the placebo is a tablet comprising an inactive (e.g., cytisine) component that is identical, substantially identical, similar, or substantially similar to the test composition. In these embodiments, the placebo comprises at least the same, substantially identical, similar, or substantially similar excipients, fillers, preservatives, lubricants, sweeteners, flavorings, and / or coloring agents as the test composition, and at least one other inactive ingredient such as cellulose. In some embodiments, the placebo tablet and the test composition tablet have the same or substantially the same weight, size, shape, color, and / or are contained in the same or substantially the same packaging.

[0114] Those skilled in the art will be familiar with suitable fillers, preservatives and lubricants, as well as suitable sweeteners, flavorings and coloring agents and other additives, in addition to those specifically mentioned above. The pharmaceutical composition of cytisine useful in the methods of the present disclosure may include a coating, such as a film coating, and may be coated according to any method known in the art, for example, using collodion, shellac, gum arabic, talc, titanium dioxide or sugar.

[0115] The pharmaceutical composition comprising cytisine can be prepared by any suitable method. For example, capsules can be prepared by mixing cytisine with one or more inert carriers such as lactose or sorbitol and packaging them in gelatin capsules. Tablets can be prepared by known compression methods.

[0116] In one embodiment, the compositions of the present disclosure exhibit at least about 90%, at least about 95%, at least about 97.5%, or at least about 99% of the active ingredient originally present therein when stored in a closed container maintained at room temperature, refrigerated (e.g., about 5°C to about -10°C) temperature, or frozen for a period of about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.

[0117] method

[0118] The present disclosure provides a method for treating nicotine addiction or nicotine dependence in a subject in need thereof, the treatment comprising administering an effective amount of cytisine to the subject. In some embodiments, the method for treating nicotine addiction or nicotine dependence comprises preventing a subject in need from smoking relapse and / or promoting a subject in need to quit or reduce smoking.

[0119] In some embodiments, the present disclosure provides a method for treating nicotine addiction or nicotine dependence in a subject in need, comprising administering a therapeutically effective amount of cytisine to the subject. In some embodiments, the present disclosure relates to a method for preventing a subject in need from smoking relapse, comprising administering a therapeutically effective amount of cytisine to the subject. In another embodiment, the present disclosure provides a method for promoting a subject in need to quit smoking, comprising administering a therapeutically effective amount of cytisine to the subject. In some embodiments, the present disclosure provides a method for promoting a subject in need to reduce smoking, comprising administering an effective amount of cytisine to the subject. In some embodiments, the present disclosure provides a method for treating nicotine addiction or nicotine dependence in a subject in need, wherein the nicotine addiction or nicotine dependence is in the form of cigarettes, smokeless tobacco, snuff, electronic cigarettes (e-cigarettes), steam cigarettes such as steam cigarettes using a steam smoking device, and / or hookahs. In some embodiments, the steam smoking device contains a liquid including nicotine, for example, about 1 mg / ml nicotine to about 12 mg / ml nicotine or greater than about 13 mg / ml nicotine. Any patient suffering from nicotine addiction or nicotine dependence can be treated by the methods disclosed herein.

[0120] In additional embodiments, the present disclosure provides a method for treating and / or preventing addiction or dependence in a subject in need, the method comprising administering a therapeutically effective amount of cytisine to the subject. Without being bound by any particular theory, it is believed that cytisine interacts with the dopamine neurotransmitter release cycle as a partial agonist of the nicotinic acetylcholine receptor (nAChR) and can be used to treat and / or prevent multiple addictions or multiple dependencies in a subject in need. Non-limiting examples of addiction and dependence that are considered to be treated and / or prevented by administering cytisine include addiction and / or dependence on substances, compounds, and / or behaviors that may be involved in the dopamine neurotransmitter release cycle. Exemplary substances, compounds, and / or behaviors include, but are not limited to, cannabidiol (CBD), alcohol and other analgesics, diet, sex, benzodiazepines, barbiturates, and inhalants. In a further embodiment, the present disclosure provides a method for promoting a subject in need to quit addiction or dependence, the method comprising administering a therapeutically effective amount of cytisine to the subject. In some embodiments, the present disclosure provides a method for promoting a reduction in addiction and / or dependence in a subject, the method comprising administering to the subject an effective amount of cytisine. The compositions and methods described herein with respect to smoking, vaping, and nicotine can be used to treat, prevent, and / or reduce addiction or dependence in a subject in need thereof, such as any subject with an addiction or dependence involving a dopamine neurotransmitter release cycle.

[0121] In another embodiment, the method for treating nicotine addiction or nicotine dependence comprises preventing a subject in need from relapsing from smoking steam and / or promoting a subject in need to quit or reduce smoking steam. In some embodiments, the present disclosure relates to a method for preventing a subject in need from relapsing from smoking steam, the method comprising administering a therapeutically effective amount of cytisine to the subject. In another embodiment, the present disclosure provides a method for promoting a subject in need to quit smoking steam, the method comprising administering a therapeutically effective amount of cytisine to the subject. In some embodiments, the present disclosure provides a method for promoting a subject in need to reduce smoking steam, the method comprising administering a therapeutically effective amount of cytisine to the subject.

[0122] In some embodiments, provided herein is a method for treating nicotine addiction or nicotine dependence in a subject, the method comprising administering cytisine to a subject in need twice a day ("bid" or "BID") or three times a day ("tid" or "TID") in equal doses. In one embodiment, each administration of the twice daily administration occurs in the morning and evening, respectively. In another embodiment, each administration of the twice daily administration occurs at intervals of about 10-12 hours. In yet another embodiment, each administration of the three daily administrations occurs in the morning, noon and evening, respectively. In another embodiment, each administration of the three daily administrations occurs at intervals of about 4-5 hours. In yet another embodiment, each administration of the three daily administrations occurs at intervals of about 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours or more. In one embodiment, the administration occurs 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 be included in any period of days or weeks during the administration period BID or TID. For example, in these embodiments, the entire administration period may be BID or TID. As another example, in these embodiments, at least a portion of the administration can be BID or TID, such as at least about one day, at least about three days, at least about one week, at least about two weeks, at least about four weeks, at least about 12 weeks. As yet another example, in these embodiments, the BID or TID administration can occur in any order, such as day 1 can be BID or TID, day 2 can be BID or TID, day 3 can be BID or TID, and so on, for the duration of the administration period.

[0123] In some embodiments, the administration is independent of whether the subject is in a fed state or a fasted state. For example, the administration can occur simultaneously with food, in parallel with food, at any amount of time before the subject ingests food, or at any amount of time after the subject ingests food. Without intending to be limited to any particular theory, it is not believed that food (or fed state or fasted state) affects the bioavailability of cytisine, which can be determined by the overall physical absorption or overall bioavailability of cytisine in the subject.

[0124] In some embodiments, the TID dose is 1 mg, 1.5 mg, 2 mg, 2.5 mg or 3.0 mg of cytisine. In some embodiments, the TID dose is 1 mg, no matter how the dose is divided. For example, each TID dose can be administered 3 times a day in the form of two 0.5 mg strength tablets or three times a day in the form of a single 1 mg tablet or administered in any other possibility. In some embodiments, the TID dose is 1.0 mg, no matter how the dose is divided between the dosage units. In some embodiments, the TID dose is 1.5 mg, no matter how the dose is divided between the dosage units. In some embodiments, the TID dose is 2 mg, no matter how the dose is divided between the dosage units. In yet another embodiment, the TID dose is 2.5 mg, no matter how the dose is divided between the dosage units. In some embodiments, the TID dose is 3.0 mg, no matter how the dose is divided between the dosage units.

[0125] In some embodiments, the subject does not experience adverse events associated with cytisine treatment. Adverse events can be mild (e.g., no interference with activity), moderate (some interference with activity but no medical intervention or minimal medical intervention is required) or severe (hindering daily activities and requiring medical intervention). Non-limiting examples of adverse events include upper respiratory tract infection (URTI), abnormal dreams, nausea, insomnia, headache, fatigue and constipation. In other embodiments, the subject experiences two or fewer adverse events associated with cytisine treatment, such as nausea, abnormal dreams, insomnia, headache and / or URTI in the subject, which increases by about 0% to about 10%, for example, about 0%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10%. In some embodiments, the subject does not experience adverse events compared to subjects administered nicotine replacement therapy (NRT), bupropion, varenicline, electronic cigarettes, steam smoke and / or combinations thereof.

[0126] In some embodiments, the subject experiences nicotine addiction or nicotine dependence by smoking cigarettes, ingesting smokeless tobacco and / or snuff, using electronic cigarettes (e-cigarettes) and / or vaping, and / or daily use of hookah, such as consuming nicotine per unit per day. In some embodiments, a subject with nicotine addiction or nicotine dependence consumes about 0 to about 100 units of nicotine per day. For example, a single cigarette can be one unit of nicotine, and a subject with nicotine addiction or nicotine dependence smokes about 0 cigarettes per day to about 100 cigarettes per day, about 5 cigarettes per day to about 75 cigarettes per day, about 5 cigarettes per day to about 50 cigarettes per day, about 5 cigarettes per day to about 25 cigarettes per day, about 10 cigarettes per day to about 50 cigarettes per day, about 20 cigarettes per day to about 50 cigarettes per day, about 25 cigarettes per day to about 75 cigarettes per day, about 25 cigarettes per day to about 50 cigarettes per day, for example, about 0 cigarettes per day, about 1 cigarette per day, about 2 cigarettes per day, about 3 cigarettes per day, about 4 cigarettes per day, about 5 cigarettes per day, about 6 cigarettes per day, about 7 cigarettes per day, about 8 cigarettes per day, about 9 cigarettes per day, about 10 cigarettes per day, about 15 cigarettes per day, about 16 cigarettes per day, about 17 cigarettes per day, about 18 cigarettes per day, about 19 cigarettes per day, about 20 cigarettes per day, about 25 ... 8 cigarettes per day, about 9 cigarettes per day, about 10 cigarettes per day, about 11 cigarettes per day, about 12 cigarettes per day, about 13 cigarettes per day, about 14 cigarettes per day, about 15 cigarettes per day, about 16 cigarettes per day, about 17 cigarettes per day, about 18 cigarettes per day, about 19 cigarettes per day, about 20 cigarettes per day, about 25 cigarettes per day, about 30 cigarettes per day, about 35 cigarettes per day, about 40 cigarettes per day, about 45 cigarettes per day, about 50 cigarettes per day, about 55 cigarettes per day, about 60 cigarettes per day, about 65 cigarettes per day, about 70 cigarettes per day, about 75 cigarettes per day, about 80 cigarettes per day, about 85 cigarettes per day, about 90 cigarettes per day, or about 100 cigarettes per day. In other examples, the unit of nicotine also includes ingestion of smokeless tobacco and / or snuff, use of electronic cigarettes (e-cigarettes) and / or vapor cigarettes (e.g., smoking vapor cigarettes) and / or daily use of hookahs instead of cigarettes or a combination of hookahs and cigarettes.

[0127] In some embodiments, the administration of cytisine reduces the number of units of nicotine ingested by the subject per day, such as the number of cigarettes smoked by the subject per day. In some embodiments, after treatment with 1.0 mg TID, 1.5 mg TID or 3.0 mg TID of cytisine, the method of the present technology reduces the percentage of cigarettes smoked by the 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% compared to control subjects, placebo controls and / or baseline.

[0128] In some embodiments, administration of cytisine increases abstinence in a subject following treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine. In these embodiments, abstinence in a subject is increased by about 5% to about 30% after cytisine treatment relative to abstinence achieved without cytisine treatment, e.g., about 5% to about 15%, about 5% to about 10%, about 5% to about <10%, about 10% to about 25%, about 15% to about 20%, about 20% to about 30%, or about 25% to about <30%, about 5% to about 100%, about 5% to about 75%, about 5% to about 50%, about 5% to about 60%, about 5% to about 75%, about 5% to about 80%, about 5% to about 90%, about 5% to about 100%, about 5% to about 15 ... 0%, about 25% to about 75%, about 25% to about 50%, about 30% to about 50%, about 30% to about 50%, about 30% to about 75%, about 30% to about <100%, or about 30% to about 100%, such as at least about 10%, at least about 15%, at least about 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%, or at least about 55%. In some embodiments, withdrawal is withdrawal for a period of time, such as about 2 weeks withdrawal, about 3 weeks withdrawal, about 4 weeks withdrawal, about 5 weeks withdrawal, about 6 weeks withdrawal, about 7 weeks withdrawal, about 8 weeks withdrawal, about 12 weeks withdrawal, about 16 weeks withdrawal, about 20 weeks withdrawal, about 24 weeks withdrawal, about 28 weeks withdrawal, or about 32 weeks withdrawal. In certain embodiments, the period of abstinence is from about 1 day to about 4 weeks, from about 1 week to about 8 weeks, from about 2 weeks to about 12 weeks, from about 4 weeks to about 24 weeks, or from about 8 weeks to about 32 weeks.

[0129] In some embodiments, administration of cytisine increases the smoking cessation rate of a subject following treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine. In these embodiments, after a 4-week abstinence period between Week 5 and Week 8 following cytisine treatment, or during continued abstinence, the subject's smoking cessation rate is about 5% to about 30%, e.g., about 5% to about 15%, about 5% to about 10%, about 5% to about <10%, about 10% to about 25%, about 15% to about 20%, about 20% to about 30%, or about 25% to about <30%, about 5% to about 100%, about 5% to about 75%, about 5% to about 80%, about 5% to about 100%, about 5% to about 15 ... % to about 50%, about 25% to about 75%, about 25% to about 50%, about 30% to about 50%, about 30% to about 50%, about 30% to about 75%, about 30% to about <100%, or about 30% to about 100%, such as at least about 10%, at least about 15%, at least about 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%, or at least about 55%. In some embodiments, the quit rate is determined after a period of abstinence, such as about 1 day of abstinence, about 3 days of abstinence, about 7 days of abstinence, about 10 days of abstinence, about 2 weeks of abstinence, about 3 weeks of abstinence, about 4 weeks of abstinence, about 5 weeks of abstinence, about 6 weeks of abstinence, about 7 weeks of abstinence, about 8 weeks of abstinence, about 9 weeks of abstinence, about 10 weeks of abstinence, about 11 weeks of abstinence, about 12 weeks of abstinence, about 16 weeks of abstinence, about 20 weeks of abstinence, about 24 weeks of abstinence, about 28 weeks of abstinence, or about 32 weeks of abstinence. In certain embodiments, the period of abstinence 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.

[0130] In some embodiments, prior to treatment with cytisine, the subject has an exhaled CO level of about 0 ppm to about 50 ppm, e.g., about 10 ppm to about 40 ppm, about 10 ppm to about 30 ppm, about 10 ppm to about <20 ppm, about 20 ppm to about 30 ppm, about 20 ppm to about 40 ppm, about 20 ppm to about <50 ppm, or about 20 ppm to about 50 ppm, e.g., about 0 ppm, about 2 ppm, about 4 ppm, about 6 ppm, about 8 ppm, about 10 ppm, about 12 ppm, about 14 ppm, about 16 ppm, about 18 ppm, about 20 ppm, about 22 ppm, about 24 ppm, about 26 ppm, about 28 ppm, about 30 ppm, about 32 ppm, about 34 ppm, about 36 ppm, about 38 ppm, about 40 ppm, about 42 ppm, about 44 ppm, about 46 ppm, about 48 ppm, or about 50 ppm. In some embodiments, administration or treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine reduces the level of exhaled CO in the 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%, compared to control subjects, placebo control, and / or baseline. In some embodiments, following treatment with cytisine, the subject has an exhaled CO level of about 0 ppm to about 30 ppm, e.g., about 10 ppm to about 25 ppm, about 10 ppm to about 20 ppm, about 10 ppm to about <20 ppm, about 5 ppm to about 15 ppm, about 5 ppm to about 10 ppm, about 1 ppm to about <10 ppm, or about 10 ppm to about 5 ppm, e.g., about 0 ppm, about 2 ppm, about 4 ppm, about 6 ppm, about 8 ppm, about 10 ppm, about 12 ppm, about 14 ppm, about 16 ppm, about 18 ppm, or about 20 ppm.

[0131] In some embodiments, following treatment with cytisine, the subject's serum and / or plasma cotinine level is about 5 ng / mL to about 500 ng / mL, about 25 ng / mL to about 400 ng / mL, about 25 ng / mL to about 400 ng / mL, about 25 ng / mL to about 300 ng / mL, about 50 ng / mL to about 200 ng / mL, about 75 ng / mL to about 150 ng / mL, about 85 ng / mL to about 100 ng / mL, about 100 ng / mL to about 400 ng / mL, about 100 ng / mL to about 300 ng / mL, about 100 ng / mL to about 200 ng / mL, about 200 ng / mL to about 300 ng / mL, about 200 ng / mL to about 400 ng / mL, about 200 ng / mL to about 500 ng / mL. In some embodiments, the present invention relates to a pharmaceutical composition having an amount of at least about 1 ng / mL, about 2 ng / mL, about 3 ng / mL, about 4 ng / mL, about 5 ng / mL, about 6 ng / mL, about 7 ng / mL, about 8 ng / mL, about 9 ng / mL, about 10 ng / mL, about 12 ng / mL, about 15 ng / mL, about 17 ng / mL, about 20 ng / mL, about 22 ng / mL, about 25 ng / mL, about 27 ng / mL, about 30 ng / mL, about 32 ng / mL, about 35 ng / mL, about 37 ng / mL, about 40 ng / mL, about 42 ng / mL, about 45 ng / mL, about 47 ng / mL, or about 50 ng / mL. In some embodiments, administration of or treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine reduces serum and / or plasma cotinine levels in the subject by at least about 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 control, and / or baseline.In some embodiments, following treatment with cytisine, the subject's serum and / or plasma cotinine level is about 0.1 ng / mL to about 20 ng / mL, about 0.1 ng / mL to about 15 ng / mL, about 0.5 ng / mL to about 10 ng / mL, about 1 ng / mL to about 10 ng / mL, about 0.5 ng / mL to about 5 ng / mL, or about 0.5 ng / mL to about 1 ng / mL, for example, about 0.1 ng / mL, about 0.5 ng / mL, about 1 ng / mL, about 1.5 ng / mL, about 3 ng / mL, about 5 ng / mL, about 7 ng / mL, about 8 ng / mL, about 9 ng / mL, about 10 ng / mL, about 15 ng / mL, or about 20 ng / mL.

[0132] In some embodiments, administration of cytisine increases the odds ratio of a subject after 4 weeks of treatment, after 8 weeks of treatment, and 4 weeks after the end of treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine. In these embodiments, the odds ratio of the subject is 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, a placebo control, and / or a baseline.

[0133] In some embodiments, the subject's vital signs, hematology and chemistry levels, and ECG are measured before and / or after administration of cytisine. In some embodiments, the subject exhibits no clinically significant changes in vital signs, hematology and chemistry levels, and ECG after administration of cytisine.

[0134] In some embodiments, the subject is a heavy, moderate or light nicotine user, such as a smoker or steam smoker using nicotine can be classified as a "heavy smoker" or "heavy steam smoker", "moderate smoker" or "moderate steam smoker" or "light smoker" or "light steam smoker". For example, a "heavy smoker" as provided herein refers to a subject who reports consuming 20 or more cigarettes per day. A "moderate smoker" as provided herein refers to a subject who reports consuming 11-19 cigarettes per day. A "light smoker" as provided herein refers to a subject who reports consuming 1-10 cigarettes per day. As another example, a "heavy steam smoker" as provided herein refers to a subject who reports performing 20 or more steam smoking sessions per day, consuming 20 or more puffs from a steam smoking device per day, or otherwise reports using a steam smoking device 20 or more times per day. As provided herein, "moderate steam smokers" refer to subjects who report performing 11-19 steam smoking sessions per day, consuming 11-19 puffs from a steam smoking device per day, or additionally report using a steam smoking device 11-19 times per day. As provided herein, "light steam smokers" refer to subjects who report performing 1-10 steam smoking sessions per day, consuming 1-10 puffs from a steam smoking device per day, or additionally report using a steam smoking device 1-10 times per day. In some embodiments, the administration of cytisine reduces the cotinine level of a subject identified as a heavy smoker or a heavy steam smoker. In some embodiments, the administration of cytisine reduces the cotinine level of a subject identified as a moderate smoker or a moderate steam smoker. In yet another embodiment, the administration of cytisine reduces the cotinine level of a subject identified as a light smoker or a light steam smoker.

[0135] In some embodiments, the subject has smoked cigarettes or vaporized cigarettes 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 administration of cytisine.

[0136] In some embodiments, the subject began smoking cigarettes or vaping as a teenager. In some embodiments, the subject began smoking cigarettes or vaping between the ages of 10 and 19. In some embodiments, the subject began smoking cigarettes or vaping as a teenager and has smoked cigarettes 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 prior to administration of cytisine.

[0137] In some embodiments, the length of administration is up to about 26 weeks. In certain embodiments, the length of administration is from about 6 weeks to about 12 weeks, and in some embodiments, cytisine is administered as described above for about 6 weeks.

[0138] Compared to the commercial 25-day titration schedule using a unit dose of 1.5 mg cytisine, in the regimen according to e.g. Figure 7 The percentage of smokers who remained abstinent among subjects treated with the methods disclosed herein was demonstrated to be surprisingly high.

[0139] In some embodiments, the subject is a smoker, e.g., a smoker who smokes about 3 or more cigarettes per day. In some embodiments, the subject is a smoker who smokes about 5 or more or about 10 or more cigarettes per day. In some embodiments, the subject has a measurable exhaled CO concentration of about 10 ppm or more prior to administration of cytisine.

[0140] In certain embodiments, the subject is a refractory patient. As used herein, "refractory patient" or "refractory subject" is a subject who has failed to be treated with one or more nicotine addiction or nicotine dependence treatments. In certain embodiments, nicotine addiction or nicotine dependence treatments include both treatments approved by regulatory agencies and smoking cessation methods, such as steam cigarettes and behavioral support. Non-limiting examples of behavioral support include behavioral support that can be used to reduce, prevent or additionally treat anxiety, depression and / or addiction symptoms. In certain embodiments, behavioral support includes consultation, diary, wearable device, application, network-based smoking cessation plan, text message intervention and a combination thereof. In further embodiments, to non-refractory patients, such as control patients (e.g., baseline, placebos were applied, smoking, steam cigarettes or nicotine cessation drugs not comprising cytisine were applied), behavioral support is provided. In certain embodiments, nicotine addiction or nicotine dependence treatments include first-line smoking cessation drugs approved by FDA, such as NRT, bupropion and varenicline. Nicotine replacement therapy can come in the form of patches, gums, lozenges, sprays, and inhalers.

[0141] In some embodiments, the subject is a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments. For example, the subject has 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 subject is a refractory patient who has failed treatment for nicotine addiction or nicotine dependence, the treatment comprising NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof.

[0142] In some embodiments, the subject has previously attempted to quit smoking or vaping at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or more times prior to administration of cytisine.

[0143] In some embodiments, the refractory subject has 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 administration of cytisine.

[0144] In one aspect, the method includes administering cytisine to the subject, wherein the cytisine is provided in a unit dose of about 1.0 mg to about 5.0 mg. In certain embodiments, the unit dose of cytisine is about 1.0 mg. In certain embodiments, the unit dose of cytisine is about 1.5 mg. In certain embodiments, the unit dose of cytisine is about 3.0 mg. In some embodiments, a unit dose of cytisine is administered to the subject three to six times a day. In some embodiments, a unit dose of cytisine is administered to the subject three times a day. In some embodiments of the methods disclosed herein, the unit dose is about 1.0 mg three times a day, about 1.5 mg three times a day, or about 3.0 mg three times a day, for 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. In certain embodiments, the cytisine used in a unit dose lasts up to about 2 weeks, lasts from about 2 weeks to about 6 weeks, lasts from about 3 weeks to about 6 weeks, or lasts from about 9 weeks to about 12 weeks. In certain embodiments, for a subject who uses a unit dose of cytisine and continues for at least about 4 weeks, the relapse rate is lower than the subject who uses a unit dose of cytisine and continues for at least about 2 weeks. In other embodiments, for a subject who uses a unit dose of cytisine and continues for at least about 6 weeks, the relapse rate is lower than the subject who uses a unit dose of cytisine and continues for at least about 4 weeks. In further embodiments, for a subject who uses a unit dose of cytisine and continues for at least about 8 weeks, the relapse rate is lower than the subject who uses a unit dose of cytisine and continues for at least about 4 weeks. In still further embodiments, for a subject who uses a unit dose of cytisine and continues for at least about 12 weeks, the relapse rate is lower than the subject who uses a unit dose of cytisine and continues for at least about 4 weeks.

[0145] In some embodiments, compared with subjects using a commercial 1.5 mg per unit dose titration schedule, the administration of cytisine to subjects causes significantly better nicotine use cessation rates (smoking cessation rates or vaping continuation rates). In some embodiments, a unit dose of 3.0 mg of cytisine is administered three times daily for 6 weeks (e.g., the first 6 weeks), followed by a placebo for 6 weeks (e.g., the second six weeks). In certain embodiments, behavioral support is provided to the subject during at least a portion of the first 6 weeks, during at least a portion of the second 6 weeks, before at least a portion of the first 6 weeks, after at least a portion of the second 6 weeks, or during a combination thereof. In some embodiments, a unit dose of 3.0 mg of cytisine is administered three times daily for 12 weeks. In certain embodiments, behavioral support is provided to the subject during at least a portion of 12 weeks, before 12 weeks, after 12 weeks, or a combination thereof. Thereafter, in some embodiments, the subject exhibits one or more of the following:

[0146] (a) a reduction in units of nicotine used per day, such as cigarettes smoked per day or vapor smoked per day, compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0147] (b) a decrease in exhaled CO levels compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0148] (c) a decrease in serum and / or plasma cotinine levels in the subject compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0149] (d) increased smoking cessation rates compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0150] (e) no change, no increase, or a decrease in adverse events compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0151] (f) an increase in the odds ratio of a subject compared to subjects taking NRT, control subjects, placebo controls, and / or baseline;

[0152] (g) increased withdrawal compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0153] (h) reduced nicotine craving and / or tobacco craving compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0154] (i) a reduction in the severity of nicotine withdrawal symptoms compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0155] (j) a reduction in the severity of anxiety compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline; and / or

[0156] (k) reduction in the severity of depression compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline.

[0157] In one embodiment, the method of the present disclosure includes measuring the baseline level of one or more markers shown in (a)-(k) above before administering to the subject or subject group. In another embodiment, the method includes administering a composition as disclosed herein to the subject after determining the baseline level of one or more markers shown in (a)-(k), and then performing additional measurements of the one or more markers. In another embodiment, when treated with the composition of the present disclosure, the subject exhibits one or more of the following:

[0158] (a) a reduction in daily nicotine use, such as units of cigarettes smoked per day or units of vapor smoked per day, of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or more compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0159] (b) a decrease in exhaled CO levels of about 5% to about 100% compared to baseline, control or placebo levels, e.g., a decrease of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more compared to subjects administered NRT, control subjects, placebo controls, and / or baseline;

[0160] (c) a decrease in serum and / or plasma cotinine levels of at least about 5%, at least about 10%, at least about 15%, at least about 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%, or more compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0161] (d) an increase in smoking cessation rate of about 5% to about 100%, about 5% to about 75%, about 5% to about 50%, about 25% to about 75%, about 25% to about 50%, about 30% to about 50%, about 30% to about 75%, about 30% to about <100%, or about 30% to about 100% compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0162] (e) adverse events are unchanged, not increased, or decreased by about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more compared to subjects administered NRT, control subjects, placebo controls, and / or baseline;

[0163] (f) an increase in the odds ratio of the subject by about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0164] (g) an increase in withdrawal of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0165] (h) a reduction in tobacco craving of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0166] (i) a reduction in the severity of nicotine withdrawal symptoms by about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more compared to subjects already taking NRT, control subjects, placebo controls, and / or baseline;

[0167] (j) a reduction in the severity of anxiety by about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more compared to subjects administered NRT, control subjects, placebo controls, and / or baseline; and / or

[0168] (k) a reduction in the severity of depression by about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more compared to subjects already taking NRT, control subjects, placebo controls and / or baseline.

[0169] In some embodiments, the method of the present disclosure comprises treating nicotine addiction, nicotine dependence in a subject in need, promoting a subject in need to quit smoking and / or vaping and / or promoting a subject in need to reduce smoking and / or vaping, the method comprising administering cytisine provided in a unit dose of 3.0 mg, 1.5 mg or 1.0 mg cytisine to the subject three times a day. In certain embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the 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 cytisine treatment. In some embodiments, the administration of cytisine continues for about 6 weeks or continues for about 12 weeks. In some embodiments, the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments, the subject is a refractory patient who has failed treatment with one or more nicotine addiction, nicotine dependence or smoking cessation treatments. In some embodiments, the nicotine addiction, nicotine dependence or smoking cessation treatment is selected from NRT, administration of bupropion, administration of varenicline, electronic cigarettes, steam cigarettes and combinations thereof. In some embodiments, the subject (a) smokes ten or more cigarettes or uses ten or more steam cigarettes per day before the administration of cytisine, (b) the CO concentration in the exhaled air before the administration of cytisine is about 10 ppm or higher, or (c) a combination of (a) and (b). In some embodiments, the method further comprises providing behavioral support to the subject.

[0170] In some embodiments, the method of the present disclosure comprises treating nicotine addiction, nicotine dependence in a subject in need, promoting a subject in need to quit smoking and / or vaping, and / or promoting a subject in need to reduce smoking and / or vaping, the method comprising administering cytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg cytisine to the subject three times daily, wherein the subject experiences no adverse events after receiving cytisine treatment. In some embodiments, the adverse events are selected from the group consisting of: URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0171] In some embodiments, the method of the present disclosure comprises treating nicotine addiction, nicotine dependence, promoting abstinence from smoking and / or vaping in a subject in need thereof, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, the method comprising administering cytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg cytisine to the subject three times daily, wherein the subject does not experience nausea following treatment with cytisine.

[0172] In some embodiments, the method of the present disclosure comprises treating nicotine addiction, nicotine dependence, promoting a subject in need to quit smoking and / or vaping, and / or promoting a subject in need to reduce smoking and / or vaping, the method comprising administering cytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg cytisine to the subject three times daily for about 6 weeks or for about 12 weeks. In some embodiments, the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0173] In some embodiments, the method of the present disclosure comprises treating nicotine addiction, nicotine dependence in a subject in need, promoting a subject in need to quit smoking and / or vaping, and / or promoting a subject in need to reduce smoking and / or vaping, the method comprising administering cytisine provided in a unit dose of 3.0 mg, 1.5 mg or 1.0 mg cytisine to the subject three times daily, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction, nicotine dependence or smoking cessation treatments. In some embodiments, the nicotine addiction, nicotine dependence or smoking cessation treatment is selected from NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and combinations thereof.

[0174] In some embodiments, the method of the present disclosure comprises treating nicotine addiction, nicotine dependence, promoting abstinence from smoking and / or vaping in a subject in need thereof, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, the method comprising administering to the subject cytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg cytisine three times daily, wherein the subject (a) smokes ten or more cigarettes per day prior to the administration of cytisine, (b) has a CO concentration of about 10 ppm or greater in exhaled air prior to the administration of cytisine, or (c) a combination of (a) and (b).

[0175] In some embodiments, the method of the present disclosure comprises treating nicotine addiction, nicotine dependence, promoting a subject in need thereof to quit smoking and / or vaping, and / or promoting a subject in need thereof to reduce smoking and / or vaping, the method comprising administering to the subject cytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg cytisine three times daily, and providing behavioral support to the subject.

[0176] The method of the present disclosure further comprises treating nicotine addiction or nicotine dependence in a subject in need, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments. In certain embodiments, the nicotine addiction or nicotine dependence treatment comprises NRT, administration of bupropion, administration of varenicline, electronic cigarettes, steam smoking, or a combination thereof. In some embodiments, cytisine is provided to a subject in need three to six times a day at a unit dose of about 1.0 mg to about 6.0 mg of cytisine. In certain embodiments, cytisine is provided to a subject in need three times a day at a unit dose of 3.0 mg of cytisine. In some embodiments, the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments, the administration of cytisine lasts for about 6 weeks or for about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of: URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation. In some embodiments, the subject (a) smokes ten or more cigarettes per day before the administration of cytisine, (b) the CO concentration in the exhaled air before the administration of cytisine is about 10 ppm or higher, or (c) a combination of (a) and (b).

[0177] The method of the present disclosure further provides a method for preventing a subject in need from relapse to smoking and / or vaping, the method comprising administering to the subject three times daily cytisine provided in the following unit doses: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments, cytisine is administered for about 6 weeks or for about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of: URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation. In some embodiments, the subject (a) smokes ten or more cigarettes per day before administering cytisine, (b) the CO concentration in the exhaled air before administering cytisine is about 10 ppm or higher, or (c) a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation treatments. In certain embodiments, the smoking cessation therapy comprises NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof.

[0178] The method of the present disclosure further comprises a method for preventing a subject in need from relapsing to smoking and / or vaping, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation treatments, the one or more smoking cessation treatments being selected from the group consisting of: NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof. In some embodiments, the subject (a) smokes ten or more cigarettes per day before administering cytisine, (b) has a CO concentration of about 10 ppm or higher in the exhaled air before administering cytisine, or (c) a combination of (a) and (b). In some embodiments, the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine, three times daily to the subject, and wherein cytisine is administered for about 6 weeks or for about 12 weeks. In some embodiments, the subject does not experience an adverse event selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving cytisine treatment.

[0179] The present disclosure also provides a drug, such as a drug comprising a unit dose of 3.0 mg, 1.5 mg or 1.0 mg of cytisine, which is used to treat nicotine addiction, nicotine dependence in a subject in need, promote a subject in need to quit smoking and / or vaping, and / or promote a subject in need to reduce smoking and / or vaping, wherein the drug is used to be orally administered to the subject three times a day. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the 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 cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or for about 12 weeks. In some embodiments, the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments, the subject is a refractory patient who has failed treatment with one or more nicotine addiction, nicotine dependence or smoking cessation treatments. In certain embodiments, the nicotine addiction, nicotine dependence or smoking cessation treatment is selected from NRT, administration of bupropion, administration of varenicline, electronic cigarettes, steam smoking and combinations thereof. In some embodiments, the subject (a) smokes ten or more cigarettes per day before administering cytisine, (b) the CO concentration in the exhaled air before administering cytisine is about 10 ppm or higher, or (c) a combination of (a) and (b). In some embodiments, the method further comprises providing behavioral support to the subject.

[0180] The present disclosure also provides a drug, such as a drug comprising a unit dose of 3.0 mg, 1.5 mg or 1.0 mg of cytisine, for treating nicotine addiction, nicotine dependence, promoting a subject in need to quit smoking and / or vaping, and / or promoting a subject in need to reduce smoking and / or vaping, wherein the drug is for oral administration to the subject three times a day, and wherein the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse event is 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 cytisine treatment.

[0181] The present disclosure also provides a medicament, such as a medicament comprising a unit dose of 3.0 mg, 1.5 mg or 1.0 mg of cytisine, for treating nicotine addiction, nicotine dependence, promoting a subject in need to quit smoking and / or vaping, and / or promoting a subject in need to reduce smoking and / or vaping, and wherein the cytisine is administered for about 6 weeks or for about 12 weeks. In some embodiments, the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0182] In some embodiments, the present disclosure further provides a medicament comprising a unit dose of 3.0 mg, 1.5 mg or 1.0 mg of cytisine, the medicament being used to treat nicotine addiction, nicotine dependence in a subject in need, promoting a subject in need to quit smoking and / or vaping, and / or promoting a subject in need to reduce smoking and / or vaping, and wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation treatments. In certain embodiments, the nicotine addiction or smoking cessation treatment is selected from NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and combinations thereof.

[0183] In some embodiments, the present disclosure further provides a medicament comprising a unit dose of 3.0 mg, 1.5 mg or 1.0 mg of cytisine, the medicament being used to treat nicotine addiction, nicotine dependence, promoting a subject in need thereof to quit smoking and / or vaping, and / or promoting a subject in need thereof to reduce smoking and / or vaping, and wherein the subject (a) smokes ten or more cigarettes per day before the administration of cytisine, (b) has a CO concentration of about 10 ppm or more in the exhaled air before the administration of cytisine, or (c) a combination of (a) and (b).

[0184] The present disclosure further provides a drug, such as a drug including cytisine for treating nicotine addiction or nicotine dependence in a subject, the subject being a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments, wherein the drug is for oral administration to the subject three times a day. In some embodiments, the nicotine addiction or nicotine dependence treatment includes NRT, administration of bupropion, administration of varenicline, electronic cigarettes, steam smoking, or a combination thereof. In some embodiments, cytisine is provided to a subject in need at a unit dose of about 1.0 mg to about 6.0 mg cytisine three to six times a day. In certain embodiments, cytisine is provided to a subject in need three times a day at a unit dose of 3.0 mg cytisine. In some embodiments, the unit dose of cytisine includes: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments, the administration of cytisine lasts for about 6 weeks or for about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of: URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation. In some embodiments, the subject (a) smokes ten or more cigarettes per day before the administration of cytisine, (b) the CO concentration in the exhaled air before the administration of cytisine is about 10 ppm or higher, or (c) a combination of (a) and (b).

[0185] In some embodiments, the drug comprises a unit dose of cytisine in the form of: (a) two tablets, each containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine, the drug is used to prevent relapse of smoking and / or vaping in subjects in need, and wherein the drug is used to be orally administered to the subject three times a day. In certain embodiments, cytisine is administered for about 6 weeks or for about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of: URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation. In some embodiments, the subject (a) smokes ten or more cigarettes a day before the administration of cytisine, (b) the CO concentration in the exhaled air before the administration of cytisine is about 10 ppm or higher, or (c) a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapies include NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof.

[0186] The present disclosure further provides a medicament, such as a medicament comprising cytisine for preventing a subject from relapsing to smoking and / or vaping, the subject being a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments, the one or more nicotine addiction treatments being selected from the group consisting of NRT, administration of bupropion, administration of varenicline, electronic cigarettes, or vaping, wherein the medicament is for oral administration to the subject three times daily. In some embodiments, the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has a CO concentration of about 10 ppm or more in exhaled air prior to administration of cytisine, or (c) a combination of (a) and (b). In some embodiments, the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine, and wherein the cytisine is administered for about 6 weeks or for about 12 weeks. In some embodiments, the subject does not experience an adverse event selected from the group consisting of: URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation after receiving cytisine treatment.

[0187] In some embodiments, the present disclosure provides a unit dose of 3.0 mg, 1.5 mg or 1.0 mg of cytisine for treating nicotine addiction, nicotine dependence in a subject in need, promoting a subject in need to quit smoking and / or vaping, and / or promoting a subject in need to reduce smoking and / or vaping, wherein the cytisine is used for oral administration to the subject three times a day. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the 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 cytisine treatment. In some embodiments, the administration of cytisine continues for about 6 weeks or continues for about 12 weeks. In some embodiments, the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments, the subject is a refractory patient who has failed treatment with one or more nicotine addiction, nicotine dependence or smoking cessation treatments. In certain embodiments, the nicotine addiction, nicotine dependence or smoking cessation treatment is selected from NRT, administration of bupropion, administration of varenicline, electronic cigarettes, steam smoking and combinations thereof. In some embodiments, the subject (a) smokes ten or more cigarettes per day before administering cytisine, (b) the CO concentration in the exhaled air before administering cytisine is about 10 ppm or higher, or (c) a combination of (a) and (b). In some embodiments, the use further comprises providing behavioral support to the subject.

[0188] The present disclosure further provides the use of cytisine, which is used to treat nicotine addiction or nicotine dependence in a subject, such as a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments, wherein the cytisine is used to be orally administered to the subject three times a day. In certain embodiments, the nicotine addiction or nicotine dependence treatment includes NRT, administration of bupropion, administration of varenicline, electronic cigarettes, steam smoking, or a combination thereof. In some embodiments, cytisine is provided to a subject in need at a unit dose of about 1.0 mg to about 6.0 mg cytisine three to six times a day. In certain embodiments, cytisine is provided to a subject in need three times a day at a unit dose of 3.0 mg cytisine. In certain embodiments, the unit dose of cytisine includes: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments, the administration of cytisine lasts for about 6 weeks or for about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of: URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation. In some embodiments, the subject (a) smokes ten or more cigarettes per day before the administration of cytisine, (b) the CO concentration in the exhaled air before the administration of cytisine is about 10 ppm or higher, or (c) a combination of (a) and (b).

[0189] In some embodiments, the use of a unit dose of cytisine in the form of the following comprises preventing a subject in need from relapsing from smoking: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine, wherein the cytisine is used for oral administration to the subject three times a day. In some embodiments, cytisine is administered for about 6 weeks or for about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of: URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject (a) smokes ten or more cigarettes a day before the administration of cytisine, (b) the CO concentration in the exhaled air before the administration of cytisine is about 10 ppm or higher, or (c) a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation treatments. In certain embodiments, the smoking cessation therapy comprises NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof.

[0190] In some embodiments, the use of cytisine is used to prevent a subject from relapsing from smoking, the subject is a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments, the one or more nicotine addiction treatments being selected from the group consisting of: NRT, administration of bupropion, administration of varenicline, electronic cigarettes or smoking steam, wherein the drug is for oral administration to the subject three times a day. In some embodiments, the subject (a) smokes ten or more cigarettes a day before the administration of cytisine, (b) the CO concentration in the exhaled air before the administration of cytisine is about 10 ppm or higher, or (c) a combination of (a) and (b). In certain embodiments, the unit dose of cytisine includes: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine, and wherein the administration of cytisine continues for about 6 weeks or continues for about 12 weeks. In some embodiments, the subject does not experience an adverse event selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving cytisine treatment.

[0191] The present disclosure further provides the use of a tablet comprising about 1.0 mg or 1.5 mg of cytisine, which is used to orally administer about 3.0 mg of cytisine to a subject three times daily to treat nicotine addiction, nicotine dependence, promote the subject to quit smoking and / or vaping, and / or promote the subject to reduce smoking and / or vaping. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the 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 cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or for about 12 weeks. In some embodiments, the unit dose of cytisine includes: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments, the subject is a refractory patient who has failed treatment with one or more nicotine addiction, nicotine dependence or smoking cessation treatments. In certain embodiments, the nicotine addiction, nicotine dependence or smoking cessation treatment is selected from NRT, administration of bupropion, administration of varenicline, electronic cigarettes, steam cigarettes and combinations thereof. In some embodiments, the subject (a) smokes ten or more cigarettes per day before the administration of cytisine, (b) the CO concentration in the exhaled air before the administration of cytisine is about 10 ppm or higher, or (c) a combination of (a) and (b). In some embodiments, the use further comprises providing behavioral support to the subject.

[0192] In some embodiments, the use of a tablet comprising about 1.0 mg or 1.5 mg of cytisine is for orally administering about 3.0 mg of cytisine to a subject three times daily to treat the subject's nicotine addiction or nicotine dependence, and the subject is a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments. In certain embodiments, the nicotine addiction or nicotine dependence treatment includes NRT, administration of bupropion, administration of varenicline, electronic cigarettes, steam smoking, or a combination thereof. In some embodiments, cytisine is provided to a subject in need three to six times a day at a unit dose of about 1.0 mg to about 6.0 mg of cytisine. In certain embodiments, cytisine is provided to a subject in need three times a day at a unit dose of 3.0 mg of cytisine. In some embodiments, the unit dose of cytisine comprises: (a) two tablets, each containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine. In some embodiments, cytisine is administered for about 6 weeks or for about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of: URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation. In some embodiments, the subject (a) smokes ten or more cigarettes a day before administering cytisine, (b) the CO concentration in the exhaled air before administering cytisine is about 10 ppm or higher, or (c) a combination of (a) and (b).

[0193] In some embodiments, the use of a tablet comprising about 1.0 mg or about 1.5 mg of cytisine is for oral administration of about 3.0 mg of cytisine to a subject three times daily to prevent the subject from smoking and / or relapse of smoking vaping. In certain embodiments, the cytisine is applied for about 6 weeks or for about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of: URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation. In some embodiments, the subject (a) smokes ten or more cigarettes a day before applying cytisine, (b) the CO concentration in the exhaled air before applying cytisine is about 10 ppm or higher, or (c) (a) and (b) combination. In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation treatments. In certain embodiments, the smoking cessation treatment includes NRT, application of bupropion, application of varenicline, electronic cigarettes, smoking vaping or a combination thereof.

[0194] In some embodiments, the use of a tablet comprising about 1.0 mg or about 1.5 mg of cytisine is for orally administering about 3.0 mg of cytisine to a subject three times daily to prevent the subject from relapsing to smoking, wherein the subject is a subject who has failed treatment with one or more nicotine addiction or nicotine dependence treatments, wherein the one or more nicotine addiction treatments are selected from the group consisting of: NRT, administration of bupropion, administration of varenicline, electronic cigarettes, or vaping. In some embodiments, the subject (a) smokes ten or more cigarettes per day before the administration of cytisine, (b) has a CO concentration of about 10 ppm or more in the exhaled air before the administration of cytisine, or (c) a combination of (a) and (b). In some embodiments, the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine, and wherein the cytisine is administered for about 6 weeks or for about 12 weeks. In some embodiments, the subject does not experience an adverse event selected from the group consisting of: URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation after receiving cytisine treatment.

[0195] Therefore, on the other hand, there is provided herein a method for treating nicotine addiction or nicotine dependence in a subject, the method comprising administering cytisine to a subject in need, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments. A suitable unit dose comprises a dose between about 1.0 mg and about 6 mg, which can be administered three to six times a day, for example, at approximately equal intervals. For example, in some embodiments, the method comprises administering cytisine provided in a unit dose of 3.0 mg cytisine to a refractory patient three times a day. Any suitable duration of administration can be used in the methods 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.

[0196] In some embodiments, the methods disclosed herein may further include providing behavioral support to the subject, e.g., a refractory patient. The behavioral support may include counseling, which may further include, but is not limited to, topics such as withdrawal, past quitting experiences, anticipating triggers or challenges in upcoming attempts, alcohol use, proximity to other nicotine users (e.g., smokers, vapers) and approximately the same frequency as other nicotine users, identifying risky situations, and developing coping skills.

[0197] In some embodiments, the methods disclosed herein may further include providing the subject with one or more questionnaires. Non-limiting examples of the one or more questionnaires include an e-cigarette dependence scale questionnaire, a nicotine dependence questionnaire, a The present invention relates to a method for the treatment of nicotine withdrawal, wherein the subject is provided with a questionnaire survey. The method comprises the following steps: (i) a questionnaire survey of the nicotine withdrawal scale (MNWS), ...

[0198] The cited patents, patent applications and scientific literature mentioned herein are hereby incorporated by reference in their entirety, as if each individual publication, patent or patent application was specifically and individually indicated as being incorporated by reference. Any conflict between any reference cited herein and the specific teachings of this specification sheet should be resolved in a manner that is favorable to the latter. Similarly, any conflict between the definition of a word or phrase understood in the art and the definition of a word or phrase specifically taught in this specification sheet should be resolved in a manner that is favorable to the latter.

[0199] As can be understood from the above disclosure, the present invention has various applications.The present invention is further illustrated by the following examples, which are merely illustrative and are not intended to limit the definition and scope of the present invention in any way.

[0200] Example 1: Effect of Cytisine on the Treatment of Nicotine Addiction

[0201] This is a six-group, multicenter, double-blind, randomly assigned, placebo-controlled study performed in male or female adults aged ≥18 years, smoking 10+ cigarettes per day and willing to set a quit date 5-7 days after randomization. This study was designed to evaluate the effectiveness of 1.5 mg of cytisine against placebo using a commercial titration schedule approved in Central and Eastern Europe. The study also evaluated the effectiveness of a simplified TID dosing schedule of 1.5 mg and a 3.0 mg increase in dose (using a commercial titration (COM) and a simplified TID dosing schedule). The overall goal of the study was to obtain estimates of the effect size of efficacy and safety endpoints, which will be used to provide information for the design of future Phase 3 studies.

[0202] The dosing regimen of the study was Figure 1The study was double-blind with respect to dose, but not with respect to schedule of administration, and the study groups were Figure 2 Study treatment was started the day after randomization, allowing study treatment to be initiated before the quit date, as shown in Figure 3 shown.

[0203] The primary efficacy endpoint of this study was the percent reduction in the number of cigarettes smoked during the treatment period, which was calculated as follows:

[0204]

[0205] Where N = total number of cigarettes smoked, B = number of cigarettes smoked at baseline, and D = number of days.

[0206] The secondary efficacy endpoint was smoking cessation rate (confirmed by CO < 10 ppm) and included analyses at Week 4 (ie, end of treatment) and sustained (4 weeks) abstinence (ie, weaning from treatment) from Weeks 5 to 8.

[0207] Subject demographics Figure 4 The number of cigarettes smoked by the subjects before and after treatment was summarized in Figure 5 Shown in.

[0208] 1.1 Results

[0209] Table 1 summarizes the demographics of the subjects. In total, 254 male or female adults aged ≥18 years who smoked ≥10 cigarettes per day and were willing to set a quit date of 5 to 7 days after randomization were enrolled in the study. The demographic and baseline characteristics were generally well balanced across schedules and treatment groups.

[0210] Table 1: Subject Demographics

[0211]

[0212] In the study population, 53% were female and 47% were male. 79% of the study population were white, 18% were black, and 3% were other races. The smoking diary compliance that the primary analysis was based on was high in all treatment groups. Study drug compliance was >94% in all treatment groups, with slightly higher compliance (>98%) for the TID schedule. The average treatment duration was 23.4 days, and 96.6% of the subjects received the average dose of cytisine.

[0213] Table 2 summarizes the smoking history of the subjects in all treatment groups. Overall, the study population represented highly addicted smokers who were on average 48.4 years old and had smoked for 32 years, meaning that most of the population had started smoking during their teenage years. In addition, these individuals had an average of 4.5 previous quit attempts, with the last quit attempt being approximately 3.7 years before study entry, and currently smoked an average of one pack of cigarettes per day. In previous quit attempts, 35% of the subjects had previously received varenicline, 16% of the subjects had received bupropion, and 48% of the subjects had received NRT.

[0214] Table 2: Smoking history of subjects

[0215]

[0216] Analysis from the international EAGLES trial clearly demonstrates that smoking at a younger age and being of U.S. origin are associated with lower success rates in quitting. The lower success rates among U.S. smokers support the view that smokers in the U.S. may have reached a point in the tobacco epidemic where those who continue to smoke, despite strong cultural pressures to do otherwise, have special characteristics that make it more difficult to stop smoking.

[0217] Overall, study medication compliance was high in all treatment groups, with the TID schedule (98.18%) being superior to the commercial schedule (94.90%). More specifically, study medication compliance for all treatment groups is summarized in Table 3. Study medication compliance ranged from 96.7% to 99.5% in the TID group, while study medication compliance ranged from 94.2% to 96.4% in the COM group.

[0218] Table 3: Study drug compliance

[0219]

[0220]

[0221] *Defined as [(# of prescribed doses - # of missed doses) / # of prescribed doses] X 100.

[0222] The reduction in cigarettes smoked in all treatment groups was Figure 6The results from the preliminary analysis showed that the percentage of cigarettes smoked (cigarette score) expected in both COM groups was significantly reduced. When the placebo groups were combined, the cigarette score was significantly reduced in both COM groups - the 1.5 mg TID group, and approached significance in the 3.0 mg TID group. Subjects treated with 1.5 mg or 3.0 mg of cytisine using the COM schedule smoked approximately 14% to 16% fewer cigarettes than expected for placebo. Subjects treated with 1.5 mg or 3.0 mg of cytisine on a TID schedule smoked approximately 9% to 12% fewer cigarettes than expected for the placebo group.

[0223] Table 4: Cigarettes smoked and CO reduction

[0224] Fewer cigarettes smoked p-value CO reduction Titration 1.5 80％ 0.001 78％ 3.0 78％ 0.003 71％ Placebo 62％ 40％ TID 1.5 79％ 0.009 71％ 3.0 74％ 0.052 80％ Placebo 62％ 29％

[0225] Although the reductions on the TID schedule were not as high as those seen on the COM schedule, it should be noted that subjects in the placebo group on the TID schedule reported a greater reduction in cigarettes smoked than subjects in the placebo group on the COM schedule. TID placebo subjects smoked only one-third of the cigarettes they would normally smoke (LS mean: 35.30%), while COM placebo subjects smoked only half of the cigarettes (LS mean: 47.10%), which may have masked the effects of cytisine treatment on the TID schedule.

[0226] Exhaled CO levels were also measured during this study as an objective biochemical marker of smoking reduction. The reduction in CO in all treatment groups was Figure 6 The results are shown in Table 4 and summarized in Table 4. In all cytisine-treated groups, the reduction in CO (55% to 62% reduction) was consistent with the reduction in reported cigarettes smoked (e.g., ranging from 25% to 32% as the cigarette score indicated a 75% to 68% reduction in cigarettes smoked). In contrast, in the placebo-treated group, the reduction in the number of reported cigarettes smoked (e.g., 41% as the cigarette score indicated a 59% reduction in cigarettes smoked) was not paralleled by a corresponding reduction in CO of only 29%. A similar pattern was observed for plasma cotinine levels, with a greater reduction in cotinine levels in the cytisine groups than in the placebo group.

[0227] Changes in these objective markers suggest that, in general, placebo-treated subjects over-reported that they smoked fewer cigarettes. This also suggests that the actual differences in cigarette scores between subjects treated with cytisine and those treated with placebo were greater than those actually observed.

[0228] The smoking cessation rate in the TID schedule group was Figure 7 and 8The results of the initial quit rates at week 4 showed that both groups of the TID schedule had a high chance of successfully quitting smoking compared to placebo; the best chance of success in quitting smoking in the 3.0 mg cytisine group was: OR: 6.31 (95% CI: 2.28, 18.45). The OR for the 1.5 mg cytisine group on the TID schedule was 5.81 (95% CI: 2.12, 16.87). In the COM schedule, the ORs for the 1.5 and 3.0 mg cytisine groups were 5.59 (95% CI: 2.03, 16.29) and 5.38 (95% CI: 1.95, 15.72), respectively.

[0229] Table 5: Smoking cessation rates - Cytisine versus placebo

[0230]

[0231] refer to Figure 7 and 8 As shown in Table 5, for the extended abstinence from the 5th week to the 8th week endpoint, the two groups of the TID schedule had a higher success rate of abstinence than placebo; subjects in the 3.0 mg cytisine group had the best success rate of abstinence from the 5th week to the 8th week, with an OR of 5.04 (95% CI: 1.42, 22.32). The OR of the 1.5 mg cytisine group on the TID schedule was 4.33 (95% CI: 1.21, 19.30). In the COM schedule, the ORs of the 1.5 mg cytisine and 3.0 mg groups were 3.23 (95% CI: 0.86, 14.85) and 2.24 (95% CI: 0.55, 10.82), respectively.

[0232] Table 6 summarizes the comparison of exhaled CO levels and smoking cessation rates in the cytisine 3.0 mg group versus placebo at Week 4 and Weeks 5 to 8.

[0233] Table 6: Reduction in smoking cessation rates with CO 3 mg TID versus placebo

[0234]

[0235]

[0236] Subjects in the cytisine group on the TID schedule had higher odds of smoking abstinence at the 6-week, 7-week, and 8-week time points compared to the corresponding group of placebo subjects on the COM schedule, as demonstrated by higher ORs at each time point.

[0237] 1.2 Sensitivity Targets and General Approach

[0238] Sensitivity analyses were performed on the primary outcome (cigarette score) and the main secondary abstinence outcome. The main secondary abstinence outcomes were initial abstinence rate at week 4 and 4 weeks of abstinence confirmed by exhaled CO <10 ppm from week 5 to week 8, designated as Cess / W5-8 / CO success. The objectives were to assess the robustness of the findings from the trial and to perform alternative analyses that might confirm the observed results or challenge the conclusions of the trial.

[0239] Other outcomes related to objective biochemical assessments were also analyzed. The associations between these biochemical assessments are particularly important when used as part of the definition of smoking cessation and abstinence, but are also important due to the lack of subjectivity of the assessments.

[0240] These sensitivity analyses in this report focus on the comparison of the 3.0 mg cytisine TID group with the pooled placebo (0 mg cytisine) group. Some analyses will show other comparisons for comparison.

[0241] Modification Effect Analysis Method

[0242] A common method for evaluating the robustness, consistency, and significance of the results from a trial is to perform an effect modifier analysis (EMA). The goal of EMA is to evaluate the extent to which the group effects estimated for discrete values ​​of a baseline attribute are different. For example, the EMA for gender estimates the gender-specific group effects and evaluates whether these estimates are different. If the baseline attribute to be evaluated using EMA is not discrete, the attribute is discrete by specifying a cutoff based on an external standard or by using percentiles calculated from the merged data (median, tertiles, or quartiles). For example, the baseline CO level is divided when it is less than or not less than 10 ppm or using the merged quartile values.

[0243] EMA fits a statistical model to the data. The EMA model has an interaction term that is used to detect the presence of differences in group effects between discrete factor values. Heterogeneity of effect estimates is detected when an interaction term substantially improves the fit of the model over a model without the interaction term. The improvement in fit by the interaction term is measured by the interaction P value, where small P values, typically less than 0.10, indicate an improvement in fit.

[0244] There are two types of interactions: qualitative and quantitative. Quantitative interactions exist when the direction of the group effect estimate is the same for all discrete values ​​of the factor. Qualitative interactions exist when the directions of the effects for the values ​​of the factor are mixed.

[0245] The results of the multiple EMAs performed in this study are compactly displayed as forest plots, which show the frequencies (distributions between groups), effect estimates, and applicable confidence intervals associated with subsets of each factor value. The EMA forest plot provides a gestalt about the stability of the overall effect estimates of the factors included in the plot. The full EMA forest plot also shows quantitative assessments of heterogeneity from the EMA model, such as interaction P values, for each factor. In addition, the group effect estimates and confidence intervals for each value of the factor are displayed in the forest plot. (Such forest plots appear later.)

[0246] Justification for the combined control group

[0247] Between-group comparisons are pairwise comparisons of each active group with the pooled placebo group. The justification for comparisons with the pooled placebo is based on:

[0248] ●For stratified between-control comparisons of cigarette scores, week 4, and Cess / W5-8 / CO success outcomes, there was no evidence that the two placebo groups differed with respect to the primary or two secondary outcomes at P values ​​of 0.1197, 0.9963, and 0.9996, respectively.

[0249] • There was no evidence that random assignment between placebo groups differed with respect to any of the baseline attributes, including clinical site, used as factors in the subsequently proposed EMAs.

[0250] For the purposes of sensitivity assessment, this absence of evidence of a difference in the placebo group was considered to justify pooling where the benefit was increased statistical sensitivity.

[0251] Descriptive graph of the average number of cigarettes reported per day

[0252] A longitudinal graph of the mean number of cigarettes smoked per study treatment day (Days 1-25 after randomization) reported in the diary is presented below. Each group and the combined placebo group are shown in a different color or dashed versus solid lines. Figure 5 It was demonstrated that, each day, subjects did reduce the daily number of cigarettes smoked in their quit attempts through the planned quit interval (Day 5-Day 7), with abstinence achieved by Day 8.

[0253] 1.3 Biochemical validation analysis

[0254] Below are two longitudinal graphs showing visit means and 95% confidence intervals for CO and cotinine for the combined placebo and cytisine-treated groups, respectively.

[0255] CO levels (ppm) were assessed at screening, baseline, end of study treatment intervention (week 4), and weekly through week 8 during the study ( Fig. 9). The CO mean values ​​for the screening and baseline visits were approximately equal for all groups. At week 4, a significant reduction in CO levels was observed for all subjects treated in the cytisine-treated group, regardless of schedule. During the follow-up period from week 4 to week 8 (with behavioral support only), the CO mean values ​​for the combined placebo groups were approximately constant, but somewhat lower than the mean values ​​before the start of the study treatment intervention. For all follow-up visits, the mean values ​​for the active treatment groups remained significantly lower than the combined placebo groups, but the mean values ​​showed a slight upward trend.

[0256] Serum cotinine levels were exploratory and assessed only at screening, week 4, and week 8. Cotinine results reported as <10 ng / mL were converted to 0 ng / mL prior to statistical analysis. Fig.10 The cotinine graph in shows the same pattern as observed for CO. All subjects in the cytisine-treated group had a substantial decrease in cotinine levels at week 4 and showed a slight upward trend by week 8.

[0257] 1.4 Cigarette Rating Analysis

[0258] and model stratification and covariate assumptions

[0259] The primary model of cigarette score comprises the covariate of BMI stratification (3 grades) and the average number of cigarettes reported by screening diary. The validity of the conclusion of the result from the primary model depends on the absence of interaction between each covariate and the group variable in these covariates. If one or two interactions in these interactions are substantial in the statistical model, the magnitude of the estimated group effect will be a function of the average number of cigarettes reported by BMI grade and / or screening diary.

[0260] The planned statistical analyses of the primary endpoints were performed, and as part of these analyses, each of the cytisine treatment groups was compared to the pooled placebo group for the primary efficacy endpoint (cigarette score). These analyses were performed using a randomized controlled trial with treatment groups and BMI (18.5 to <25 kg / m 2 ; 25 to <30 kg / m 2 ; 30 to <35 kg / m 2 ) with the covariate of baseline cigarette count. The analysis used a BMI variable derived from the subject's actual BMI and omitted one subject (104-144) because the subject's BMI (39.9 kg / m 2 ) is greater than the upper limit of the highest BMI category (30 to <35 kg / m 2 ).

[0261] As part of the sensitivity analysis, two variations of this analysis were performed. These variations were:

[0262] A BMI variable derived from the subject's actual BMI was used, but the model included all 254 subjects in all randomized sets. The BMI categories used in this analysis were: 18.5 to <25 kg / m 2 ; 25 to <30 kg / m 2 ; 30 to <35 kg / m 2 and ≥35 kg / m 2 .

[0263] ● Model using BMI stratification variable at randomization. Subjects 104-144 were included in this analysis within the BMI strata reported at randomization (30 to <35 kg / m 2 ). Therefore, this analysis included all 254 subjects in all randomized sets. The BMI categories used in this analysis were: 18.5 to <25 kg / m 2 ; 25 to <30 kg / m 2 ; and 30 to <35 kg / m 2 .

[0264] Figures 11A-11B Comparisons between the homogeneity of each group (COM 0 mg vs. TID 0 mg, and between TID 0 mg vs. TID 3.0) as a factor of the percentage of cigarettes smoked as intended (cigarette score) are shown.

[0265] Fig.16 and Fig.17 An additional assessment of the interaction between BMI and mean number of cigarettes smoked at baseline was performed for the 3.0 mg TID group compared with the pooled placebo groups.

[0266] For BMI, this assessment of the presence of an interaction with group is evaluated as an EMA using BMI as a factor, where the size of the interaction P will provide information on the presence of this interaction ( Fig.16 ). The EMA interaction P value for BMI was 0.1303, which is not small enough to cause concern, but based on the stratum-specific effect size estimates, it may be possible that efficacy is higher in patients with high BMI compared with subjects with lower BMI.

[0267] Evidence for interaction between group and baseline average number of cigarettes (model covariate) was assessed by the parallelism between the groups in the linear relationship between cigarette rating and baseline average number of cigarettes. Fig.17 ) has a P value of 0.2754 for this assessment of parallelism, providing no evidence that parallelism does not exist.

[0268] Analysis of ratings of alternative cigarettes

[0269] The primary outcome was based on the number of cigarettes smoked per day according to the diary. The cigarette score used the diary data for the planned 25 days of study treatment. A sensitivity analysis related to the changes in the primary analysis of the cigarette score was proposed for the comparison of the 3.0 mg TID group with the pooled placebo group. The alternative definition of the cigarette score was characterized by the number of cigarettes recorded in the diary after the planned 5-7 day abstinence period, i.e., starting from day 8, rather than from day 1.

[0270] An alternative analysis was based on reanalysis of the primary cigarette score and the above alternative cigarette score, with weights related to the standard error of the mean number of cigarettes estimated from the diary entries. The weight used for each subject was 1 / (SE) 2 , where SE is the standard error of the mean estimate, and a type of weighting known as inverse variance weighting is often used. This weighting gives more weight to means estimated with smaller SEs. However, a small modification to the definition of this weighting is required. In calculating 1 / (SE) 2 When SE = 0, specific rules are used, specifically when all diary entry values ​​are equal. In these cases, SE is calculated as if one and only one of the recorded values ​​were greater than one. It can be shown that when the data are modified in this way, SE = 1 / N, where N is the number of daily (day) entries by the subject.

[0271] Table 7 shows the P values ​​and effect estimates and 95% confidence intervals for the four analyses described for the comparison of the 3.0 mg TID group with the combined placebo group. When the diary data starts on the 8th day instead of the 1st day, the effect estimate is more favorable to some extent (-11.8 to -9.5 for the primary cigarette score, respectively) because the smoking data before the planned quitting day is excluded. Compared to 0.0675 for the unweighted analysis of the primary cigarette score, the effect estimate P value is 0.0466 for the analysis in which weighting is applied to the primary cigarette score. This is because the diary data before the planned quitting day (before the 8th day) and subsequent smoking cessation lead to greater SE, thereby reducing the weight of the quitters. This reduction in weight is not applicable to the redefined cigarette score using the diary data starting on the 8th day, and therefore, compared with the unweighted primary cigarette score starting from the 1st day, the weighted effect size of the redefined cigarette score is significantly more favorable (-15.0 to -9.5, respectively).

[0272] Table 7: P values ​​and effect estimates

[0273]

[0274]

[0275] The analysis of whether there was evidence of heterogeneity of effect across the 8 clinical sites (subject sources) was performed as an EMA, with the interaction P value providing a measure of heterogeneity of effect. This analysis was performed for the cigarette score primary outcome variables and Cess / W5-8 / CO success. For cigarette score, the EMA model had additional covariates stratified by BMI and the average number of cigarettes reported by the screening diary. For Cess / W5-8 / CO success, covariates were not added to the EMA model due to the possibility of empty cells in the cross-classification of discrete variables for binary outcomes, groups, and clinical sites. For example, there are cases where a particular clinical site does not have subjects who are successful in one or both groups.

[0276] Figure 18-25 Results of EMA analyses for each of the four comparisons of the active cytisine groups with the pooled placebo groups and for the two outcome variables are presented. No evidence of heterogeneity of effect due to clinical site was found from any of these EMAs, that is, the interaction P values ​​were not small enough to raise concerns about heterogeneity due to clinical site.

[0277] 1.5 Cytisine and Comparison of smoking cessation rates

[0278] Fig.12 Table 8 shows the methods for preparing cytisine (cytisine) and A comparative study design was performed. The duration of treatment with cytisine (12 weeks) was approximately 3.5 times longer than that with cytisine (25 days). The sustained abstinence time point for cytisine (12 weeks measured after the last 4 weeks of treatment) was longer than that for cytisine (8 weeks measured after the end of treatment within 4 weeks). Table 8 contains the data for the sustained abstinence time points for cytisine and Additional details of the experiment.

[0279] Table 8: For the reaction of cytisine with Details of the studies compared

[0280]

[0281]

[0282] Fig.13 showed that at 4 and 12 weeks of treatment, 3.0 mg of cytisine was significantly lower than 3.0 mg of The CO-confirmed smoking cessation rate among Data are 7-day point prevalence for cytisine and 1-day point prevalence for cytisine. At the end of treatment, the CO-confirmed end-of-treatment abstinence rate for subjects treated with 3.0 mg of cytisine exceeded that for subjects treated with 3.0 mg of The abstinence rate of treated subjects. In comparison, cytisine is more effective.

[0283] Fig.14 Tables 9-11 show the relationship between cytisine and The odds ratio of cytisine and had similar odds ratios and efficacy. Although the 95% CIs for the two treatments overlapped, the odds ratios for cytisine treatment were consistently superior to

[0284] Table 9: Cytisine and The odds ratio

[0285]

[0286] Table 10: Cytisine and The odds ratio

[0287]

[0288] Table 11: Cytisine and The odds ratio

[0289]

[0290] Table 12 shows the most recent EAGLES study published in 2018 comparing smoking cessation rates in the United States with those in non-US regions. This study showed that smoking cessation rates in the United States were significantly lower than those in non-US regions. The overall quit rate of 22% at 24 weeks for subjects treated with TRAIL-T was only 16% for U.S. patients (N=1065). The quit rate was significantly lower than that of the previous All trials were US-based. The 24-week abstinence rate in the EAGLES study was lower than the 52-week abstinence rate in the pivotal trial. Poor abstinence outcomes were associated with younger age of initiation and US origin.

[0291] Table 12: Smoking cessation rates in the United States versus non-U.S.

[0292]

[0293] Fig.15 The odds ratios for cytisine compared with existing products are shown at 4 weeks, end of treatment, and 4 weeks off treatment. Although the 94% CIs for treatment overlapped slightly, the odds ratios for cytisine treatment were consistently superior to NRT,

[0294] 1.6 Analysis of baseline attributes and smoking status

[0295] Effect Modification Analyses of Baseline Patient Attributes

[0296] A range of baseline attributes including age, race, sex, smoking duration, and number of quit attempts were analyzed for both the primary outcome variables of cigarette score and Cess / W5-8 / CO success ( Fig.26 and 27 ). Only the comparison between the cytisine 3.0 mg TID group and the pooled placebo group is presented. The same EMA model used for the analysis of clinical sites was used. The forest plots for these analyses are as follows. (Note: In these forest plots, (M), (T), or (Q) at the end of the factor label indicates that the pooled data were divided into medians, tertiles, or quartiles, respectively. Hx means "historical.")

[0297] The only notable interaction P value was the duration of smoking history divided by the quartiles of cigarette scores ("Smoking Hx Dur(y)(Q)"), with P = 0.0800. Since the 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 about heterogeneity of effect.

[0298] Effect modification analysis of anti-smoking intervention history

[0299] The cytisine 3.0 mg TID group was compared with the pooled placebo group for the primary outcome variables of cigarette score and Cess / W5-8 / CO success to account for previous anti-smoking interventions ( Fig.28 and 29 ). The factors analyzed included: whether there were more than 2 anti-smoking intervention attempts and whether the Treatment or recent treatment with any of vaping or nicotine replacement therapy. The same EMA model used for the analysis of clinical settings was performed. Forest plots for these analyses are shown below.

[0300] The only notable interaction P value was for the cigarette score. (“ Hx”) with a history of previous use, where P = 0.0508. However, As a recent intervention (“ The P value for the interaction with the factor variable for the most recent (“recent”) does not indicate concern (P = 0.3179). Since the interaction appears quantitative and the findings for the most recent use are inconsistent, Concerns as an effect modifier are reduced.

[0301] Effect modification analysis of baseline laboratory markers associated with smoking

[0302] Baseline laboratory factors were analyzed for the primary outcome variables of cigarette score and Cess / W5-8 / CO success, comparing the cytisine 3.0 mg TID group to the combined placebo group ( Fig.30 and 31 ). These factors included nicotine metabolic rate (NMR), exhaled CO, and serum cotinine, and were analyzed using median, tertiles, and quartiles. The same EMA model used for the analysis of clinical sites was performed. Forest plots for these analyses follow Fig.30 and Fig.31 (Note: In these forest plots, (M), (T), or (Q) at the end of the factor label indicates that the pooled data were divided into medians, tertiles, or quartiles, respectively.)

[0303] For the cigarette score, only the interaction P values ​​for the median and tertile of baseline cotinine, 0.0434 and 0.0652, respectively, met the criteria to indicate effect modification. However, the interaction P values ​​for the secondary outcome of sustained abstinence were 0.2925, 0.3738, and 0.9732 for the median, tertile, and quartile, respectively, which showed no modification of baseline cotinine levels. As 4-week abstinence is planned as the primary outcome of a future phase 3 study, concerns about baseline cotinine acting as an effect modifier are less concerning.

[0304] 1.7 Analysis of critical points in the 5th to 8th week of smoking cessation

[0305] A critical point analysis was successfully performed for Cess / W5-8 / CO for the comparison of cytisine 3.0 mg TID versus the pooled placebo groups and the critical point analysis was Fig.32 . The goal of a tipping point analysis is to assess the extent to which reallocation of cases defined as failures due to insufficient evaluation data will affect the results. The tipping point evaluation reanalyzes the data for all possible reversals of the assignment of failures to successes, with the graph showing which reallocations meet the statistical criteria. The horizontal axis represents the number of possible control group reallocations, and the vertical axis represents the number of possible experimental group reallocations. Each combination of reallocations is reanalyzed to assess whether the statistical criteria are met. The lower left point represents a case that was not reallocated (i.e., the planned analysis). Areas where the reallocations meet the statistical criteria are patterned, while areas where the reallocations do not meet the statistical criteria are gray.

[0306] There were 6 control group cases and 3 experimental group cases that qualified as reallocations. The most important finding from this figure is that if there were 0 to 1 reallocations in the experimental group, the statistical criteria were not met when there were 3 or more reallocations in the control group. Similarly, if there were 2 to 3 reallocations in the experimental group, the statistical criteria were not met when there were 5 or more reallocations in the control group. Therefore, the sustained abstinence secondary outcome was robust to reallocations.

[0307] In summary, the results of the initial abstinence rates at week 4 for all cytisine-treated groups showed a significant increase in the initial rate (50% to 54%) compared to the combined placebo (16%), and the OR ranged from 5.38 to 6.31. Extended abstinence from week 5 to week 8 (i.e., 4 weeks of treatment discontinuation) also showed that the extended abstinence rates in the cytisine-treated groups were significantly increased by 16% to 30% compared to 8% for the combined placebo, and the OR ranged from 3.23 to 5.04. Overall, the 3.0 mg TID group had the highest initial and extended abstinence rates, 54% and 30%, respectively, and the maximum ORs were 6.31 and 5.04, respectively.

[0308] Security Analysis

[0309] Overall, there were no safety concerns following dosing of the cytisine 1.5 mg or 3.0 mg treatment groups on both schedules, and no new or unexpected AEs were identified during the study.

[0310] Table 13 summarizes treatment-emergent adverse events (TEAEs). In all treatment groups, approximately half of the study population experienced TEAEs. The TEAEs of the TID dosing schedule were slightly less overall. Across the two schedules, the SOCs with the highest incidence of TEAEs in any treatment group were infections and infestations, mental disorders, and gastrointestinal disorders. Common TEAEs were AEs previously reported in other studies or in the Investigator's Manual. On the commercial schedule, the severity of all TEAEs was mild or moderate, and on the TID schedule, all events except 2 were mild or moderate: one subject experienced severe head injury, and another subject experienced severe influenza conditions. Neither event was considered to be related to the study drug.

[0311] Table 13: Summary of TEAEs in the Study Population

[0312]

[0313]

[0314] *≥5% in any treatment group (3 subjects)

[0315] There were no relevant 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 occurring on the TID schedule.

[0316] Table 14 summarizes the relationship between cytisine and the previous 2016 study. Compared with TEAEs. Less than 30% of the study population treated with cytisine or placebo experienced a TEAE. Subjects treated with cytisine experienced the highest incidence of TEAEs. The incidence of most TEAEs with cytisine treatment was only slightly higher than placebo.

[0317] Table 14: Cytisine and other drugs in the 2016 study Compared to TEAE

[0318]

[0319] Overall, there were no serious or severe adverse events, and the overall incidence of adverse events was low. Results from the study further showed no clinically significant changes in vital signs, routine hematology and / or chemistry, and no changes in ECG. Overall, no new safety signals were observed during the conduct of this study.

[0320] in conclusion

[0321] Results from the study indicate that the benefits of cytisine occur across all baseline characteristics and attributes. Specifically, the benefits of cytisine occur across subject demographics, baseline CO levels, and the number of cigarettes smoked per day, as well as based on smoking history. In terms of subject demographics, the benefits were consistent across subjects regardless of race, gender, age, and BMI. Additionally, in terms of smoking history, the benefits were consistent across subjects regardless of duration of smoking, quit attempts, and prior smoking cessation medication use (e.g., Regardless of their history of NRT, vaping, or smoking, subjects showed the same benefit from the administration of cytisine.

[0322] Results further demonstrated that subjects showed similar benefits when administered cytisine, regardless of their ability to metabolize nicotine. Specifically, no treatment relationship was observed based on subjects' baseline nicotine metabolite ratios, and the benefits of cytisine were similar for both fast and slow nicotine metabolizers.

[0323] Results from the primary analysis showed that the percentage of intended tobacco smoked was reduced in both schedules compared with the pooled placebo. Results for the initial abstinence endpoint showed that the two cytisine groups on the TID schedule had a higher chance of success than placebo; subjects in the cytisine 3.0 mg group had the best chance of quitting smoking at week 4.

[0324] For extended abstinence from the 5th to 8th week endpoint, both groups of the TID schedule had a higher chance of success than placebo; subjects in the 3.0 mg cytisine group had the best chance of abstinence from weeks 5 to 8. The study showed that cytisine is an effective aid to smoking cessation with a favorable adverse event profile, and the 3.0 mg TID dose was more effective overall without an increase in adverse events.

[0325] Overall, there were no safety concerns following dosing in the 1.5 mg or 3.0 mg groups on either schedule.

[0326] Example 2: Effect of sustained treatment with cytisine on smoking cessation

[0327] This example describes a phase 3, multicenter, double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of cytisine in adult smokers. This study was designed to improve efficacy results and determine whether continued treatment can prevent early smoking relapse. The study was designed to evaluate treatment across 3 treatment groups: placebo (A), treatment with cytisine (e.g., cytisine) for 6 weeks (B), and treatment with cytisine for 12 weeks (C), as Fig.33 As shown in the schematic diagram. Subjects were randomly assigned to one of three groups A, B or C. In Group A, subjects were treated with placebo for 12 weeks plus behavioral support. In Group B, subjects were treated with 3.0 mg cytisine TID for 6 weeks, followed by placebo for 6 weeks plus behavioral support. In Group C, subjects were treated with 3.0 mg cytisine TID for 12 weeks plus behavioral support. Cytisine treatment will be evaluated in the study population for 6 or 12 weeks, with the primary efficacy endpoint being 4 weeks of continuous abstinence during treatment, and the cytisine treatment will include a 6-month follow-up period.

[0328] 2.1 Research objectives

[0329] 2.1.1 Common primary efficacy goals

[0330] The study will be based on two comparisons, where study success can be based on success in either comparison, and the common primary efficacy objectives will be the following:

[0331] ● To assess whether subjects randomized to Group B had a higher probability of abstinence from Week 3 to Week 6 after randomization than subjects randomized to Group A; and

[0332] ●To assess whether subjects randomized to Group C have a higher probability of abstinence from Week 9 to Week 12 after randomization than subjects randomized to Group A.

[0333] 2.1.2 Secondary efficacy targets

[0334] If the corresponding primary comparison passes the statistical criteria, analyses of the following secondary objectives will be performed. The secondary efficacy objectives of the study will be the following:

[0335] To assess whether participants randomized to Group B had a higher probability of sustained abstinence from Week 6 to Week 24 after randomization than participants randomized to Group A; and

[0336] ●To assess whether subjects randomized to Group C have a higher probability of sustained abstinence from Week 12 to Week 24 after randomization than subjects randomized to Group A.

[0337] If the co-primary comparison passes statistical criteria, analyses of the following additional secondary objectives will be performed. Additional secondary efficacy objectives for the study will be the following:

[0338] To assess the reduction in risk of relapse from week 6 to week 24 in subjects who received 3.0 mg cytisine for 6 weeks and then continued 3.0 mg cytisine from week 6 to week 12 (Group C) or switched to placebo from week 6 to week 12 (Group B).

[0339] Subjects who were not abstinent at week 6 were considered to have relapsed.

[0340] 2.1.3 Other goals

[0341] Other objectives of this research will be the following:

[0342] ● Compare the groups (Group B vs Group A; Group C vs Group A) with respect to 7-day point prevalent abstinence rates weekly from Weeks 2 to 12 and then at Weeks 16, 20, and 24;

[0343] ● Comparison of the groups (group B vs. group A; group C vs. group A) with respect to serum cotinine levels every other week from week 2 to week 12, and then at weeks 16, 20, and 24;

[0344] ● Comparison of the groups (group B vs group A; group C vs group A) with respect to exhaled CO levels weekly from weeks 2 to 12 and then at weeks 16, 20, and 24;

[0345] ● Comparison of the two groups (Group B vs. Group A; Group C vs. Group A) regarding use of any non-cigarette nicotine product, including vaping, during study treatment weeks 2 to 12 and study follow-up weeks 16 to 24;

[0346] ● To assess whether subjects randomized to Group B had a higher probability of abstinence from Week 9 to Week 12 than subjects randomized to Group A (placebo);

[0347] ● Among the subset of subjects who achieved abstinence from Week 3 to Week 6, to assess whether subjects randomized to Group B had a higher probability of sustained abstinence from Week 3 to Week 24 after randomization than subjects randomized to Group A;

[0348] ● In the subset of subjects who achieved abstinence from Week 9 to Week 12, to assess whether subjects randomized to Group C had a higher probability of sustained abstinence from Week 9 to Week 24 after randomization than subjects randomized to Group A;

[0349] ● Among subjects who achieved abstinence from Week 3 to Week 6, time to failure was compared with time to abstinence between maintenance groups (Group B vs Group A; Group C vs Group A) at Week 24;

[0350] Explore the magnitude of treatment effect between groups across subgroups defined by demographic and baseline characteristics of primary and secondary outcomes; and

[0351] ●Explore potential relationships between subject-reported outcomes (e.g., anxiety, depression, withdrawal symptoms, and tobacco cravings) and primary and secondary outcomes.

[0352] 2.1.4 Security Goals

[0353] The safety objectives of the study will be the following:

[0354] To evaluate the safety profile of cytisine 3.0 mg TID compared with placebo (e.g., Group B vs. Group A and Group C vs. Group A);

[0355] - Compare the safety profile of Group B subjects to Group C subjects with respect to adverse events occurring after Study Week 6.

[0356] 2.2 Study design

[0357] The population for this study will be male or female adults who are daily cigarette smokers, intend to quit smoking, and are willing to set a quit date within 5 to 7 days of treatment initiation. Study treatment will begin the day after randomization.

[0358] Subjects will meet all requirements listed in the inclusion and exclusion criteria. A total of approximately 750 subjects will be randomly assigned to one of three groups with equal probability (Group A, 12 weeks of placebo: N = 250; Group B, 6 weeks of cytisine followed by 6 weeks of placebo: N = 250; Group C, 12 weeks of cytisine: N = 250) as follows Fig.33 shown.

[0359] Each randomized subject will receive 12 weeks of treatment using a TID dosing schedule. Smoking abstinence assessments will begin at Week 2 (Day 14 ± 1 after randomization) and will continue weekly during the treatment period through the follow-up periods of Weeks 16, 20, and 24 by subject self-report of abstinence with biochemical confirmation of CO.

[0360] All subjects will receive concurrent smoking cessation behavioral support during the study treatment period (Week 1 - Week 12). Additional behavioral support will be provided during the follow-up period based on issues, concerns and / or questions raised by the subjects.

[0361] Safety assessments at clinic visits will be performed on Days 2 and 7 of Cycle 1, and then weekly throughout the treatment period. Laboratory hematology and chemistry assessments will be performed at Days 7, Weeks 6, and Weeks 12 (end of treatment "EOT") during the treatment period. Any ongoing adverse events at Week 12 will be followed until resolved or determined to be chronic. The end of the study is defined as the last follow-up visit to the last subject (until the Week 24 visit).

[0362] 2.3 Treatment period

[0363] The treatment period will start the day after randomization. The study treatment will be blinded, and subjects will take one study tablet three times during the day, approximately 5 hours apart. Subjects randomized to Group A will take one placebo tablet per day with each dosing for 12 weeks. Group B subjects will take one cytisine tablet per day with each dosing for the first 6 weeks, and then one placebo tablet per day with each dosing for the last 6 weeks. Group C subjects will take one cytisine tablet per day with each dosing for 12 weeks.

[0364] 2.4. Inclusion criteria

[0365] Subjects who meet all of the following criteria will be eligible to participate in the study:

[0366] ●Male or female subjects aged ≥18 years.

[0367] ●Current daily cigarette smokers (averaging at least 10 cigarettes per day after completing a 7-day screening smoking diary) and smokers who intend to quit smoking.

[0368] ●CO in exhaled air ≥10ppm.

[0369] ●At least one previous failed attempt to stop smoking, with or without treatment support.

[0370] Willing to start study treatment the day after randomization and set a quit date within 5 to 7 days of starting treatment.

[0371] ● Willing to actively participate in the research smoking cessation behavior support provided throughout the study.

[0372] ●Be able to fully understand the study requirements, be willing to participate, and adhere to the dosing schedule.

[0373] ●Sign the informed consent form.

[0374] 2.5. Exclusion criteria

[0375] Subjects will be excluded from participating in the study if any of the following criteria apply:

[0376] ●There is more than 1 study participant in the same household.

[0377] ● Previous cytisine treatment or any other cytisine use in previous clinical studies.

[0378] ●Known hypersensitivity to cytisine or any of the excipients.

[0379] - A positive urine drugs of abuse screen established within 28 days prior to the first dose of cytisine.

[0380] ●Clinically significant abnormal serum chemistry or hematology values ​​within 28 days of randomization (ie, requiring treatment or monitoring).

[0381] ●Presence of clinically significant abnormalities in the 12-lead ECG determined after a minimum of 5 minutes in the supine position within 28 days of randomization (ie, requiring treatment or further evaluation).

[0382] ●BMI categorized as underweight (<18.5 kg / m2) or obese (≥grade 2) (≥35 kg / m2).

[0383] ●Recent (within 3 months) history of acute myocardial infarction, unstable angina, stroke, cerebrovascular event, or hospitalization for congestive heart failure.

[0384] ●Currently, hypertension is not under control (blood pressure ≥160 / 100 mmHg).

[0385] ●A documented diagnosis of schizophrenia or bipolar disorder; current psychosis; suicidal thoughts / risk (yes to question 4 or question 5 OR yes to any suicidal behavior question on the C-SSRS); or current symptoms of moderate to severe depression (HADS score ≥11).

[0386] ● Renal impairment, defined as creatinine clearance (CrCl) < 60 mL / min (estimated using the Cockroft-Gault equation).

[0387] ●Hepatic impairment defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 times the upper limit of normal (ULN).

[0388] ●Pregnant or breastfeeding women.

[0389] ● Male or female subjects with the potential to bear children who do not agree to use an acceptable method of birth control during the study treatment period.

[0390] ● Participated in a clinical study using study drug within 4 weeks prior to randomization.

[0391] ●Treatment with other smoking cessation medications (bupropion, varenicline, nortriptyline, or any nicotine replacement therapy [NRT]) within 4 weeks prior to randomization or planned use of these other smoking cessation medications during the study.

[0392] ●Use of non-cigarette and / or non-combustible nicotine products (pipe tobacco, cigars, snuff, smokeless tobacco, hookah, e-cigarette / vapor) or smoking vapor within 2 weeks prior to randomization or planned use during the study period.

[0393] ●Any other reason why the researcher believes that the subject should not participate or is unable to meet the requirements of the study.

[0394] 2.6 Prior and concomitant medications

[0395] All subjects will continue to receive any existing prescribed medications. Every effort will be made to ensure that the regimen of existing medications remains stable during the study.

[0396] At the investigator's discretion, use of non-study medications (prescription or over the counter) may be offered if clinically indicated during the study. Full details of any new medications will be recorded on the subject's Case Report Form (CRF).

[0397] All concomitant medications taken during the trial and any changes (additions, deletions, dose changes) will be recorded in the CRF.

[0398] 2.7 Treatment compliance

[0399] Treatment compliance will be monitored by reviewing dosage times and drug interpretability during the 84-day (12-week) treatment period. Subjects will have a daily treatment diary that will record the number of tablets taken and the time of taking. Subjects will be instructed to carry their medication packages (blister packs) at each clinic visit so that clinic staff can check the treatment diary to record the number of tablets taken and the number of tablets missed. In addition, an optional text messaging system will be implemented that will provide each subject with a reminder text corresponding to the approximate time of administration.

[0400] 2.8 Study Procedure

[0401] All subjects will be evaluated for inclusion in the study during the 28-day screening period after providing signed informed consent. Subjects who meet the inclusion criteria will be asked to provide a quit date that must be within 5-7 days of treatment initiation and agree to initiate study treatment the day after randomization. Both the planned quit date and treatment start date will be recorded to confirm inclusion. Once all eligibility criteria have been confirmed, randomization can be performed. Study Day 1 will be defined as the first day of treatment. Subjects will complete clinic visits on Days 2, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, and 86. Follow-up visits will be scheduled at Weeks 16, 20, and 24.

[0402] 2.8.1 Procedural Timetable

[0403] A summary of the required study assessments is provided in Table 15. Screening assessments will be performed within the 28-day interval from the start of the screening assessment to randomization. Subjects will initiate study treatment the day after randomization, such that study treatment is initiated on Day 1, within 5-7 days of Day 1, prior to the quit date.

[0404] Table 15: Timeline of Study Procedures During Treatment Period

[0405]

[0406]

[0407]

[0408] Table 16: Schedule of procedures during the follow-up period

[0409]

[0410] 2.8.2 Subject diary

[0411] A 7-day smoking diary will be collected during the screening period to capture the number of cigarettes smoked daily for 7 consecutive days. This data will be used to calculate the average number of cigarettes smoked per day to support inclusion criterion #2.

[0412] In addition, a study treatment diary will be kept by each subject to record the date and time of study drug administration during the treatment period. The diary will be configured with specific sections to support the above reporting by the subject.

[0413] 2.9 Efficacy Standards

[0414] This study will follow general criteria applicable to previous and current cessation aid trials, where participants have a clear target quit date and have face-to-face contact with study staff or clinic staff. Endpoint analyses of abstinence (4 weeks of abstinence documented during the final 4 weeks of treatment) and sustained abstinence (documented continuously through week 24 after randomization) will incorporate the following criteria:

[0415] ●Self-report of smoking cessation since the last clinic visit for each clinical assessment.

[0416] ●Biochemical verification of withdrawal via exhaled CO at each clinic visit.

[0417] ● Use of an “intention-to-treat” approach that included data from all randomized smokers in the analysis.

[0418] ●Subjects whose smoking status is unknown or who are lost to follow-up at the Week 6, Week 12, and Week 24 assessments will be classified as having failed to quit.

[0419] - Self-report of smoking abstinence during the follow-up period only (weeks 12 to 24) will follow the Russell Standard.

[0420] • Treatment assignment remained blinded during follow-up data collection through Week 24.

[0421] 2.9.1 Security Assessment

[0422] All subjects will be monitored for adverse events starting at Screening (pre-existing), by telephone contact on Day 1, clinic visits on Days 2 and 7 during Week 1, then weekly throughout the treatment period (Weeks 2 to 12 / EOT), and monthly during the follow-up period (see Tables 15 and 16). Laboratory (hematology and chemistry) evaluations will be performed using a central laboratory at Weeks 1, 6, and 12 clinic visits.

[0423] Safety will be assessed by considering all adverse events reported or elicited by the subject and abnormalities detected in hematology and serum chemistry tests. Exacerbations of other pre-existing medical conditions and any changes in concomitant medications / treatments will also be considered in this evaluation.

[0424] 2.9.2 Laboratory

[0425] Routine laboratory evaluation

[0426] As identified in Table 15, routine laboratory safety samples for each subject will be analyzed by the central laboratory at screening and clinic visits. The decision on whether the results outside the reference range are clinically significant will be made by the investigator, and the report will be annotated accordingly. Clinically significant abnormalities occurring during the study will be recorded on the AE page. Reference ranges for laboratory parameters will also be entered in the database and filed in the investigator site file.

[0427] Hematology: Hemoglobin, erythrocytes, leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelets.

[0428] Chemistry: Total protein, albumin, total bilirubin, SGPT (ALT), SGOT (AST), alkaline phosphatase, glucose, sodium, potassium, calcium, creatinine, and urea.

[0429] CO in exhaled air

[0430] Calibrated instruments (e.g., Bedfont) provided and maintained by the clinical site will be used. ) to obtain exhaled CO. Each clinical site will have documentation and current calibration of the instrument used. CO values ​​will be reported in parts per million (ppm) at Week 2, weekly through Week 12, and at Weeks 16, 20, and 24.

[0431] Serum cotinine level

[0432] Serum samples will be collected for cotinine levels at Weeks 2, 4, 6, 8, 10, 12, 16, 20, and 24. Baseline cotinine testing will use frozen serum collected at the SV1 visit for randomized subjects. Cotinine levels will be determined in a central laboratory.

[0433] 2.9.3 Vital signs

[0434] Systolic / diastolic blood pressure, pulse rate, and oral temperature measurements will be recorded in the seated position. Weight will also be recorded. Height will be recorded at Screening Visit #1 to calculate BMI.

[0435] 2.9.4 Physical examination

[0436] A physical examination will be performed by the investigator. The examination will include overall general appearance, head, ears, eyes, nose, throat, neck, skin, cardiovascular system, respiratory system, gastrointestinal system, central nervous system, lymph nodes, and musculoskeletal. If necessary, the investigator may examine other body systems at his or her discretion.

[0437] 2.10 Primary Outcomes of Subjects

[0438] The primary efficacy outcome for each subject (biochemically verified abstinence in the last 4 weeks of cytisine treatment) will be binary: success versus failure. For subjects, success will be defined as smoking abstinence (no cigarettes since the last clinic visit) reported at each clinical assessment from Week 3 to Week 6 (Group B) and Week 9 to Week 12 (Group C), with biochemical verification performed at each assessment. Biochemical verification will be defined by a carbon monoxide concentration of less than 10 ppm in exhaled breath. A similar time frame and analysis will also be performed for Group A placebo subjects.

[0439] 2.11 Secondary Outcomes of Subjects

[0440] Secondary efficacy outcomes 1 and 2 (sustained biochemically verified abstinence to Week 24) for each subject will be binary: success versus failure. For a subject, success will be defined as smoking abstinence since the last clinic visit as reported at each clinical assessment from Week 6 (Group B) or Week 12 (Group C) to Week 24, with biochemical verification performed at each assessment. Biochemical verification will be defined by a carbon monoxide concentration of less than 10 ppm in exhaled breath. During the follow-up smoking abstinence assessments from Week 12 to Week 24, self-reporting of smoking abstinence will be based on the Russell criteria.

[0441] Secondary Efficacy Outcome 3 will be success in not relapsing at Week 24. Each subject (in both Group C and Group B) will be assessed for Secondary Efficacy Outcome 3 (reduction in risk of relapse from Week 6 to Week 24 in Group C vs. Group B). Subjects who are not abstinent at Week 6 will be considered to have relapsed.

[0442] 2.12 Safety Goals

[0443] Safety assessments will include reported adverse events, laboratory test results, and vital signs.Safety variables will be summarized for the Safety Analysis Set (SAS), which is defined as all randomized subjects who took at least one dose of study drug.

[0444] Adverse events will be coded using the MedDRA dictionary. The coding will include system organ classes (SOC) and preferred terms (PT). All verbatim descriptions and coded terms for all AEs will be listed. Various embodiments of the present invention are described below in paragraphs 272 to 391:

[0445] A method for treating nicotine addiction, nicotine dependence, promoting abstinence from smoking and / or vaping in a subject in need thereof, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, the method comprising administering to the subject three times daily cytisine provided in a unit dose of 3.0 mg, 1.5 mg or 1.0 mg cytisine.

[0446] The method of paragraph 272, wherein the subject experiences no adverse events following treatment with cytisine.

[0447] The method of paragraphs 272 and 273, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0448] The method of paragraphs 272 to 274, wherein the subject does not experience nausea after receiving cytisine treatment.

[0449] The method of paragraphs 272 to 275, wherein the cytisine is administered for about 6 weeks or for about 12 weeks.

[0450] The method according to paragraphs 272 to 276, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0451] The method of paragraphs 272 to 277, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation therapies.

[0452] The method of paragraphs 272 to 278, wherein the nicotine addiction or smoking cessation treatment is selected from NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and combinations thereof.

[0453] The method of paragraphs 272 to 279, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0454] The method of paragraphs 272 to 280, further comprising providing behavioral support to the subject.

[0455] A method of treating nicotine addiction and / or nicotine dependence in a subject in need thereof, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction therapies.

[0456] The method of paragraphs 282, wherein the nicotine addiction treatment comprises NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and combinations thereof.

[0457] The method according to paragraphs 282 and 283, wherein cytisine is provided to a subject in need thereof at a unit dosage of about 1.0 mg to about 6.0 mg cytisine three to six times daily.

[0458] The method according to paragraphs 282 to 284, wherein cytisine is provided to a subject in need thereof at a unit dose of 3.0 mg cytisine three times daily.

[0459] The method according to paragraphs 282 to 285, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0460] The method of paragraphs 282 to 286, wherein cytisine is administered for about 6 weeks or for about 12 weeks.

[0461] The method of paragraphs 282 to 287, wherein the subject experiences no adverse events following treatment with cytisine.

[0462] The method of paragraphs 282 to 288, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0463] The method of paragraphs 282 to 289, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0464] A method for preventing relapse to smoking and / or vaping in a subject in need thereof, the method comprising administering to the subject three times daily cytisine provided in the following unit doses: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0465] The method of paragraph 291, wherein cytisine is administered for about 6 weeks or for about 12 weeks.

[0466] The method according to paragraphs 291 and 292, wherein the subject experiences no adverse events after receiving cytisine treatment.

[0467] The method of paragraphs 291 to 293, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0468] The method of paragraphs 291 to 294, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0469] The method of paragraphs 291 to 295, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies.

[0470] The method of paragraphs 291 to 296, wherein the smoking cessation therapy comprises NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof.

[0471] A method of preventing relapse to smoking and / or vaping in a subject in need thereof, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies, the one or more smoking cessation therapies being selected from the group consisting of: NRT, administration of bupropion, administration of varenicline, electronic cigarettes, and vaping.

[0472] The method of paragraph 298, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0473] The method of paragraphs 298 and 299, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine, and wherein the cytisine is administered for about 6 weeks or for about 12 weeks.

[0474] The method of paragraphs 298 to 300, wherein the subject does not experience an adverse event selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving cytisine treatment.

[0475] A medicament comprising a unit dose of 3.0 mg, 1.5 mg or 1.0 mg of cytisine, the medicament being used for treating nicotine addiction, nicotine dependence, promoting a subject in need thereof to quit smoking and / or vaping, and / or promoting a subject in need thereof to reduce smoking and / or vaping, wherein the medicament is used for oral administration to the subject three times a day.

[0476] The medicament according to paragraph 302, wherein the subject experiences no adverse events following treatment with cytisine.

[0477] The medicament according to paragraphs 302 and 303, wherein the adverse event is selected from the group consisting of: URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0478] The medicament according to paragraphs 302 to 304, wherein the subject does not experience nausea after receiving cytisine treatment.

[0479] The medicament according to paragraphs 302 to 305, wherein cytisine is administered for about 6 weeks or for about 12 weeks.

[0480] The medicament according to paragraphs 302 to 306, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0481] The medicament according to paragraphs 302 to 307, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation therapies.

[0482] The medicament of paragraphs 302 to 308, wherein the nicotine addiction or smoking cessation treatment is selected from NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and combinations thereof.

[0483] The medicament of paragraphs 302 to 309, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0484] The medicament of paragraphs 302 to 310, further comprising providing behavioral support to the subject.

[0485] A medicament comprising cytisine for treating nicotine addiction or nicotine dependence in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments, wherein the medicament is for oral administration to the subject three times daily.

[0486] The medicament of paragraph 312, wherein the nicotine addiction or dependence treatment comprises NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof.

[0487] The medicament according to paragraphs 312 and 313, wherein cytisine is provided to a subject in need thereof at a unit dose of about 1.0 mg to about 6.0 mg cytisine three to six times daily.

[0488] The medicament according to paragraphs 312 to 314, wherein cytisine is provided to a subject in need thereof at a unit dose of 3.0 mg cytisine three times a day.

[0489] The medicament according to paragraphs 312 to 315, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0490] The medicament of paragraphs 312 to 316, wherein cytisine is administered for about 6 weeks or for about 12 weeks.

[0491] The medicament according to paragraphs 312 to 317, wherein the subject experiences no adverse events after receiving cytisine treatment.

[0492] The medicament according to paragraphs 312 to 318, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0493] The medicament of paragraphs 312 to 319, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0494] A medicament comprising a unit dose of cytisine in the form of: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine, the medicament being used to prevent relapse to smoking and / or vaping in a subject in need thereof, and wherein the medicament is for oral administration to the subject three times daily.

[0495] The medicament of paragraph 321, wherein cytisine is administered for about 6 weeks or for about 12 weeks.

[0496] The medicament according to paragraphs 321 and 322, wherein the subject experiences no adverse events after receiving cytisine treatment.

[0497] The medicament according to paragraphs 321 to 323, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0498] The medicament of paragraphs 321 to 324, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0499] The medicament according to paragraphs 321 to 325, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies.

[0500] The medicament of paragraphs 321 to 326, wherein the smoking cessation therapy comprises NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof.

[0501] A medicament comprising cytisine for preventing relapse to smoking and / or vaping in a subject, the subject being a refractory patient who has failed treatment with one or more nicotine addiction treatments, the one or more nicotine addiction treatments being selected from the group consisting of NRT, administration of bupropion, administration of varenicline, electronic cigarettes, and vaping, wherein the medicament is for oral administration to the subject three times daily.

[0502] The medicament of paragraph 328, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0503] The medicament according to paragraphs 328 and 329, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine, and wherein the cytisine is administered for about 6 weeks or for about 12 weeks.

[0504] The medicament according to paragraphs 328 to 330, wherein the subject does not experience adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation after receiving cytisine treatment.

[0505] A use of cytisine at a unit dose of 3.0 mg, 1.5 mg or 1.0 mg for treating nicotine addiction, nicotine dependence, promoting a subject in need to quit smoking and / or vaping, and / or promoting a subject in need to reduce smoking and / or vaping, wherein the cytisine is for oral administration to the subject three times a day.

[0506] The use according to paragraph 332, wherein the subject experiences no adverse events following treatment with cytisine.

[0507] The use according to paragraphs 332 and 333, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0508] The use according to paragraphs 332 to 334, wherein the subject does not experience nausea after receiving cytisine treatment.

[0509] The use according to paragraphs 332 to 335, wherein cytisine is administered for about 6 weeks or for about 12 weeks.

[0510] The use according to paragraphs 332 to 336, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0511] The use according to paragraphs 332 to 337, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation therapies.

[0512] The use according to paragraphs 332 to 338, wherein the nicotine addiction or smoking cessation treatment is selected from NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and combinations thereof.

[0513] The use according to paragraphs 332 to 339, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0514] The use of paragraphs 332 to 340, further comprising providing behavioral support to the subject.

[0515] A use of cytisine for treating nicotine addiction or nicotine dependence in a subject, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments, wherein the cytisine is for oral administration to the subject three times daily.

[0516] The use according to paragraphs 342, wherein the nicotine addiction treatment comprises NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and combinations thereof.

[0517] The use according to paragraphs 342 and 343, wherein cytisine is provided to a subject in need thereof at a unit dose of about 1.0 mg to about 6.0 mg cytisine three to six times daily.

[0518] The use according to paragraphs 342 to 344, wherein cytisine is provided to a subject in need thereof at a unit dose of 3.0 mg cytisine three times a day.

[0519] The use according to paragraphs 342 to 345, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0520] The use according to paragraphs 342 to 346, wherein cytisine is administered for about 6 weeks or for about 12 weeks.

[0521] The use according to paragraphs 342 to 347, wherein the subject experiences no adverse events after receiving cytisine treatment.

[0522] The use according to paragraphs 342 to 348, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0523] The use according to paragraphs 342 to 349, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0524] A use of a unit dose of cytisine in the form of: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine, for preventing relapse to smoking and / or vaping in a subject in need thereof, wherein the cytisine is for oral administration to the subject three times daily.

[0525] The use according to paragraph 351, wherein cytisine is administered for about 6 weeks or for about 12 weeks.

[0526] The use according to paragraphs 351 and 352, wherein the subject experiences no adverse events after receiving cytisine treatment.

[0527] The use according to paragraphs 351 to 353, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0528] The use according to paragraphs 351 to 354, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0529] The use according to paragraphs 351 to 355, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies.

[0530] The use according to paragraphs 351 to 356, wherein the smoking cessation therapy comprises NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof.

[0531] A use of cytisine for preventing a subject from relapsing to smoking and / or vaping, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments, wherein the one or more nicotine addiction treatments are selected from the group consisting of: NRT, administration of bupropion, administration of varenicline, electronic cigarettes, and vaping, wherein the cytisine is for oral administration to the subject three times daily.

[0532] The use according to paragraph 358, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has a CO concentration in exhaled air of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0533] The use according to paragraphs 358 and 359, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine, and wherein the cytisine is administered for about 6 weeks or for about 12 weeks.

[0534] The use according to paragraphs 358 to 360, wherein the subject does not experience adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation after receiving cytisine treatment.

[0535] A use of a tablet comprising about 1.0 mg or about 1.5 mg of cytisine for orally administering about 3.0 mg of cytisine to a subject three times daily to treat the subject's nicotine addiction, nicotine dependence, promote the subject's cessation of smoking and / or vaping, and / or promote the subject's reduction of smoking and / or vaping.

[0536] The use according to paragraph 362, wherein the subject experiences no adverse events following treatment with cytisine.

[0537] The use according to paragraphs 362 and 363, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0538] The use according to paragraphs 362 to 364, wherein the subject does not experience nausea after receiving cytisine treatment.

[0539] The use according to paragraphs 362 to 365, wherein cytisine is administered for about 6 weeks or for about 12 weeks.

[0540] The use according to paragraphs 362 to 366, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0541] The use according to paragraphs 362 to 367, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation therapies.

[0542] The use according to paragraphs 362 to 368, wherein the nicotine addiction or smoking cessation treatment is selected from NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and combinations thereof.

[0543] The use according to paragraphs 362 to 369, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0544] The use of paragraphs 362 to 370, further comprising providing behavioral support to the subject.

[0545] A use of a tablet comprising about 1.0 mg or about 1.5 mg of cytisine for orally administering about 3.0 mg of cytisine three times daily to a subject for treating nicotine addiction and / or nicotine dependence in the subject, the subject being a refractory patient who has failed treatment with one or more nicotine addiction therapies.

[0546] The use according to paragraphs 372, wherein the nicotine addiction treatment comprises NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and combinations thereof.

[0547] The use according to paragraphs 372 and 373, wherein cytisine is provided to a subject in need thereof at a unit dose of about 1.0 mg to about 6.0 mg cytisine three to six times daily.

[0548] The use according to paragraphs 372 to 374, wherein cytisine is provided to a subject in need thereof at a unit dose of 3.0 mg cytisine three times a day.

[0549] The use according to paragraphs 372 to 375, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg of cytisine; or (b) a single tablet, the single tablet containing 3.0 mg of cytisine.

[0550] The use according to paragraphs 372 to 376, wherein cytisine is administered for about 6 weeks or for about 12 weeks.

[0551] The use according to paragraphs 372 to 377, wherein the subject experiences no adverse events after receiving cytisine treatment.

[0552] The use according to paragraphs 372 to 378, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0553] The use according to paragraphs 372 to 379, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0554] A use of a tablet comprising about 1.0 mg or about 1.5 mg of cytisine for orally administering about 3.0 mg of cytisine to a subject three times daily to prevent the subject from relapsing to smoking and / or vaping.

[0555] The use according to paragraph 381, wherein cytisine is administered for about 6 weeks or for about 12 weeks.

[0556] The use according to paragraphs 381 and 382, ​​wherein the subject experiences no adverse events following treatment with cytisine.

[0557] The use according to paragraphs 381 to 383, wherein the adverse event is selected from the group consisting of upper respiratory tract infection (URTI), abnormal dreams, nausea, insomnia, headache, fatigue and constipation.

[0558] The use according to paragraphs 381 to 384, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0559] The use according to paragraphs 381 to 385, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies.

[0560] The use according to paragraphs 381 to 386, wherein the smoking cessation therapy comprises NRT, administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof.

[0561] A use of a tablet comprising about 1.0 mg or about 1.5 mg of cytisine for orally administering about 3.0 mg of cytisine three times daily to a subject who has failed treatment with one or more nicotine addiction treatments to prevent the subject from relapsing to smoking, wherein the one or more nicotine addiction treatments are selected from the group consisting of: NRT, administration of bupropion, administration of varenicline, electronic cigarettes or smoking vaping.

[0562] The use according to paragraph 388, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has a CO concentration in exhaled air of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0563] The use according to paragraphs 388 and 389, wherein the unit dose of cytisine comprises: (a) two tablets, each tablet containing 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, the single tablet containing 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each tablet containing 1.0 mg of cytisine, and wherein the cytisine is administered for about 6 weeks or for about 12 weeks.

[0564] The use according to paragraphs 388 to 390, wherein the subject does not experience adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation after receiving cytisine treatment.

Claims

1. A unit dose of 1.5 mg of cytisine for use in treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping and / or promoting reduction of smoking and / or vaping in a subject in need thereof, the subject having 3 or more previous attempts to quit smoking, wherein the unit dose of 1.5 mg of cytisine is for oral administration to the subject three times daily for at least 3 weeks.

2. A unit dose of 3.0 mg of cytisine for use in treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping in a subject in need thereof, the subject having 3 or more previous attempts to quit smoking, wherein the unit dose of 3.0 mg of cytisine is for oral administration to the subject three times daily for at least 3 weeks.

3. A unit dose of 1.5 mg of cytisine for use in preventing relapse to smoking and / or vaping in a subject in need thereof who has had 3 or more previous attempts to quit smoking, wherein the unit dose of 1.5 mg of cytisine is for oral administration to the subject three times daily for at least 3 weeks.

4. A unit dose of 3.0 mg of cytisine for use in preventing relapse to smoking and / or vaping in a subject in need thereof who has had 3 or more prior attempts to quit smoking, wherein the unit dose of 3.0 mg of cytisine is for oral administration to the subject three times daily for at least 3 weeks.

5. The unit dose of any one of claims 1-4, wherein the subject has smoked for at least about 25 years.

6. The unit dose of any one of claims 1-5, wherein the subject has smoked for at least about 30 years.

7. The unit dose according to any one of claims 1-6, wherein the subject started smoking between the ages of 10 and 19 years old.

8. The unit dose of any one of claims 1-7, wherein the subject is a refractory patient who has previously received one or more smoking cessation therapies.

9. The unit dose of claim 8, wherein the one or more smoking cessation treatments are selected from the group consisting of nicotine replacement therapy, administration of varenicline, and administration of bupropion.

10. The unit dose of any one of claims 1-9, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

11. The unit dose according to any one of claims 1-10, wherein the subject is provided behavioral support.

12. The unit dose or tablet according to any one of claims 1 to 11, wherein cytisine is administered for at least 6 weeks or at least 12 weeks.

13. A tablet comprising 1.5 mg of cytisine for oral administration three times daily to a subject for at least 3 weeks for the treatment of nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping and / or promoting reduction of smoking and / or vaping, wherein the subject in need thereof has 3 or more previous attempts to quit smoking.

14. A tablet comprising 3.0 mg of cytisine for oral administration three times daily to a subject for at least 3 weeks for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping and / or promoting reduction of smoking and / or vaping, wherein the subject in need thereof has 3 or more previous quit attempts.

15. The tablet of claim 13 or 14, wherein the subject has smoked for at least about 25 years.

16. The tablet of any one of claims 13-15, wherein the subject has been smoking for at least about 30 years.

17. The tablet according to any one of claims 13-16, wherein the subject started smoking between the ages of 10 and 19 years old.

18. The tablet according to any one of claims 13-17, wherein the subject is a refractory patient who has previously received one or more smoking cessation therapies.

19. The tablet of claim 18, wherein the smoking cessation therapy is selected from the group consisting of nicotine replacement therapy, administration of varenicline, and administration of bupropion.

20. The tablet of any one of claims 13-19, wherein the subject (a) smokes ten or more cigarettes per day prior to administration of cytisine, (b) has an exhaled air CO concentration of about 10 ppm or more prior to administration of cytisine, or (c) a combination of (a) and (b).

21. The tablet according to any one of claims 13-20, wherein the subject is provided behavioral support.

22. The unit dose or tablet according to any one of claims 13 to 21, wherein cytisine is administered for at least 6 weeks or at least 12 weeks.

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