COMPOSITIONS COMPRISING CYTISINE IN THE TREATMENT AND / OR PREVENTION OF ADDICTION IN A SUBJECT IN NEED OF TREATMENT AND / OR PREVENTION OF ADDICTION - Patent application

Abstract

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

Description

[Background technology]

[0001] Priority claims This application claims priority to U.S. Provisional Application No. 62 / 988,890, filed March 12, 2020, and U.S. Provisional Application No. 62 / 899,637, filed September 12, 2019, the entire contents of each of which are incorporated herein by reference.

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

[0003] Tobacco smoking is responsible for approximately 7 million premature deaths worldwide each year. Smoking is highly addictive, and over 95% of unassisted quit attempts do not last six months. It is estimated that each year a person delays quitting smoking beyond their mid-30s, they lose three months of life expectancy. The World Health Organization Framework Convention on Tobacco Control identified evidence-based approaches to promoting smoking cessation and includes mass media campaigns, increased tobacco taxes, and support for smokers who want to quit.

[0004] Pharmacotherapy currently available in the United States and Western Europe to help smokers quit includes nicotine replacement therapy (NRT) and two non-nicotine-containing medications, including bupropion (Zyban®, Glaxo-SmithKline) and varenicline (Chantix® / Champix®, Pfizer). NRT and bupropion appear to be approximately equally effective. Varenicline is more effective than either NRT or bupropion alone, while the combined NRTs are comparable in efficacy.

[0005] (-)-Cytisine (cytisinicline, commonly referred to simply as cytisine) is a plant-based alkaloid isolated from the seeds of Cytisus laburnum L (Golden chain). References to cytisine herein refer to (-)-cytisine, cytisinicline.

[0006] Cytisine's mechanism of action is helping basic pharmacologists understand the complex pharmacology of the various subtypes of nicotinic acetylcholine receptors. These studies show that both nicotine and cytisine bind strongly and preferentially to alpha4, beta2 (α4β2) receptors, which mediate dopamine release in the nucleus accumbens shell and elsewhere. This receptor subtype is involved in the development and maintenance of nicotine dependence and was the primary target of the aforementioned drug, varenicline.

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

[0008] There is a need for nicotine addiction treatments with patient-friendly regimens that are less expensive, more effective, have an improved safety profile, and / or can better treat individuals who have failed to quit nicotine using known treatments. Summary of the Invention

[0009] In one aspect, provided herein is a method of treating nicotine addiction in a subject, the method comprising administering to a subject in need thereof cytisine in equal dosage amounts twice daily (“bid” or “BID”) or three times daily (“tid” or “TID”).

[0010] In another aspect, provided herein is a method of treating nicotine addiction, promoting smoking cessation, and / or promoting a reduction in smoking in a subject in need thereof, the method comprising administering to the subject cytisine provided in a 3.0 mg or 1.5 mg unit dose of cytisine three times daily.

[0011] In 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 at a dose of either 1.5 mg or 3.0 mg cytisine three times daily.

[0012] In yet another aspect, provided herein is a method of treating nicotine dependence in a subject, the method comprising administering cytisine to a subject in need thereof at a dose of either 1.5 mg or 3.0 mg of cytisine three times daily.

[0013] In yet another aspect, provided herein is a method of treating nicotine addiction in a subject, 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.

[0014] In yet another aspect, provided herein are methods of preventing smoking relapse in a subject in need thereof, the methods comprising administering to the subject three times daily cytisine provided in a unit dose of: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine.

[0015] In a further aspect, provided herein is a method of preventing smoking relapse 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 selected from the group consisting of NRT, bupropion administration, varenicline administration, electronic cigarettes (e-cigarettes), and vaping.

[0016] In one embodiment, three daily doses are administered in the morning, midday, and evening, respectively, or at approximately 4-5 hour intervals. In one embodiment, administration is administered for at least about 6 weeks, at least about 12 weeks, at least about 24 weeks, or indefinitely. In another embodiment, administration is administered for a period of at least about 6 weeks or at least about 12 weeks, or is repeated indefinitely for 6-12 weeks.

[0017] In some embodiments, cytisine is provided to a subject in need thereof in a unit dose of about 1.0 mg to about 6.0 mg of cytisine 1 to 6 times daily. In some embodiments, cytisine is provided to a subject in need thereof in a unit dose of about 1.0 mg to about 6.0 mg of cytisine 3 to 6 times daily. In some embodiments, cytisine is provided to a subject in need thereof in a unit dose of 1.5 mg of cytisine 3 times daily. In some embodiments, cytisine is provided to a subject in need thereof in a unit dose of 1.5 mg of cytisine 6 times daily. In some embodiments, cytisine is provided to a subject in need thereof in a unit dose of 3.0 mg of cytisine 3 times daily. In some embodiments, cytisine is provided to a subject in need thereof in a unit dose of 3.0 mg of cytisine 6 times daily.

[0018] 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 contains 1.0 mg of cytisine. In some embodiments, each unit dose (e.g., tablet or capsule) of cytisine contains 1.5 mg of cytisine. In some embodiments, a unit dose of cytisine contains 3.0 mg of cytisine. In some embodiments, each unit dose is a tablet, e.g., a compressed and film-coated tablet.

[0019] 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, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0020] In some embodiments, the subject smoked 10 or more cigarettes per day prior to administration of cytisine. In some embodiments, the subject has an exhaled carbon monoxide (CO) concentration of about 10 parts per million (ppm) or greater prior to administration of cytisine. In some embodiments, the subject (a) smoked 10 or more cigarettes per day prior to administration of cytisine, (b) has an exhaled CO concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0021] In some embodiments, the subject does not experience an adverse event after receiving cytisine treatment, hi some embodiments, the adverse event is selected from the group consisting of upper respiratory tract infection (URTI), abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0022] In some embodiments, the method further comprises providing behavioral support to the subject. [Brief explanation of the drawings]

[0023] [Figure 1] FIG. 1 is a schematic diagram of the dosing schedule according to the study design of Example 1 according to the present technology.

[0024] [Figure 2] FIG. 1 is a schematic diagram of the study design of Example 1 according to the present technology.

[0025] [Figure 3] FIG. 1 is a schematic diagram of the dose intensity, schedule, and duration according to the study design of Example 1 according to the present technology.

[0026] [Figure 4] FIG. 1 is a schematic diagram showing subject population placement according to the study of Example 1 according to the present technology.

[0027] [Figure 5] 1 is a representative graph showing the number of cigarettes smoked per treatment group on treatment days according to the study of Example 1 in accordance with the present technology.

[0028] [Figure 6] 1 is a representative graph showing the reduction in cigarettes smoked versus exhaled CO in the subject population of Example 1 according to the present technology.

[0029] [Figure 7] 1 is a representative graph showing a comparison of the abstinence rate after 4 weeks of abstinence and the abstinence rate during continued abstinence (weeks 5-8) in the subject population of Example 1 according to the present technology.

[0030] [Figure 8] Representative graph showing a comparison of smoking cessation rates between 3.0 mg three times daily (TID) and placebo after 4 weeks of abstinence and during sustained abstinence (weeks 5-8).

[0031] [Figure 9]1 is a representative plot showing exhaled CO levels in ppm for pooled placebo, 1.5 mg TID, 3.0 mg TID, 1.5 mg commercial titration schedule (COM), and 3.0 mg COM treatment groups at the screening visit, week 4, and week 8 according to the present technology.

[0032] [Figure 10] 1 is a representative plot showing serum cotinine levels for pooled placebo, 1.5 mg TID, 3.0 mg TID, COM 1.5 mg, and COM 3.0 mg at the screening visit, week 4, and week 8 according to the present technology.

[0033] [Figures 11A-11B] 10 is a representative plot showing a comparison between group equalizations for predicted percentage of cigarettes smoked (cigarette score) compared between COM 0 mg and TID 0 mg, and between TID 0 mg and TID 3.0 mg according to the present technology.

[0034] [Figure 12] FIG. 1 is a schematic diagram of the study design to compare cytisinicline (cytisine) with Chantix® according to the present technology.

[0035] [Figure 13] 1 is a representative graph showing CO-confirmed abstinence rates between 3.0 mg cytisinicline and 3.0 mg Chantix® at 4 and 12 weeks of treatment with the present technology.

[0036] [Figure 14] 1 is a representative plot comparing odds ratios for cytisinicline and Chantix® according to the present technology at 4 weeks, end of treatment, and 4 weeks after end of treatment.

[0037] [Figure 15]10 is a representative plot comparing odds ratios for citisinicline with the present technology to the current product at 4 weeks, end of treatment, and 4 weeks after end of treatment.

[0038] [Figure 16] 10 is a representative plot showing the interaction between the 3.0 mg TID group and BMI stratification factors according to the present technology.

[0039] [Figure 17] 1 is a representative plot showing the evaluation of the linear correlation between cigarette score and baseline mean number of cigarettes using the present technique with parallelism between groups.

[0040] [Figure 18] 1 is a representative plot showing an effect modification factor analysis (EMA) of tobacco scores across clinical sites for cytisine 1.5 mg TID compared to placebo pooled according to the present technology.

[0041] [Figure 19] 1 is a representative plot showing the EMA of tobacco scores across clinical sites for cytisine 3.0 mg TID compared to pooled placebo according to the present technology.

[0042] [Figure 20] 10 is a representative plot showing the EMA of tobacco scores across clinical sites for cytisine 1.5 mg COM compared to pooled placebo according to the present technology.

[0043] [Figure 21] 10 is a representative plot showing the EMA of tobacco scores across clinical sites for cytisine 3.0 mg COM compared to pooled placebo according to the present technology.

[0044] [Figure 22]1 is a representative plot showing EMA for 4-week abstinence sustained through weeks 5 through 8 (Cess / W5-8 / CO success) confirmed by <10 ppm exhaled CO across clinical sites for cytisine 1.5 mg TID compared to pooled placebo by the present technology.

[0045] [Figure 23] 1 is a representative plot showing EMA for 4-week abstinence sustained through weeks 5 through 8 (Cess / W5-8 / CO success) confirmed by <10 ppm exhaled CO across clinical sites for cytisine 3.0 mg TID compared to pooled placebo by the present technology.

[0046] [Figure 24] 1 is a representative plot showing EMA for 4-week abstinence sustained through weeks 5 through 8 (Cess / W5-8 / CO success) confirmed by <10 ppm exhaled CO across clinical sites for cytisine 1.5 mg COM compared to pooled placebo by the present technology.

[0047] [Figure 25] 1 is a representative plot showing EMA for 4-week abstinence sustained through weeks 5 through 8 (Cess / W5-8 / CO success) confirmed by <10 ppm exhaled CO across clinical sites for cytisine 3.0 mg COM compared to pooled placebo by the present technology.

[0048] [Figure 26] 10 is a representative plot showing EMA in tobacco scores across baseline (race, Hispanic, sex, age (M), age (T), strat BMI, smoking Hx duration (y) (M), smoking Hx duration (y) (T), smoking Hx duration (y) (Q), >2 quit Hx, screening mean cigarettes / day (M)) attributes for cytisine 3.0 mg TID compared to pooled placebo by the present technology.

[0049] [Figure 27]10 is a representative plot showing EMA for 4-week abstinence sustained through weeks 5 through 8 (Cess / W5-8 / CO success) confirmed by <10 ppm exhaled CO across baseline attributes (race, Hispanic, sex, age (M), age (T), strat BMI, smoking Hx duration (y) (M), smoking Hx duration (y) (T), smoking Hx duration (y) (Q), >2 abstinence Hx, screening mean cigarettes / day (M)) for cytisine 3.0 mg TID compared to pooled placebo by the present technology.

[0050] [Figure 28] 1 is a representative plot showing EMA in tobacco scores across prior anti-smoking interventions (>2 quit Tx, Chantix® Hx, Zyban® Hx, Vape Hx, NRT Hx, Chantix® (current), Zyban® (current), Vape (current), and NRT with cytisine 3.0 mg TID (current)) compared to pooled placebo according to the present technology.

[0051] [Figure 29] 1 is a representative plot showing EMA for 4-week abstinence sustained through weeks 5 through 8 (Cess / W5-8 / CO success) confirmed by <10 ppm exhaled CO across prior anti-smoking interventions (>2 quit Tx, Chantix® Hx, Zyban® Hx, Vape Hx, NRT Hx, Chantix® (current), Zyban® (current), Vape(current), and NRT(current)) at cytisine 3.0 mg TID compared to pooled placebo according to the present technology.

[0052] [Figure 30] 1 is a representative plot showing EMA for tobacco scores across baseline laboratory markers (NMR, CO, cotinine) at cytisine 3.0 mg TID compared to pooled placebo according to the present technology.

[0053] [Figure 31] 1 is a representative plot showing EMA across baseline laboratory markers (NMR, CO, cotinine) at cytisine 3.0 mg TID compared to pooled placebo by the present technology for 4-week abstinence sustained through weeks 5 through 8 confirmed by <10 ppm exhaled CO (Cess / W5-8 / CO success).

[0054] [Figure 32] 1 is a representative graph showing a turning point analysis in 4-week abstinence confirmed by <10 ppm exhaled CO through weeks 5 through 8 (Cess / W5-8 / CO success) in the cytisine 3.0 mg TID group compared to the pooled placebo group according to the present technology.

[0055] [Figure 33] FIG. 1 is a schematic diagram of the study design of Example 2 according to current technology. DETAILED DESCRIPTION OF THE INVENTION

[0056] While the present disclosure may be embodied in various forms, the following description of several embodiments is made with the understanding that the present disclosure should be considered as an exemplification of the invention and is not intended to limit the invention to the particular embodiments shown. Headings are provided for convenience only and should not be construed as limiting the invention in any way. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

[0057] The use of numerical values ​​in the various quantitative values ​​specified in this application, unless expressly stated otherwise, is described as approximations, as if both the minimum and maximum values ​​within the specified range were preceded by the word "about." It is understood, although not always explicitly stated, that all numerical designations are preceded by the term "about." Such range formats are used for convenience and brevity and should be understood flexibly to include the numerical values ​​explicitly specified as range limits, but also to include all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were expressly specified. For example, a percentage range of about 1 to about 200 should be understood to include the explicitly recited limits of about 1 and about 200, but also to include individual percentages such as about 2, about 3, and about 4, as well as subranges such as about 10 to about 50, about 20 to about 100, etc. It is also understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0058] As used herein, the term "about," when referring to a measurable value such as an amount or concentration, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or 0.1% of the specified amount.

[0059] The disclosure of ranges is also intended as a continuous range, including every value between the minimum and maximum values ​​recited, and any range that can be formed by such values. Also disclosed herein are any and all ratios (and any such ratio ranges) that can be formed by dividing a disclosed numerical value into any other disclosed numerical value. Accordingly, one of ordinary skill in the art will understand that many such ratios, ranges, and ratio ranges are clearly obtainable from the numerical values ​​presented herein, and that in all cases, such ratios, ranges, and ratio ranges represent various embodiments of the present disclosure.

[0060] As used herein, the phrase "statistical significance" refers to a result from data generated by a test or experiment that is unlikely to have occurred randomly or by chance, but instead is likely to be attributable to a specific cause. Statistical significance is assessed from a calculated probability (p-value), where the p-value is a function of the mean and standard deviation of the data sample and indicates the probability that the statistical result occurred by chance or sampling error. A p-value of 0.05 or less is considered statistically significant, corresponding to a 95% confidence level.

[0061] "Comprising" or "comprises" is intended to mean that compositions and methods include the recited elements, but do not exclude others. "Consisting essentially of," when used to define compositions and methods, is intended to mean excluding other elements of any essential importance to the combination for the stated purpose. Thus, a composition consisting essentially of elements as defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" is intended to mean excluding more than trace amounts of other components and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0062] As used herein, the phrase "control subject" refers to any subject used as a standard for comparison with a test subject. Control subjects include, but are not limited to, any subject who does not receive a composition, who receives a composition other than the test composition (e.g., 1.5 mg cytisine three times a day, or 3.0 mg cytisine three times a day), or who receives a placebo.

[0063] The term "treatment" in relation to a given disease or disorder includes, but is not limited to, inhibiting the disease or disorder, e.g., halting the progression of the disease or disorder, alleviating the disease or disorder, e.g., causing regression of the disease or disorder, or alleviating a condition caused by or resulting from the disease or disorder, e.g., alleviating or treating the symptoms of the disease or disorder. The term "prevention" in relation to a given disease or disorder means preventing the onset of disease progression if none has occurred, preventing the disease or disorder from occurring in a subject who may be susceptible to the disorder or disorder but has not yet been diagnosed with the disorder or disorder, and / or preventing further progression of the disease / disorder if the disease or disorder is already present.

[0064] "Vaping" refers to the act of a subject inhaling vapor generated by a device from a solution carried in a cartridge or chamber. In some embodiments, the device is electronic and mimics smoking. A vaping device includes, but is not limited to, a power source, an atomizer, and a cartridge or chamber. In some embodiments, vaping refers to the consumption of e-liquid or vaping activities, such as drawing in or otherwise consuming a puff of vapor from a vaping device, performing a vaping activity with a vaping device, or otherwise ingesting vapor using a vaping device. In another embodiment, vaping refers to the consumption of e-liquid. In an alternative embodiment, vaping refers to the consumption of e-liquid, or drawing in or otherwise consuming a puff of vapor from a vaping device. In yet another embodiment, vaping refers to a vaping activity. In other embodiments, vaping refers to drawing in or otherwise consuming a puff of vapor from a vaping device, performing a vaping activity with a vaping device, or otherwise ingesting vapor using a vaping device. In further embodiments, vaping refers to drawing in or otherwise consuming a puff of vapor from a vaping device or otherwise taking in vapor using a vaping device, hi yet other embodiments, vaping refers to taking in vapor using a vaping device.

[0065] As used herein, the terms "reduced vaping," "reduced vaping," and "reducing 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 e-liquid consumed, a decrease in the number or frequency of puffs of vapor taken from or otherwise consumed from a vaping device, a decrease in the number or frequency of vaping activities performed with a vaping device, or a decrease in the use of a vaping device to ingest vapor.

[0066] As used herein, the term "adverse event" (AE) refers to any untoward medical occurrence in a subject administered a composition, which does not necessarily result from treatment. Thus, an AE may be any undesirable and unintended sign (including abnormal laboratory findings), symptom, or disease temporarily associated with the use of the composition, whether or not considered related to the composition.

[0067] As used herein, the term "adverse drug reaction" refers to any untoward and unintended response to an administered composition. The term "response to a composition" means that attribution has at least a reasonable possibility (i.e., a relationship cannot be ruled out and is judged by the investigator to be at least possible) (see definition below).

[0068] The terms "serious adverse event" (SAE) and "serious adverse reaction" (SAR) refer to an AE that results in at least one of the following: death, is life-threatening, requires hospitalization or prolongs a subject's current hospitalization, results in persistent or significant disability or incapacity, results in a congenital anomaly or birth defect, or is a significant medical event that requires medical intervention to prevent any of the aforementioned outcomes.

[0069] As used herein, the term "suspected unexpected serious adverse reaction" (SUSAR) refers to a serious, unexpected AE for which there is at least a reasonable probability that the event is attributable to a composition. A serious medical event may not be immediately life-threatening, but may endanger the subject and require intervention to prevent one of the other serious outcomes listed above. Examples of such events are allergic bronchospasm that does not result in hospitalization, or blood cachexia, or intensive care in the emergency room or at home for seizures. The term "life-threatening" refers to an event in which the subject was at risk of death at the time of the event, and does not refer to an event that could hypothetically have caused death if it had been more severe. For example, drug-induced hepatitis that resolves without evidence of liver failure is not considered life-threatening, even though drug-induced hepatitis can be fatal. Hospitalization or extension of current hospitalization means that the inpatient's hospitalization and / or extension of hospitalization was required for treatment of the AE or occurred as a result of the event. It does not refer to pre-planned elective hospitalizations for treatment of pre-existing conditions that have not significantly worsened, or diagnostic procedures.

[0070] The terms "cytisine arm," "active arm," "arm," "active arm," and "study arm" are used interchangeably throughout and refer to subjects to whom a composition comprising cytisine is administered.

[0071] List of abbreviations: ADR, adverse drug reaction; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; Cmax, maximum observed plasma concentration; CrCl, creatinine clearance; CRF, case report form; DSM, data safety monitor; ECG, electrocardiogram; GCP, Good Clinical Practice; ICH, International Conference on Harmonisation of Technical Requirements for Pharmaceuticals; IMP, study drug (in this protocol, refers to cytisine 3.0 mg film-coated tablets); MedDRA, Glossary of Therapeutic Terms; 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.

[0072] composition Compositions for use in the methods of the present disclosure comprise cytisine or a pharmaceutically acceptable derivative, conjugate, or salt thereof, or a mixture of any of the foregoing, collectively referred to herein as "cytisine." The term "pharmaceutically acceptable" in this context means that the substance does not cause unacceptable toxicity to the subject or interact with other components of the composition. Cytisine, (-)-cytisine, and cytisiniculine are referred to interchangeably.

[0073] 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.

[0074] Compositions for use in accordance with the present disclosure may be formulated as one or more dosage units. As used herein, the terms "dose unit" and "dosage unit" refer to a portion of a pharmaceutical composition containing an amount of a therapeutic agent suitable for single administration to provide a therapeutic effect. Such dosage units may be administered one to multiple times (i.e., 1 to about 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 times) per day, or as many times as needed to elicit a therapeutic response.

[0075] A unit dose can include a single tablet, such as a tablet containing 3.0 mg of cytisine, or it can include two or more tablets that together contain a unit dose (e.g., 3.0 mg of cytisine). For example, a 3.0 mg unit dose can include two tablets, such as two Tabex® tablets, each containing 1.5 mg of cytisine. Each Tabex® tablet is typically formulated as a compressed, film-coated tablet containing 1.5 mg of cytisine in a single tablet along with multiple tablet-forming excipients (calcium sulfate, cellulose powder, colloidal silica, magnesium stearate) and coated with a colored film coating containing polyvinyl alcohol, titanium dioxide, and iron oxide. As another example, a 3.0 mg unit dose can include three tablets, such as three tablets formulated at least similarly to Tabex® tablets, each containing 1.0 mg of cytisine.

[0076] Alternatively, cytisine can be formulated into a capsule or other vehicle for oral administration, and can be orally delivered, or can be formulated into a composition for nasal or topical administration. As used herein, the term "orally deliverable" or "oral administration" includes any form of delivery of a therapeutic agent or composition thereof to a subject, in which the agent or composition is placed in the subject's mouth, regardless of whether the agent or composition is swallowed. Thus, "oral administration" includes buccal and sublingual administration, as well as esophageal administration.

[0077] Tablets and other dosage forms (hereinafter all referred to as "compositions") can contain one or more excipients, such as those common in the art. Excipients that can be used in the compositions include, for example, fillers, disintegrants, preservatives, lubricants, and wetting agents.

[0078] Examples of fillers that can be used include lactose (eg, either anhydrous or monohydrate), cellulose, starch (eg, corn and / or wheat starch), calcium phosphate, calcium sulfate, and mannitol.

[0079] Preservatives prevent bacterial or fungal contamination of the formulation and include various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid.

[0080] Suitable lubricants include stearic acid and its salts. One example of a lubricant for use in the compositions of the present disclosure is magnesium stearate.

[0081] The pharmaceutical composition may further comprise a sweetening, flavoring, or coloring agent.

[0082] In some embodiments, the placebo is a tablet containing the same, substantially the same, similar, or substantially similar inactive (e.g., cytisine) ingredient as the test composition. In these embodiments, the placebo contains at least the same, substantially the same, similar, or substantially similar excipients, fillers, preservatives, lubricants, sweeteners, flavorings, and / or colorants as the test composition, and at least one inactive ingredient, such as cellulose. In some embodiments, the placebo tablet and the test composition tablet are the same or substantially the same weight, size, shape, color, and / or contained in the same or substantially the same packaging.

[0083] Those skilled in the art will be familiar with suitable fillers, preservatives, and lubricants, as well as suitable sweeteners, flavors, colorants, and other additives other than those specifically mentioned above. The pharmaceutical compositions of cytisine useful in the methods of the present disclosure can include a coating, e.g., a film coating, and can be coated according to any method known in the art, for example, with kollidon, shellac, gum arabic, talc, titanium dioxide, or sugar.

[0084] The pharmaceutical composition containing 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 packing it into gelatin capsules.Tablets can be prepared by known compression methods.

[0085] In one embodiment, a composition of the present disclosure exhibits at least about 90%, at least about 95%, at least about 97.5%, or at least about 99% of the active ingredient initially present therein upon storage for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months in a sealed container maintained at room temperature, refrigerated (e.g., about 5 to about −10° C.) temperature, or frozen.

[0086] method The present disclosure provides for treating nicotine addiction or nicotine dependence in a subject in need thereof, comprising administering to the subject an effective amount of cytisine. In some embodiments, the method of treating nicotine addiction or nicotine dependence comprises preventing smoking relapse and / or promoting smoking cessation or reduction in a subject in need thereof.

[0087] In some embodiments, the present disclosure provides a method of treating nicotine addiction or nicotine dependence in a subject in need thereof, comprising administering a therapeutically effective amount of cytisine to the subject. In some embodiments, the present disclosure relates to a method for preventing smoking relapse in a subject in need thereof, comprising administering a therapeutically effective amount of cytisine to the subject. In another embodiment, the present disclosure provides a method of promoting smoking cessation in a subject in need thereof, comprising administering a therapeutically effective amount of cytisine to the subject. In some embodiments, the present disclosure provides a method for promoting smoking cessation in a subject in need thereof, comprising administering an effective amount of cytisine to the subject. In some embodiments, the present disclosure provides a method of treating nicotine addiction or nicotine dependence in a subject in need thereof, wherein the nicotine addiction or nicotine dependence is in the form of cigarettes, smokeless tobacco, snus, electronic cigarettes (e-cigs), vaping using a vaping device, and / or hookah. In some embodiments, the vaping device contains a liquid containing nicotine, e.g., about 1 mg / ml to about 12 mg / ml of nicotine, or greater than about 13 mg / ml of nicotine. Any patient with nicotine addiction or dependence can be treated by the methods disclosed herein.

[0088] In additional embodiments, the present disclosure provides a method for treating and / or preventing addiction or dependence in a subject in need thereof, comprising administering a therapeutically effective amount of cytisine to the subject. Without intending to be bound by any particular theory, cytisine interacts with the dopamine neurotransmitter release cycle as a partial agonist of the nicotinic acetylcholine receptor (nAChR) and is useful for treating and / or preventing multiple addictions or multiple dependencies in a subject in need thereof. Non-limiting examples of addictions and dependencies that may be treated and / or prevented by administering cytisine include addiction and / or dependence on substances, compounds, and / or behaviors that may involve the dopamine neurotransmitter release cycle. Exemplary substances, compounds, and / or behaviors include, but are not limited to, marijuana, cannabis, tetrahydrocannabinol (THC), cannabidiol (CBD), alcohol, opioids and other painkillers, cocaine, eating, gambling, sexual activity, heroin, benzodiazepines, barbiturates, stimulants, and inhalants. In further embodiments, the present disclosure provides a method for promoting cessation of an addiction or dependence in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of cytisine. In some embodiments, the present disclosure provides a method for promoting a reduction in a subject's addiction and / or dependence, comprising administering to the subject an effective amount of cytisine. The compositions and methods described herein relating 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 the dopamine neurotransmitter release cycle.

[0089] In further embodiments, methods of treating nicotine addiction or nicotine dependence include preventing vaping relapse and / or promoting cessation or reduction in vaping in a subject in need thereof. In some embodiments, the present disclosure relates to a method for preventing vaping relapse in a subject in need thereof, comprising administering a therapeutically effective amount of cytisine to the subject. In another embodiment, the present disclosure provides a method for promoting vaping cessation in a subject in need thereof, comprising administering a therapeutically effective amount of cytisine to the subject. In some embodiments, the present disclosure provides a method for promoting vaping reduction in a subject in need thereof, comprising administering a therapeutically effective amount of cytisine to the subject.

[0090] In some embodiments, provided herein are methods of treating nicotine addiction or nicotine dependence in a subject, comprising administering to a subject in need thereof equal doses of cytisine twice daily ("bid" or "BID") or three times daily ("tid" or "TID"). In one embodiment, each of the two daily doses is administered in the morning and evening, respectively. In another embodiment, each of the two daily doses is administered approximately 10-12 hours apart. In yet another embodiment, each of the three daily doses is administered in the morning, afternoon, and evening. In another embodiment, each of the three daily doses is administered approximately 4-5 hours apart. In yet another embodiment, each of the three daily doses is administered approximately 4, 5, 6, 7, 8, 9, 10, or more hours apart. In one embodiment, administration is administered for at least about 6 weeks, at least about 12 weeks, at least about 24 weeks, or indefinitely. In this embodiment, administration can include BID or TID for any period of days or weeks during administration. For example, in these embodiments, the entire period of administration can be BID or TID. As another example, in these embodiments, at least a portion of the administration can be BID or TID, e.g., at least about 1 day, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 12 weeks, etc. As yet another example, in these embodiments, BID or TID administration can be in any order, such as day 1 can be BID or TID, day 2 can be BID or TID, and day 3 can be BID or TID during the administration period.

[0091] In some embodiments, administration is carried out regardless of whether the subject is in a fed or fasted state.For example, administration can be carried out simultaneously with food, with food, any time before the subject ingests food, or any time after the subject ingests food.Without intending to be limited to a particular theory, it is not believed that food (or fed or fasted state) affects the bioavailability of cytisine or the overall bioavailability of cytisine, which can be determined by the systemic absorption of cytisine in the subject.

[0092] 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, regardless of how the dose is divided. For example, each TID dose can be given as two 0.5 mg strength tablets administered three times daily, or one 1 mg tablet administered three times daily, or any other possibility. In some embodiments, the TID dose is 1.0 mg, regardless of how the dose is divided between dosage units. In some embodiments, the TID dose is 1.5 mg, regardless of how the dose is divided between dosage units. In some embodiments, the TID dose is 2 mg, regardless of how the dose is divided between dosage units. In yet other embodiments, the TID dose is 2.5 mg, regardless of how the dose is divided between dosage units. In some embodiments, the TID dose is 3.0 mg, regardless of how the dose is divided between dosage units.

[0093] In some embodiments, the subject does not experience any adverse events associated with cytisine treatment. Adverse events can be mild (e.g., no interference with activities), moderate (interference with activities but no or minimal need for medical intervention), or severe (interference with daily activities and need for medical intervention). Non-limiting examples of adverse events include upper respiratory tract infections (URTIs), abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In other embodiments, the subject experiences no more than two adverse events associated with cytisine treatment, such as an increase of about 0% to about 10%, e.g., about 0%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, of nausea, abnormal dreams, insomnia, headache, and / or URTIs in the subject. In some embodiments, the subject experiences fewer adverse events compared to subjects administered nicotine replacement therapy (NRT), bupropion, varenicline, e-cigarettes, vaping, and / or combinations thereof.

[0094] In some embodiments, a subject experiences nicotine addiction or nicotine dependence by smoking cigarettes, consuming smokeless tobacco and / or snus, using an electronic cigarette (e-cig) and / or vaping, and / or using a hookah daily, such as consuming 100 units of nicotine per day. In some embodiments, a subject with nicotine addiction or dependence consumes between about 0 and about 100 units of nicotine per day. For example, a single cigarette can be a unit of nicotine, and a subject with nicotine addiction or nicotine dependence may smoke between about 0 cigarettes per day and about 100 cigarettes per day, between about 5 cigarettes per day and about 75 cigarettes per day, between about 5 cigarettes per day and about 50 cigarettes per day, between about 5 cigarettes per day and about 25 cigarettes per day, between about 10 cigarettes per day and about 50 cigarettes per day, between about 20 cigarettes per day and about 50 cigarettes per day, between about 25 cigarettes per day and about 75 cigarettes per day, between about 25 cigarettes per day and about 50 cigarettes per day, e.g., between 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, Tobacco, 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 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, nicotine units also include the consumption of smokeless tobacco and / or snus, the use of electronic cigarettes (e-cigs) and / or vapes (e.g., vaping), and / or the use of hookah instead of or in combination with daily cigarettes.

[0095] In some embodiments, administration of cytisine reduces the number of units of nicotine a subject ingests per day, such as the number of cigarettes a subject smokes per day. In some embodiments, the methods of the present technology reduce the rate of cigarettes smoked by a subject by at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% after treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine, compared to control subjects, placebo controls, and / or baseline.

[0096] In some embodiments, administration of cytisine increases smoking cessation in a subject after treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine. In these embodiments, the subject achieves 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 50%, about 25% to about 75%, about 25% to about In some embodiments, the increase in smoking cessation is about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, or about 32 weeks. In certain embodiments, the smoking cessation period 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.

[0097] In some embodiments, administration of cytisine increases smoking cessation rates in subjects after treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine. In these embodiments, subjects experience abstinence rates of 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 50%, about 25% to about 75%, about 25% to about 50 ... % 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%, e.g., 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% abstinence rate. In some embodiments, the abstinence rate is determined after abstinence periods such as about 1 day, about 3 days, about 7 days, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, or about 32 weeks. In certain embodiments, the abstinence period is from about 1 day to about 4 weeks, from about 1 week to about 8 weeks, from about 1 week to about 2 weeks, from about 3 weeks to about 6 weeks, from about 2 weeks to about 12 weeks, from about 9 weeks to about 12 weeks, from about 4 weeks to about 24 weeks, or from about 8 weeks to about 32 weeks.

[0098] In some embodiments, the subject is administered a cytisine dose 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 and having an exhaled CO level of 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 of 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine or treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine reduces exhaled CO levels by a subject by at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% compared to control subjects, placebo controls, and / or baseline. In some embodiments, the subject has an exhaled CO level after treatment with cytisine 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.

[0099] In some embodiments, the subject has a serum cytisine level of 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, or about 200 ng / mL and / or plasma cotinine levels of about 500 ng / mL, e.g., about 10 ng / mL, about 20 ng / mL, about 30 ng / mL, about 40 ng / mL, about 50 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, about 100 ng / mL, about 125 ng / mL, about 150 ng / mL, about 175 ng / mL, about 200 ng / mL, about 225 ng / mL, about 250 ng / mL, about 275 ng / mL, about 300 ng / mL, about 325 ng / mL, about 350 ng / mL, about 375 ng / mL, about 400 ng / mL, about 425 ng / mL, about 450 ng / mL, about 475 ng / mL, or about 500 ng / mL. In some embodiments, administration of 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine 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 a subject by at least 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% compared to control subjects, placebo controls, and / or baseline.In some embodiments, the subject has a serum and / or plasma cotinine level of 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, e.g., 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, after treatment with cytisine.

[0100] In some embodiments, administration of cytisine increases the odds ratio in a subject after 4 weeks of treatment, after 8 weeks of treatment, and 4 weeks after treatment ends with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID cytisine. In these embodiments, the subject has an odds ratio of about 1.1 to about 20, about 1.1 to about 15, about 1.1 to about 10, about 1.1 to about 5, about 5 to about 10, about 5 to about 15, about 10 to about 15, about 10 to about <20, or about 10 to about 20, compared to control subjects, placebo controls, and / or baseline.

[0101] 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 does not exhibit clinically significant changes in vital signs, hematology and chemistry levels, and ECG after administration of cytisine.

[0102] In some embodiments, a subject is a heavy, moderate, or light nicotine user, such as a nicotine smoker or vaper, and can be categorized as a "heavy smoker" or "heavy vaper," a "moderate smoker" or "moderate vaper," or a "light smoker" or "light vaper." For example, a "heavy smoker" provided herein refers to a subject who reports consuming 20 or more cigarettes per day. A "moderate smoker" provided herein refers to a subject who reports consuming 11 to 19 cigarettes per day. A "light smoker" provided herein refers to a subject who reports consuming 1 to 10 cigarettes per day. As another example, a "heavy vaper" provided herein refers to a subject who engages in vaping activity 20 or more times per day, reports consuming puffs from a vaping device 20 or more times per day, or otherwise reports using a vaping device 20 or more times per day. As provided herein, a "moderate vaper" refers to a subject who reports engaging in 11 to 19 vaping activities per day, consuming 11 to 19 puffs from a vaping device per day, or otherwise reporting 11 to 19 vaping device uses per day. As provided herein, a "light vaper" refers to a subject who engages in 1 to 10 vaping activities per day, consuming 1 to 10 puffs from a vaping device per day, or otherwise reporting 1 to 10 vaping device uses per day. In some embodiments, administration of cytisine reduces cotinine levels in subjects identified as heavy smokers or heavy vapers. In some embodiments, administration of cytisine reduces cotinine levels in subjects identified as moderate smokers or moderate vapers. In yet another embodiment, administration of cytisine reduces cotinine levels in subjects identified as light smokers or light vapers.

[0103] In some embodiments, the subject has been smoking or vaping for at least about 1 year, at least about 5 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 35 years, at least about 40 years, at least about 45 years, at least about 50 years, or more, prior to administration of cytisine.

[0104] In some embodiments, the subject began smoking or vaping during adolescence. In some embodiments, the subject began smoking or vaping between the ages of 10 and 19. In some embodiments, the subject began smoking or vaping during adolescence and has been smoking or vaping for at least about 20 years, at least about 25 years, at least about 30 years, at least about 35 years, at least about 40 years, at least about 45 years, at least about 50 years, or more, prior to administration of cytisine.

[0105] 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 above for about 6 weeks.

[0106] Compared to a commercially available 25-day titration schedule with a 1.5 mg unit dose of cytisine, the percentage of smokers with sustained smoking cessation is surprisingly high in patients treated according to the methods disclosed herein, as shown, for example, in FIG. 7.

[0107] In some embodiments, the subject is a smoker, e.g., smoking about 3 or more cigarettes per day. In some embodiments, the subject is a smoker, e.g., smoking about 5 or more cigarettes per day, or about 10 or more cigarettes per day. In some embodiments, the subject has a measurable exhaled CO2 concentration of about 10 ppm or greater before administration of cytisine.

[0108] In some embodiments, the subject is a refractory patient. As used herein, a "refractory patient" or "refractory subject" refers to a subject who has failed treatment with one or more nicotine addiction or nicotine dependence treatments. In some embodiments, nicotine addiction or nicotine dependence treatments include both regulatory-approved treatments and smoking cessation methods, such as vaping and behavioral support. Non-limiting examples of behavioral support include behavioral support useful for reducing, preventing, or otherwise treating anxiety, depression, and / or withdrawal symptoms. In certain embodiments, behavioral support includes counseling, diaries, wearable devices, apps, web-based smoking cessation programs, text message interventions, and combinations thereof. In further embodiments, behavioral support is provided to non-refractory patients, such as control patients (e.g., baseline, placebo-administered, citisinicline-free smoking, vaping, or nicotine cessation medication-administered). In some embodiments, nicotine addiction or nicotine dependence treatments include FDA-approved first-line smoking cessation medications, such as NRT, bupropion, and varenicline. Nicotine replacement therapy can be in the form of patches, gums, lozenges, sprays, and inhalers.

[0109] In some embodiments, the subject is the refractory patient who has failed in one or more nicotine addiction or nicotine dependence treatments.For example, the subject has failed in 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 the refractory patient who has failed in one or more nicotine addiction or nicotine dependence treatments, including NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or combinations thereof.

[0110] 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.

[0111] In some embodiments, the refractory subject has previously received nicotine addiction and / or nicotine dependence treatment 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.

[0112] In one aspect, the method includes administering cytisine to a 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, the unit dose of cytisine is administered to the subject three to six times daily. In some embodiments, the unit dose of cytisine is administered to the subject three times daily. In some embodiments of the methods disclosed herein, the unit dose is about 1.0 mg administered three times daily, about 1.5 mg administered three times daily, or about 3.0 mg administered three times daily 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 unit dose of cytisine is administered for up to about 2 weeks, about 2 weeks to about 6 weeks, about 3 weeks to about 6 weeks, or about 9 weeks to about 12 weeks. In some embodiments, the relapse rate is lower in subjects administered a unit dose of cytisine for at least about 4 weeks compared to subjects administered a unit dose of cytisine for at least about 2 weeks. In other embodiments, the relapse rate is lower in subjects receiving a unit dose of cytisine for at least about 6 weeks compared to subjects receiving a unit dose of cytisine for at least about 4 weeks. In further embodiments, the relapse rate is lower in subjects receiving a unit dose of cytisine for at least about 8 weeks compared to subjects receiving a unit dose of cytisine for at least about 4 weeks. In yet further embodiments, the relapse rate is lower in subjects receiving a unit dose of cytisine for at least about 12 weeks compared to subjects receiving a unit dose of cytisine for at least about 4 weeks.

[0113] In some embodiments, administering cytisine to subjects resulted in significantly better nicotine cessation rates (quit rate or vaping continuity rate) compared to subjects administered a commercially available 1.5 mg per unit dose schedule. In some embodiments, a 3.0 mg unit dose of cytisine is administered three times daily for six weeks (e.g., the first six weeks), followed by six weeks of placebo (e.g., the next six weeks). In certain embodiments, behavioral support is provided during at least a portion of the first six weeks, during at least a portion of the next six weeks, before at least a portion of the first six weeks, after at least a portion of the next six weeks, or a combination thereof. In some embodiments, a 3.0 mg unit dose of cytisine is administered three times daily for 12 weeks. In certain embodiments, behavioral support is provided to subjects during at least a portion of the 12 weeks, before the 12 weeks, after the 12 weeks, or a combination thereof. Thereafter, in some embodiments, the subject:

[0114] (a) a reduction in units of nicotine used per day, such as cigarettes smoked per day or vaping per day, compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0115] (b) a decrease in exhaled CO levels compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0116] (c) a decrease in serum and / or plasma cotinine levels in a subject compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0117] (d) increased abstinence rates compared with subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0118] (e) no change, no increase, or a decrease in adverse events compared with subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0119] (f) an increase in the odds ratio of a subject compared with subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0120] (g) increased smoking cessation compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0121] (h) a reduction in nicotine craving and / or tobacco craving compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0122] (i) a reduction in the severity of nicotine withdrawal symptoms compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0123] (j) a reduction in the severity of anxiety compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline; and / or

[0124] (k) exhibiting one or more of the following: a reduction in the severity of depression compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline.

[0125] In one embodiment, the method of the present disclosure comprises measuring a baseline level of one or more markers set forth in (a)-(k) above prior to administration to a subject or group of subjects. In another embodiment, the method comprises administering a composition disclosed herein to a subject after a baseline level of one or more markers set forth in (a)-(k) has been determined, followed by an additional measurement of the one or more markers. In another embodiment, treatment with a composition of the present disclosure results in a subject:

[0126] (a) at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or more reduction in units of nicotine used per day, such as cigarettes smoked per day or vaping per day, compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0127] (b) a reduction in exhaled CO levels of about 5 to about 100% compared to baseline, control, or placebo levels, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, 30%, about 35%, about 40%, about 45%, about 50%, or more compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0128] (c) a reduction 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 receiving NRT, control subjects, placebo controls, and / or baseline;

[0129] (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%, 30% to about 50%, about 30% to about 75%, about 30% to about <100%, or about 30% to about 100%, compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0130] (e) no change, no increase, or about a 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or greater reduction in adverse events compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline;

[0131] (f) an increase in the odds ratio of subjects receiving NRT, control subjects, placebo controls, and / or baseline 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;

[0132] (g) an increase in smoking cessation 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 receiving NRT, control subjects, placebo controls, and / or baseline;

[0133] (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 receiving NRT, control subjects, placebo controls, and / or baseline;

[0134] (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 receiving NRT, control subjects, placebo controls, and / or baseline;

[0135] (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 receiving NRT, control subjects, placebo controls, and / or baseline; and / or

[0136] (k) exhibiting one or more of the following: about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more reduction in depression severity compared to subjects receiving NRT, control subjects, placebo controls, and / or baseline.

[0137] In some embodiments, the disclosed methods include treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, the methods comprising administering cytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine three times daily to the subject. In certain 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 URTIs, 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 about 12 weeks. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each 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, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. In some embodiments, the subject (a) smoked 10 or more cigarettes or vaped 10 or more times per day before administration of cytisine; (b) had an exhaled CO2 concentration of about 10 ppm or higher before administration of cytisine; or (c) a combination of (a) and (b). In some embodiments, the method further comprises providing behavioral support to the subject.

[0138] In some embodiments, the disclosed methods include treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, the methods comprising administering cytisine provided in a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine three times daily to the subject, wherein the subject does not experience an adverse event after receiving the cytisine treatment. In some embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0139] In some embodiments, the methods of the disclosure include treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, the methods comprising administering cytisine provided in a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine to the subject three times daily, wherein the subject does not experience nausea after receiving the cytisine.

[0140] In some embodiments, the disclosed methods include treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, the methods comprising administering cytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine to the subject three times daily for about 6 or 12 weeks. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each containing 1.0 mg of cytisine.

[0141] In some embodiments, the disclosed methods include treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, the methods comprising administering cytisine provided in a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine three times daily to the subject, wherein the subject is a refractory patient who has failed 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, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0142] In some embodiments, the methods of the disclosure include treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, the methods comprising administering cytisine provided in a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine three times daily to the subject, wherein the subject (a) smoked 10 or more cigarettes per day prior to administration of the cytisine, or (b) had an exhaled CO2 concentration of about 10 ppm or greater prior to administration of the cytisine, or (c) a combination of (a) and (b).

[0143] In some embodiments, the methods of the disclosure include treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, the methods comprising administering cytisine to the subject provided in a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine three times daily, and providing behavioral support to the subject.

[0144] The disclosed methods further include treating nicotine addiction or nicotine dependence in a subject in need thereof, the method comprising administering cytisine to the subject, wherein the subject is a treatment-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, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof. In some embodiments, cytisine is provided to a subject in need thereof in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times daily. In certain embodiments, cytisine is provided to a subject in need thereof in a unit dose of 3.0 mg of cytisine three times daily. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 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 about 12 weeks. In some embodiments, the subject does not experience any adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject (a) smoked 10 or more cigarettes per day prior to administration of cytisine, (b) had an exhaled CO2 level of about 10 ppm or higher prior to administration of cytisine, or (c) a combination of (a) and (b).

[0145] The disclosed methods further provide a method for preventing smoking and / or vaping relapse in a subject in need thereof, the method comprising administering cytisine to the subject three times daily in a unit dose of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine. In some embodiments, the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience any adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, (b) had an exhaled CO2 concentration of about 10 ppm or more before administration of cytisine, 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 therapy includes NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof.

[0146] The disclosed methods further include preventing smoking and / or vaping relapse in a subject in need thereof, wherein the method comprises administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies selected from the group consisting of NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof. In some embodiments, the subject (a) smoked 10 or more cigarettes per day prior to administration of cytisine, (b) had an exhaled CO2 level of about 10 ppm or greater 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 containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each containing 1.0 mg of cytisine, three times daily to the subject, wherein the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject, after receiving the cytisine treatment, does not experience an adverse event selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0147] The present disclosure also provides pharmaceuticals, such as pharmaceuticals comprising a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine for treating nicotine addiction, nicotine dependence, promoting smoking and / or vaping cessation, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, wherein the pharmaceuticals are for oral administration to the subject three times daily. 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 URTIs, 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 about 12 weeks. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each 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, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. In some embodiments, the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, (b) had an exhaled CO2 level of about 10 ppm or higher before administration of cytisine, or (c) a combination of (a) and (b). In some embodiments, the method further comprises providing behavioral support to the subject.

[0148] The present disclosure also provides pharmaceuticals, such as pharmaceuticals comprising a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine, for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, wherein the pharmaceutical is for oral administration to the subject three times daily, and the subject does not experience adverse events after receiving the cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving the cytisine treatment.

[0149] The present disclosure further provides pharmaceutical products, such as pharmaceutical products comprising a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, wherein the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each containing 1.0 mg of cytisine.

[0150] In some embodiments, the present disclosure further provides a pharmaceutical product comprising a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, 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, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0151] In some embodiments, the present disclosure further provides a pharmaceutical product comprising a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine for treating nicotine addiction, nicotine dependence, promoting smoking and / or vaping cessation, and / or reducing smoking and / or vaping in a subject in need thereof, wherein the subject (a) smoked 10 or more cigarettes per day prior to administration of cytisine, or (b) had an exhaled CO2 level of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0152] The present disclosure further provides pharmaceuticals, such as pharmaceuticals 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 or nicotine dependence treatments, wherein the pharmaceutical is for oral administration to the patient three times daily. In some embodiments, the nicotine addiction or nicotine dependence treatment includes NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof. In some embodiments, the cytisine is provided to a subject in need thereof in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times daily. In certain embodiments, the cytisine is provided to a subject in need thereof in a unit dose of 3.0 mg of cytisine three times daily. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 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 about 12 weeks. In some embodiments, the subject does not experience any adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject (a) smoked 10 or more cigarettes per day prior to administration of cytisine, (b) had an exhaled CO2 level of about 10 ppm or higher prior to administration of cytisine, or (c) a combination of (a) and (b).

[0153] In some embodiments, the pharmaceutical product contains a unit dose of cytisine in the following dosage forms for preventing relapse to smoking and / or vaping in a subject in need thereof: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine; the pharmaceutical product is for oral administration to the subject three times daily. In certain embodiments, the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience any adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, (b) had an exhaled CO2 concentration of about 10 ppm or more before administration of cytisine, 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 therapy includes NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof.

[0154] The present disclosure further provides a pharmaceutical product, such as a pharmaceutical product comprising cytisine, for preventing relapse to smoking and / or vaping in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, e-cigarettes, or vaping, wherein the pharmaceutical product is for oral administration to the subject three times daily. In some embodiments, the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, (b) had an exhaled CO2 concentration of about 10 ppm or higher before administration of cytisine, or (c) a combination of (a) and (b). In some embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each containing 1.0 mg of cytisine, and the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject, after receiving cytisine treatment, does not experience an adverse event selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0155] In some embodiments, the present disclosure provides for the use of a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine to treat nicotine addiction, nicotine dependence, promote smoking and / or vaping cessation, and / or promote smoking and / or vaping reduction in a subject in need thereof, wherein the cytisine is for oral administration to the subject three times daily. 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 URTIs, 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 about 12 weeks. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each 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, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. In some embodiments, the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, (b) had an exhaled CO2 level of about 10 ppm or higher before administration of cytisine, or (c) a combination of (a) and (b). In some embodiments, the use further comprises providing behavioral support to the subject.

[0156] The present disclosure further provides uses of cytisine, such as 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 or nicotine dependence treatments, wherein the cytisine is for oral administration to the patient three times daily. In certain embodiments, the nicotine addiction or nicotine dependence treatment includes NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof. In some embodiments, the cytisine is provided to a subject in need thereof in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times daily. In certain embodiments, the cytisine is provided to a subject in need thereof in a unit dose of 3.0 mg of cytisine three times daily. In certain embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 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 about 12 weeks. In some embodiments, the subject does not experience any adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject (a) smoked 10 or more cigarettes per day prior to administration of cytisine, (b) had an exhaled CO2 level of about 10 ppm or higher prior to administration of cytisine, or (c) a combination of (a) and (b).

[0157] In some embodiments, the use of a unit dose of cytisine in the form of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine, comprises preventing smoking relapse in a subject in need thereof, wherein the cytisine is for oral administration to the subject three times daily. In some embodiments, the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience any adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, (b) had an exhaled CO2 concentration of about 10 ppm or more before administration of cytisine, 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 therapy includes NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof.

[0158] In some embodiments, the present invention provides a method for preventing relapse to smoking in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, e-cigarettes, or vaping, wherein the cytisine is orally administered to the subject three times daily. In some embodiments, the subject (a) smoked 10 or more cigarettes per day before administration of the cytisine, (b) had an exhaled CO2 concentration of about 10 ppm or more before administration of the cytisine, or (c) a combination of (a) and (b). In certain embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each containing 1.0 mg of cytisine, and the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience an adverse event selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving cytisine treatment.

[0159] The present disclosure further provides the use of tablets containing about 1.0 mg or 1.5 mg of cytisine for oral administration of about 3.0 mg of cytisine to a subject three times daily for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject. 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 URTIs, 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 about 12 weeks. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each 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, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. In some embodiments, the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, (b) had an exhaled CO2 level of about 10 ppm or higher before administration of cytisine, or (c) a combination of (a) and (b). In some embodiments, the use further comprises providing behavioral support to the subject.

[0160] In some embodiments, the use of tablets containing about 1.0 mg or 1.5 mg of cytisine is for oral administration of about 3.0 mg of cytisine three times daily to a subject who is a treatment-refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments to treat nicotine addiction or nicotine dependence in the subject. In certain embodiments, the nicotine addiction or nicotine dependence treatment includes NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof. In some embodiments, the cytisine is provided to a subject in need thereof in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times daily. In certain embodiments, the cytisine is provided to a subject in need thereof in a unit dose of 3.0 mg of cytisine three times daily. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 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 about 12 weeks. In some embodiments, the subject does not experience any adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject (a) smoked 10 or more cigarettes per day prior to administration of cytisine, (b) had an exhaled CO2 level of about 10 ppm or higher prior to administration of cytisine, or (c) a combination of (a) and (b).

[0161] In some embodiments, the use of tablets containing 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 relapse to smoking and / or vaping in the subject. In certain embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience any adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, (b) had an exhaled CO2 level of about 10 ppm or higher before administration of cytisine, 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 treatment comprises NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof.

[0162] In some embodiments, the use of tablets containing about 1.0 mg or about 1.5 mg of cytisine is for oral administration of about 3.0 mg of cytisine three times daily to a subject who has failed treatment with one or more nicotine addiction or nicotine dependence treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, e-cigarettes, or vaping to prevent relapse to smoking in the subject. In some embodiments, the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, (b) had an exhaled CO2 concentration of about 10 ppm or higher before administration of cytisine, or (c) a combination of (a) and (b). In some embodiments, the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each containing 1.0 mg of cytisine, and the cytisine is administered for about 6 weeks or 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.

[0163] Thus, in yet another aspect, provided herein are methods for treating nicotine addiction or nicotine dependence in a subject, 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 or nicotine dependence treatments. Suitable unit doses include doses of about 1.0 mg to about 6 mg, which can be administered three to six times daily, e.g., at approximately equal intervals. For example, in some embodiments, the method comprises administering cytisine provided in a 3.0 mg unit dose of cytisine to a refractory patient three times daily. Any suitable administration period can be used in the methods disclosed herein, e.g., about 26 weeks, about 12 weeks, or about 6 weeks. In some embodiments, the treatment is administered for about 6 weeks.

[0164] In some embodiments, the methods disclosed herein can further include providing behavioral support to a subject, e.g., a refractory patient. The behavioral support can include counseling on topics including, but not limited to, smoking cessation, past smoking cessation experiences, anticipating motivations or challenges in future attempts, alcohol use, proximity and frequency of contact with other nicotine users (e.g., smokers), recognizing risky situations, and coping skills.

[0165] In some embodiments, the methods disclosed herein can further include providing one or more questionnaires to the subject. Non-limiting examples of the one or more questionnaires include the Electronic Cigarette Dependence Scale Questionnaire, the Marijuana Craving Questionnaire - Short Form, the Fagerstrom Test for Nicotine Dependence, the Smoking Self-Efficacy Questionnaire (SEQ-12), the Quick Smoking Urge Questionnaire (QSU-Brief) Questionnaire, the Minnesota Nicotine Withdrawal Scale (MNWS) Questionnaire, the C-SSRS "Since Last Visit" Questionnaire, and the HADS Questionnaire. In certain embodiments, the questionnaire can be provided to the subject at any time during, before, or after the administration of the composition. In some embodiments, the one or more questionnaires are provided to the subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 30 times.

[0166] The patents, patent applications, and scientific literature referenced herein are incorporated by reference in their entirety as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference. Any conflict between a reference cited herein and a specific teaching of this specification shall be resolved in favor of the latter. Similarly, any conflict between an art-understood definition of a word or phrase and a definition of a word or phrase specifically taught herein shall be resolved in favor of the latter.

[0167] As can be seen from the above disclosure, the present invention has a wide variety of applications. The present invention is further described by the following examples, which are merely illustrative and are not intended to limit the definition or scope of the invention in any way.

[0168] Example 1: The effect of cytisine in the treatment of nicotine addiction This was a six-arm, multicenter, double-blind, randomized, placebo-controlled trial conducted in male or female adults aged ≥18 years, smoking ≥10 cigarettes daily, and willing to quit 5–7 days after randomization. The trial was designed to evaluate the efficacy of 1.5 mg cytisine versus placebo using a commercially available dose-finding schedule approved in Central and Eastern Europe. The trial also evaluated the efficacy of a 1.5 mg simplified TID dosing schedule and a 3.0 mg escalated dose (using both the commercial dose-finding (COM) and simplified TID dosing schedules). The overall goal of the study was to obtain effect size estimates for efficacy and safety endpoints to be used to inform the design of future phase 3 trials.

[0169] The dosing schedule of the study is shown in Figure 1. The study was double-blinded to dose but not to dosing schedule, and the study arms are shown in Figure 2. As shown in Figure 3, study treatment began the day after randomization so that study treatment would begin before the stop date.

[0170] The primary efficacy endpoint in this study was the percentage reduction in the number of cigarettes smoked during treatment, calculated as follows:

number

[0171] Secondary efficacy endpoints were abstinence rates (confirmed by CO<10 ppm), including analyses at week 4 (i.e., end of treatment) and sustained (4-week) abstinence from week 5 through week 8 (i.e., after end of treatment).

[0172] Subject demographics are summarized in Figure 4. Cigarettes smoked by subjects before and after treatment are shown in Figure 5.

[0173] 1.1 Results Table 1 summarizes subject demographics. A total of 254 male or female adults aged ≥18 years who smoked ≥10 cigarettes daily and were willing to quit 5–7 days after randomization were assigned to the study. Demographic and baseline characteristics were well balanced across both schedules and treatment groups. [Table 1]

[0174] Of the study population, 53% were women and 47% were men. 79% of the study population were white, 18% were black, and 3% were of another race. Smoking diary adherence, on which the primary analysis was based in part, was high in all treatment groups. Study drug adherence was >94% in all treatment groups, with slightly higher adherence (>98%) for the TID schedule. The mean treatment duration was 23.4 days, and 96.6% of subjects received the mean dose of cytisine.

[0175] Table 2 summarizes the smoking histories of subjects in all treatment groups. Overall, the study population represented highly addicted smokers who were, on average, 48.4 years old and had been smoking for 32 years, meaning that most of them had started smoking during adolescence. Furthermore, they had previously attempted to quit smoking an average of 4.5 times, with their last attempt occurring approximately 3.7 years before study entry, and currently smoked an average of one pack of cigarettes per day. Of the previous quit attempts, 35% of subjects had previously received varenicline, 16% had received bupropion, and 48% had received NRT. [Table 2] An analysis of the international EAGLES trial provided clear evidence that smoking at a younger age and being born in the United States are associated with lower success rates for quitting smoking. The lower success rates among U.S. smokers support the idea that U.S. smokers may be reaching a tobacco epidemic point, and therefore those who continue to smoke have special characteristics that make it more difficult for them to quit, despite cultural pressures to the contrary.

[0176] Overall, study medication adherence was high in all treatment groups, with the TID schedule (98.18%) being better than the commercial schedule (94.90%). More specifically, Table 3 summarizes study medication adherence in all treatment groups. Study medication adherence ranged from 96.7% to 99.5% in the TID group, whereas study medication adherence ranged from 94.2% to 96.4% in the COM group. [Table 3]

[0177] The reduction in cigarettes smoked in all treatment groups is shown in Figure 6 and summarized in Table 4. Results from the primary analysis showed a significant reduction in the expected proportion of cigarettes smoked (cigarette score) in both COM groups. When placebo groups were pooled, the cigarette score decreased significantly in both COM groups, the 1.5 mg TID group, and approached significance in the 3.0 mg TID group. Using the COM schedule, subjects treated with 1.5 mg or 3.0 mg cytisine smoked approximately 14%–16% fewer cigarettes than expected compared to placebo. On the TID schedule, subjects treated with 1.5 mg or 3.0 mg cytisine smoked approximately 9%–12% fewer cigarettes than expected compared to the placebo group. [Table 4]

[0178] Although the reductions on the TID schedule were not as high as those shown on the COM schedule, it should be noted that placebo subjects on the TID schedule reported a higher reduction in cigarettes smoked than placebo subjects on the COM schedule. TID placebo subjects smoked only one-third as many cigarettes as usual (LS mean: 35.30%), whereas COM placebo subjects smoked half as many cigarettes (LS mean: 47.10%), which may have masked cytisine treatment on the TID schedule.

[0179] Exhaled CO levels were also measured during the study as an objective biochemical marker of smoking reduction. The reductions in CO in all treatment groups are shown in Figure 6 and summarized in Table 4. In all cytisine treatment groups, the reductions in CO (55%–62% reduction) coincided with a reduction in reported cigarettes smoked (e.g., a range of 25%–32% for cigarette scores represents a 75%–68% reduction in smoking). Conversely, in the placebo treatment group, the reduction in reported number of cigarettes smoked (e.g., a 41% reduction for cigarette scores represents a 59% reduction in cigarettes smoked) was not paralleled by a corresponding reduction in CO of only 29%. A similar pattern in plasma cotinine levels was observed, with a much larger reduction in cotinine levels in the cytisine group compared to the placebo group.

[0180] Changes in these objective markers suggest that placebo-treated subjects generally over-reported the reduction in cigarettes smoked, and also that the true difference in cigarette scores between cytisine- and placebo-treated subjects was greater than actually observed.

[0181] The abstinence rates for the TID schedule groups versus placebo are shown in Figures 7 and 8 and summarized in Table 5. Results of the initial abstinence rates at week 4 indicated that both TID groups had higher odds of successfully quitting smoking compared with placebo, with subjects in the 3.0 mg cytisine group having the highest odds of success with an OR of 6.31 (95% CI: 2.28, 18.45) for quitting smoking. The OR for the 1.5 mg cytisine group on the TID schedule was 5.81 (95% CI: 2.12, 16.87). On 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. [Table 5]

[0182] Referring to Figures 7 and 8 and Table 5, for long-term abstinence from smoking cessation from the 5-week to the 8-week endpoint, both groups on the TID schedule had higher odds of success in quitting smoking compared to placebo, with subjects in the 3.0 mg cytisine group having the highest odds of success in quitting smoking from 5 to 8 weeks, with an OR of 5.04 (95% CI: 1.42, 22.32). The OR for the 1.5 mg cytisine group on the TID schedule was 4.33 (95% CI: 1.21, 19.30). For the COM schedule, the ORs for 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.

[0183] Table 6 summarizes the comparison of reductions in exhaled CO levels and abstinence rates at week 4 and weeks 5-8 for the 3.0 mg cytisine group versus placebo. [Table 6]

[0184] Subjects in the cytisine group on the TID schedule also had higher odds of quitting smoking at weeks 6, 7, and 8 compared with subjects in the corresponding group on the COM schedule versus placebo, as indicated by higher ORs at each time point.

[0185] 1.2 Purpose and general method of sensitivity The primary outcome (tobacco score) and key secondary smoking cessation outcomes were subjected to sensitivity analyses. The primary secondary smoking cessation outcomes were initial abstinence rate at week 4 and sustained 4-week abstinence through weeks 5 through 8, confirmed by exhaled CO of <10 ppm, designated as Cess / W5-8 / CO success. The objective was to assess the robustness of the results from the trial and perform alternative analyses that could either confirm the observed results or challenge the trial conclusions.

[0186] 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 and because of the lack of subjectivity in the assessments.

[0187] The focus of these sensitivity analyses in this report is on the comparison of the 3.0 mg cytisine TID group with the pooled placebo (0 mg cytisine) group. Some analyses show other comparisons for contrast.

[0188] Effects of modified analytical methodology A common method for assessing the robustness, consistency, and meaning of results from clinical trials is to perform an effect modification analysis (EMA). The goal of an EMA is to assess the extent to which estimated group effects differ for discrete values ​​of a baseline attribute. For example, an EMA of gender estimates gender-specific group effects and assesses whether these estimates differ. If the baseline attribute being assessed using EMA is not discrete, the attribute is discretized by identifying cutpoints based on external criteria or by using percentiles (median, tertiles, or quartiles) calculated from pooled data. For example, baseline CO levels are divided into those less than or equal to 10 ppm or using pooled quartiles.

[0189] EMA fits a statistical model to data. The EMA model includes an interaction term to detect the presence of differences in group effects across discrete factor values. Heterogeneity of effect estimates is detected when the interaction term significantly improves the fit of the model over a model without the interaction term. The improvement in fit due to the interaction term is measured by the interaction P-value; a small P-value, typically less than 0.10, indicates an improvement in fit.

[0190] There are two types of interactions: qualitative and quantitative. A quantitative interaction exists when the direction of the group effect estimate is the same for all discrete values ​​of the factor. A qualitative interaction exists when the direction of the effect mixes across values ​​of the factor.

[0191] The results from the multiple EMAs performed in this study are displayed compactly as forest graphs, showing, for each factor value, subset-related frequencies (distribution across groups), effect estimates, and applicable confidence intervals. The EMA forest graph provides a gestalt regarding the stability of the overall effect estimates for the factors included in the graph. The full EMA forest graph also shows, for each factor, a quantitative assessment of heterogeneity from the EMA model, e.g., interaction P-values. The forest graph also displays the group effect estimates and confidence intervals at each value of the factor. (Such a forest graph is shown later.)

[0192] Justification for pooled control groups Between-group comparisons were pairwise comparisons between each active group and the pooled placebo group. The justification for comparing with the pooled placebo was: There was no evidence that the two placebo groups differed with respect to the primary or two secondary outcomes, with P values ​​of 0.1197, 0.9963, and 0.9996 in stratified control group comparisons of tobacco score, initial quit success at week 4, and Cess / W5-8 / CO success outcomes, respectively. There was no evidence that randomization between the placebo groups differed with respect to any of the baseline attributes used as factors in the subsequent EMA, including clinical site.

[0193] For the purposes of sensitivity assessment, the lack of evidence of a placebo group difference can be considered as a justification for pooling, with the benefit of increased statistical sensitivity.

[0194] Descriptive graph of average number of cigarettes reported each day Longitudinal graphs of the mean number of cigarettes reported in the diary for each study treatment day (Days 1-25 after randomization) are shown below. Each group and the pooled placebo group are shown as different colors or solid vs. dashed lines. Figure 5 shows that each day subjects attempted to quit smoking until the planned quit interval (Days 5-7) with abstinence by Day 8, reducing the daily number of cigarettes smoked.

[0195] 1.3 Biochemical validation analysis Below are two longitudinal graphs of visit means and 95% confidence intervals for CO and cotinine by pooled placebo and cytisine treatment groups, respectively.

[0196] CO levels (ppm) were assessed at screening, baseline, the end of the study treatment intervention (week 4), and weekly through week 8 throughout the study (Figure 9). CO means at the screening and baseline visits were similar for all groups. At week 4, a significant decrease in CO levels was observed in all subjects treated with cytisine, regardless of schedule. During the follow-up period from weeks 4 to 8 (with behavioral support only), CO means for the pooled placebo group remained fairly constant but were somewhat lower than the means before the start of the study treatment intervention. The active treatment group means remained significantly lower compared to the pooled placebo group for all follow-up visits, although the means showed a slight upward trend.

[0197] Serum cotinine levels were exploratory and were assessed only at screening, week 4, and week 8. Results reported with cotinine <10 ng / mL were converted to 0 ng / mL before statistical analysis. The cotinine graph in Figure 10 showed the same pattern as observed with CO. All subjects in the cytisine-treated group had a significant decrease in cotinine levels at week 4, which showed a slight upward trend through week 8.

[0198] 1.4 Tobacco Score Analysis Primary model stratification and covariate assumptions The primary model for tobacco score included covariates for BMI stratification (3 levels) and the mean number of cigarettes reported by the screening diary. The validity of conclusions from the results of the primary model depended on the absence of interactions between each of these covariates and the group variable. If one or both of these interactions were mandatory in the statistical model, the magnitude of the estimated group effect would be a function of BMI class and / or the mean number of cigarettes reported by the screening diary.

[0199] Planned statistical analyses of the primary endpoint were performed, and as part of those analyses, each of the cytisine treatment groups was compared to the pooled placebo group on the primary efficacy endpoint (cigarette score). These analyses were performed using an analysis of variables model with fixed effects for treatment group, as well as BMI (18.5 to <25 kg / m). 2 , 25~<30kg / m 2 , 30~<35kg / m 2 ) and baseline cigarette count as covariates. The analysis used a BMI variable derived from the subject's actual BMI, with one subject (104-144) excluded from the subject's BMI (39.9 kg / m 2 ) is the upper limit of the upper BMI category (30 to <35 kg / m 2 ) and therefore omitted.

[0200] Two variables in this analysis were performed as part of a sensitivity analysis. These were the following models: Models used a BMI variable derived from the subjects' actual BMI, but all 254 subjects were included in the full randomization set. The BMI categories used in this analysis were 18.5 to <25 kg / m 2 , 25~<30kg / m 2 , 30~<35kg / m2, and ≥35kg / m 2 It was. Models using BMI stratification variables at randomization. Subjects 104–144 were randomized to the BMI stratification (30–<35 kg / m) reported for that subject at randomization. 2 ) and were included in this analysis. Consequently, this analysis included all 254 subjects in the entire randomized set. The BMI categories used in this analysis were 18.5 to <25 kg / m 2 , 25~<30kg / m 2 , and 30 to <35 kg / m 2 It was.

[0201] 11A-11B show comparisons between the uniformity of each group (between COM 0 mg and TID 0 mg, and between TID 0 mg and TID 3.0) as a factor of predicted percentage of cigarettes smoked (cigarette score).

[0202] Figures 16 and 17 provide additional evaluation of the interaction between BMI and baseline mean number of cigarettes, particularly in the 3.0 mg TID group compared to the pooled placebo group.

[0203] For BMI, this assessment of the presence of an interaction with group was evaluated as an EMA using BMI as a factor, and the size of the interaction P provides information on the presence of this interaction (Figure 16). The EMA interaction P value for BMI was 0.1303, which is not small enough to raise concerns, but suggests a possible higher efficacy in patients with high BMI compared to subjects with low BMI, based on strata-specific effect size estimates.

[0204] Evidence of an interaction between group and baseline mean number of cigarettes (a model covariate) was assessed by the parallelism between groups of the linear correlation between cigarette score and baseline mean number of cigarettes. The P value for this parallelism assessment, shown in the scatterplot (Figure 17), was 0.2754, providing evidence of no parallelism.

[0205] Alternative Tobacco Score Analysis The primary outcome was based on the number of cigarettes smoked each day from the diary. The tobacco score used diary data from the planned 25 days during study treatment. Sensitivity analyses for the comparison between the 3.0 mg TID group and the pooled placebo group related to variability in the primary analysis of the tobacco score are presented. An alternative definition of the tobacco score features cigarettes recorded in the diary after a planned abstinence period of 5–7 days, i.e., after day 8 rather than after day 1.

[0206] Another alternative analysis was based on a reanalysis of the primary tobacco score and the alternative tobacco scores described above, with weighting related to the standard error of the mean number of cigarettes estimated from diary entries. The weighting used for each subject was 1 / (SE)2 where SE is the standard error of the mean estimate. This type of weighting is called inverse variance weighting and is commonly used. This weighting gives more weight to means estimated with smaller SE. However, we had to slightly modify the definition of this weighting: 1 / (SE) 2 In calculating SE, a specific rule was used when SE=0, specifically when all diary entry values ​​were equal. In these cases, SE was calculated as if only one of the recorded values ​​was greater than 1. When this correction to the data is made, it can be shown that SE=1 / N, where N is the number of target entries for each day (day).

[0207] Table 7 shows P values ​​and effect estimates with 95% confidence intervals for the four analyses describing the comparison between the 3.0 mg TID group and the pooled placebo group. When diary data began on day 8 rather than day 1, the effect estimates were somewhat better (-11.8 vs. -9.5 for the primary tobacco score, respectively), because smoking data before the planned cessation date were excluded. When weighting was applied to the primary tobacco score for the analysis, the effect estimate P value was 0.0466 compared with 0.0675 in the unweighted analysis of the primary tobacco score. This was because diary data before the planned cessation date (before day 8) and subsequent smoking cessation resulted in a larger SE, thereby reducing the weighting of quitters. This reduction in weighting did not apply to the redefined tobacco score using diary data beginning on day 8, so the weighted effect size for the redefined tobacco score was clearly more favorable compared with the unweighted primary tobacco score beginning on day 1 (-15.0 vs. -9.5, respectively). [Table 7]

[0208] Analysis of whether there was evidence of heterogeneity of effect across the eight clinical sites (subject sources) was performed as an EMA, with interaction P values ​​providing a measure of heterogeneity of effect. This analysis was performed for both the primary outcome variable of tobacco score and Cess / W5-8 / CO success. For tobacco score, the EMA model included additional covariates for BMI stratification and the average number of cigarettes reported by the screening diary. For Cess / W5-8 / CO success, no covariates were added to the EMA model due to the potential for empty cells in cross-classification across the discrete variables of binary outcome, group, and clinical site. For example, there were situations where a particular clinical site did not have subjects who succeeded in one or both groups.

[0209] Figures 18-25 provide the EMA analysis results for each of the four comparisons of active cytisine versus pooled placebo groups, and for both outcome variables. No evidence of heterogeneity of effect due to clinical center was observed from any of these EMAs; i.e., the interaction P values ​​were not small enough to raise concerns about clinical center heterogeneity.

[0210] 1.5 Comparison of cessation rates between citisinicline and Chantix® Figure 12 and Table 8 show the study design for comparing cytisinicline (cytisine) and Chantix®. The treatment duration for Chantix® (12 weeks) was approximately 3.5 times longer than the treatment duration for cytisinicline (25 days). The sustained abstinence time for Chantix® (12 weeks measured over the last 4 weeks of treatment) was longer than that for cytisinicline (8 weeks measured over 4 weeks after the end of treatment). Table 8 includes additional details regarding the clinical trial with cytisinicline and Chantix®. [Table 8]

[0211] Figure 13 shows CO-confirmed abstinence rates between 3.0 mg citisinicline and 3.0 mg Chantix® at weeks 4 and 12 of treatment. Chantix® data are 7-day point abstinence rates, while citisinicline is 1-day point abstinence rates. CO-confirmed end-of-treatment abstinence rates for subjects treated with 3.0 mg citisinicline exceeded those for subjects treated with 3.0 mg Chantix® at both week 4 and week 12 (end of Chantix® treatment). Citisinicline had greater efficacy compared to Chantix®.

[0212] Figure 14 and Tables 9-11 show the odds ratios for citisinicline and Chantix® at the end of treatment at 4 weeks and 4 weeks after treatment ended. Citisinicline and Chantix® have similar odds ratios and efficacy. While the 95% CIs for both treatments overlap, the odds ratio for citisinicline treatment is consistently superior to that of Chantix®. [Table 9] [Table 10] [Table 11]

[0213] Table 12 shows the updated EAGLES study, published in 2018, comparing quit rates in the United States with non-US regions. This study shows significantly lower quit rates in the United States compared to non-US regions. The overall quit rate of 22% at 24 weeks for subjects treated with Chantix® was only 16% for US patients (N=1065). The quit rates are significantly lower than previous nationwide-based trials of Chantix®. The 24-week quit rate in the EAGLES study was lower than the 52-week quit rate in the pivotal trial. Smoking cessation outcomes associated with early age at first smoking and US birth were poor. [Table 12]

[0214] Figure 15 shows the odds ratios for citisinicline compared to current products at week 4, end of treatment, and 4 weeks after treatment ended. Although the 94% CIs for the treatments overlap slightly, the odds ratios for citisinicline treatment are consistently superior to those for NRT, Zyban®, and Chantix®.

[0215] 1.6 Analysis of baseline characteristics and smoking status Effect-modifying analysis of baseline patient attributes A summary of baseline attributes, including age, race, sex, smoking duration, and number of quit attempts, was analyzed for both the Tobacco Score primary outcome variable and Cess / W5-8 / CO success (Figures 26 and 27). Only comparisons between the cytisine 3.0 mg TID group and the pooled placebo group are shown. The same EMA model used to analyze clinical sites was used. Forest graphs for these analyses are shown below. (Note: In these forest graphs, (M), (T), or (Q) at the end of the factor designation indicates that the pooled data was divided by median, tertiles, or quartiles, respectively. Hx indicates "historical.")

[0216] The only interaction P value of note was for smoking history duration divided by quartiles for tobacco score ("Smoking Hx Duration (Years) (Q)"), with P = 0.0800. No other smoking history duration variables had significant P values ​​(P > 0.2566), so this result was considered insignificant. None of the other factors raised concerns about heterogeneity of effects.

[0217] Effect-modification analysis of history for anti-smoking interventions Previous anti-smoking intervention factors were analyzed for the Tobacco Score primary outcome variable and Cess / W5-8 / CO success, comparing the cytisine 3.0 mg TID group with the pooled placebo group (Figures 28 and 29). Factors analyzed included whether there had been more than two anti-smoking intervention attempts and whether they had ever been or recently treated with Chantix®, Zyban®, vaping, or nicotine replacement therapy. The same EMA model used to analyze clinical sites was performed. Forest graphs for these analyses are shown below.

[0218] The only interaction P value of note was for history of past use of Chantix® ("Chantix® Hx") on tobacco score, with P=0.0508. However, the interaction P value for the factor variable indicating Chantix® as the most recent intervention ("Chantix® most recent") was not concerning (P=0.3179). Because the interaction appeared to be quantitative and the results for recent use were inconsistent, concerns about Chantix® being an effect modifier were attenuated.

[0219] Effect-modified analysis of baseline laboratory markers related to smoking Baseline test factors were analyzed for the primary outcome variable of tobacco score and success of Cess / W5-8 / CO in the cytisine 3.0 mg TID group compared with the pooled placebo group (Figures 30 and 31). These factors included nicotine metabolic ratio (NMR), exhaled CO, and serum cotinine and were analyzed by median, tertiles, and quartiles. The same EMA model used to analyze the clinical sites was performed. Forest graphs of these analyses result in Figures 30 and 31. (Note: In these forest graphs, (M), (T), or (Q) at the end of the factor label indicates that the pooled data was divided by median, tertile, or quartile, respectively.)

[0220] For tobacco score, only the interaction P values ​​of 0.0434 and 0.0652 for the median and tertile divisions of baseline cotinine, respectively, met the criteria for suggesting effect modification. However, for the secondary outcome of sustained abstinence, the interaction P values ​​were 0.2925, 0.3738, and 0.9732 for the median, tertile, and quartile divisions, respectively, indicating no effect modification for baseline cotinine levels. Because 4-week abstinence is planned to be the primary outcome of a future phase 3 trial, baseline cotinine as an effect modifier is of less concern.

[0221] 1.7 Turning point analysis for 5-8 weeks after quitting smoking A tipping point analysis was performed on Cess / W5-8 / CO success for the comparison of the cytisine 3.0 mg TID group with the pooled placebo group and is shown in Figure 32. The purpose of the tipping point analysis was to assess the extent to which case reassignment, defined as failure due to insufficient assessment data, affected the outcome. The tipping point assessment reanalyzed the data for all possible reversals of failure to success assignments, accompanied by a graph showing which reassignments met the statistical criteria. The horizontal axis represents the number of possible control group reassignments, and the vertical axis represents the number of possible experimental group reassignments. Each reassignment combination was reanalyzed to assess whether the statistical criteria were met. The bottom left point represents cases with no reassignments (i.e., planned analysis). Areas where reassignments met the statistical criteria are patterned, while areas where reassignments did not meet the statistical criteria are grayed out.

[0222] There were 6 control cases and 3 experimental cases eligible for reassignment. The most important finding from this graph is that if there are 0 or 1 reassignments in the experimental group, the statistical criterion is not met if there are 3 or more reassignments in the control group. Similarly, if there are 2 or 3 reassignments in the experimental group, the statistical criterion is not met if there are 5 or more reassignments in the control group. Therefore, the secondary outcome of continued smoking cessation was robust to reassignment.

[0223] In summary, the results for initial abstinence rates at week 4 for all cytisine treatment groups showed significantly increased initial rates (50%-54%) compared with pooled placebo (16%), with ORs ranging from 5.38 to 6.31. Long-term abstinence from weeks 5 through 8 (i.e., 4 weeks after treatment ended) also showed significantly increased long-term abstinence rates of 16%-30% compared with pooled placebo (8%) for cytisine treatment groups, with ORs ranging from 3.23 to 5.04. Overall, initial and long-term abstinence rates were highest in the 3.0 mg TID group at 54% and 30%, respectively, with maximum ORs of 6.31 and 5.04, respectively.

[0224] Safety analysis Overall, there were no safety concerns following administration of either the 1.5 mg cytisine or 3.0 mg treatment groups at both schedules, and no new or unexpected AEs were identified during the study period.

[0225] Table 13 summarizes treatment-emergent adverse events (TEAEs). TEAEs were experienced by approximately half of the study population in all treatment groups. The TID dosing schedule had slightly fewer TEAEs overall. Across both schedules, the SOCs with the highest incidence of TEAEs in any treatment group were infections and infestations, psychiatric disorders, and gastrointestinal disorders. Common TEAEs were AEs previously reported in other studies or within the investigator's brochure. All TEAEs were mild or moderate in severity with the commercial schedule; all but two events were mild or moderate with the TID schedule; one subject experienced a severe head injury, and another subject experienced a severe case of influenza. Neither event was considered related to study drug. [Table 13]

[0226] 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 important changes in vital sign measurements was low, with the lowest incidence on the TID schedule.

[0227] Table 14 summarizes TEAEs for citisinicline compared to Chantix® in the historical 2016 study. TEAEs were experienced by less than 30% of the study population treated with either citisinicline, Chantix®, or placebo. Subjects treated with Chantix® experienced the highest incidence of TEAEs compared to citisinicline and placebo. The incidence of most TEAEs with citisinicline treatment was only slightly higher than placebo. [Table 14]

[0228] In summary, there were no serious or serious adverse events, and the overall incidence of adverse events was low. Results from the study indicate that there were 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.

[0229] conclusion Results from the study showed that the benefits of cytisine occurred across all baseline characteristics and demographics. Specifically, the benefits of cytisine occurred across subject demographics, baseline CO levels, and number of cigarettes smoked daily, as well as based on smoking history. With regard to subject demographics, the benefits were consistent across the subject population, regardless of race, gender, age, and BMI. Furthermore, with regard to smoking history, subjects showed the same benefit from cytisine administration regardless of smoking duration, quit attempts, and past use of smoking cessation medications (e.g., Chantix®, Zyban®, NRT, vaping).

[0230] The results further demonstrated that subjects showed similar benefits from cytisine administration regardless of their ability to metabolize nicotine. Notably, no therapeutic relationship was observed based on the subject's baseline nicotine metabolite ratio, with similar cytisine benefits for fast and slow nicotine metabolites.

[0231] Results from the primary analysis showed a reduction in the expected proportion of cigarettes smoked for both schedules compared with placebo pooled. Results for the early abstinence rate endpoint showed that both cytisine groups on the TID schedule had higher odds of success compared with placebo, with subjects in the 3.0 mg cytisine group having the highest odds of success in quitting smoking at week 4.

[0232] For long-term smoking cessation from weeks 5 to 8, both groups on the TID schedule had higher odds of success compared with placebo, with subjects in the 3.0 mg cytisine group having the highest odds of success in smoking cessation from weeks 5 to 8. This study demonstrated that cytisine is an effective adjunct to smoking cessation with a favorable adverse event profile, with the 3.0 mg TID dose being more effective overall without an increase in adverse events.

[0233] Overall, there were no safety concerns following administration of 1.5 mg cytisine or the 3.0 mg group on either schedule.

[0234] Example 2: Effect of continued treatment with cytisine on smoking cessation This example describes a phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial designed to evaluate the efficacy and safety of cytisine in adult smokers. The trial is designed to improve efficacy outcomes and determine whether continued treatment can prevent early smoking relapse. The trial is designed to evaluate treatment across three treatment groups: placebo (A), 6 weeks of treatment with cytisine (e.g., cytisinicline) (B), and 12 weeks of treatment with cytisine (C), as shown in the schematic diagram in Figure 33. Subjects are randomized to one of three groups: A, B, or C. In group A, subjects are treated with 12 weeks of placebo plus behavioral support. In group B, subjects are treated with 6 weeks of 3.0 mg cytisine TID, followed by 6 weeks of placebo plus behavioral support. In group C, subjects are treated with 12 weeks of 3.0 mg cytisine TID plus behavioral support. Cytisine treatment will be evaluated in a 6- or 12-week study population, with a primary efficacy endpoint of continuous smoking cessation during treatment at week 4, and a 6-month follow-up period.

[0235] 2.1 Purpose of the test 2.1.1 Co-primary efficacy objectives The co-primary efficacy objective of the trial is based on two comparisons, and the success of the trial can be based on success in either comparison; To assess whether subjects randomized to Arm B are more likely to quit smoking 3 to 6 weeks after randomization compared with subjects randomized to Arm A; and To assess whether subjects randomized to Arm C are more likely to quit smoking 9 to 12 weeks after randomization compared with subjects randomized to Arm A.

[0236] 2.1.2 Secondary efficacy objectives If the corresponding primary comparisons pass the statistical criteria, subsequent analyses are performed for the secondary objectives. The secondary efficacy objectives of this study are: To assess whether subjects randomized to Arm B have a higher likelihood of continuous abstinence from 6 to 24 weeks after randomization compared with subjects randomized to Arm A; and To assess whether subjects randomized to Arm C have a higher likelihood of continuous abstinence from 12 to 24 weeks after randomization compared with subjects randomized to Arm A.

[0237] If the co-primary comparisons pass statistical criteria, subsequent analyses will be conducted for additional secondary objectives. Additional secondary efficacy objectives of this study are: To evaluate the reduction in risk of relapse from weeks 6 to 24 in subjects treated with 3.0 mg citisinicline for 6 weeks, followed by continuation of 3.0 mg citisinicline from weeks 6 to 12 (Arm C) or switching to placebo from weeks 6 to 12 (Arm B).

[0238] Subjects who have not quit smoking at 6 weeks are considered to have relapsed.

[0239] 2.1.3 Other purposes Other objectives of this study are To compare groups (Group B vs. Group A, Group C vs. Group A) in quit rates at 7 days per week from week 2 to week 12, and then at weeks 16, 20, and 24; To compare groups (Group B vs. Group A, Group C vs. Group A) on serum cotinine levels every other week from week 2 to week 12, and then at weeks 16, 20, and 24; and To compare groups (Group B vs. Group A, Group C vs. Group A) on exhaled CO2 levels weekly from week 2 to week 12, and then at weeks 16, 20, and 24; and To compare groups (Group B vs. Group A, Group C vs. Group A) regarding the use of any non-tobacco nicotine products, including vaping, during study treatment from weeks 2 to 12 and during the study follow-up period from weeks 16 to 24; and To assess whether subjects randomized to Arm B have a higher likelihood of quitting smoking from Weeks 9 to 12 compared to subjects randomized to Arm A (placebo); and To assess whether subjects randomized to Arm B have a higher likelihood of continuous abstinence from 3 to 24 weeks after randomization compared with subjects randomized to Arm A, and among the subset of subjects who achieve abstinence from 3 to 6 weeks; and To assess whether subjects randomized to Arm C have a higher likelihood of continuous abstinence from weeks 9 to 24 after randomization compared with subjects randomized to Arm A, and among the subset of subjects who achieve abstinence from weeks 9 to 12; and To compare the time to failure to maintain abstinence at 24 weeks between groups (Group B vs. Group A, Group C vs. Group A) among subjects who achieved abstinence between weeks 3 and 6; and To explore the magnitude of between-group treatment effects across various subgroups defined by demographic and baseline characteristics for primary and secondary outcomes; and To explore possible relationships between subject-reported outcomes (e.g., anxiety, depression, withdrawal symptoms, tobacco craving) and primary and secondary outcomes.

[0240] 2.1.4 Safety objectives The safety objectives of the test are: To evaluate the safety profile of 3.0 mg TID cytisinicline compared with placebo (e.g., Arm B vs. Arm A and Arm C vs. Arm A), To compare the safety profile of subjects in Group B vs. Group C with respect to adverse events occurring after Week 6 of the study.

[0241] 2.2 Study Design The study population was male or female adult daily smokers who intended to quit smoking and had a cessation date within 5 to 7 days of treatment initiation. Study treatment began the day after randomization.

[0242] Subjects will meet all requirements outlined in the inclusion and exclusion criteria. A total of approximately 750 subjects will be randomly assigned with equal probability to one of three groups (Group A, 12 weeks of placebo: N=250; Group B, 6 weeks of citisinicline followed by 6 weeks of placebo: N=250; Group C, 12 weeks of citisinicline: N=250) as shown in Figure 33.

[0243] Each randomized subject will receive 12 weeks of treatment using a TID dosing schedule. Smoking cessation assessments will begin at week 2 (day 14 ± 1 after randomization) and continue weekly throughout the treatment period through follow-up visits at weeks 16, 20, and 24. Smoking cessation will be assessed by subject self-report with CO2 chemistry verification.

[0244] All subjects will receive concurrent smoking cessation behavioral support during the study treatment period (Weeks 1-12). Additional behavioral support will be provided during the follow-up period based on any issues, concerns, and / or questions raised by the subject.

[0245] Safety assessment visits will be conducted on days 2 and 7 of week 1, and then weekly throughout the treatment period. Laboratory hematology and chemistry assessments will be conducted on days 7, 6, and 12 of the treatment period (end of treatment, "EOT"). Ongoing adverse events at week 12 will be tracked until resolved or determined to be chronic. End of study will be defined as the last subject's last follow-up visit (visit through week 24).

[0246] 2.3 Treatment duration The treatment period begins the day after randomization. The study treatment is blinded, and subjects take one study drug three times daily, approximately five hours apart. Subjects randomly assigned to Group A will take one placebo tablet per day at each dose for 12 weeks. Subjects in Group B will take one citisinicline tablet per day at each dose for the first six weeks, followed by one placebo tablet per day at each dose for the final six weeks. Subjects in Group C will take one citisinicline tablet per day at each dose for 12 weeks.

[0247] 2.4. Inclusion criteria Subjects who meet all of the following criteria are eligible to participate in the study: Male or female subjects ≥ 18 years of age. Current daily smokers (averaging at least 10 cigarettes per day at the time of completing the 7-day screening smoking diary) and those intending to quit smoking. Exhaled CO ≥ 10 ppm. · At least one previous attempt to quit smoking, with or without therapeutic support, has failed. - Willingness to start study treatment the day after randomization with a stop date within 5-7 days of treatment initiation. · Willingness to actively participate in the study's smoking cessation behavioral support provided throughout the study. -Fully understand the study requirements, willing to participate, and able to comply with the administration schedule. · Sign an informed consent form.

[0248] 2.5. Exclusion criteria Subjects will be excluded from participation in the study if any of the following criteria apply: More than one study participant in the same household. Previous cytisinicline treatment in a previous clinical trial or any other cytisine use. Known hypersensitivity to cytisinicline or any of the excipients. A positive drug of abuse urine screen determined within 28 days prior to the first dose of citisinicline. · Clinically significant abnormal serum chemistry or hematology values ​​(i.e., requiring treatment or monitoring) within 28 days of randomization. Clinically significant abnormalities (i.e., requiring treatment or further evaluation) on a 12-lead electrocardiogram determined after a minimum of 5 minutes in the supine position within 28 days of randomization. Being underweight (<18.5 kg / m²) or having class 2 obesity (≥35 kg / m²) according to BMI classification. Recent history (within 3 months) of hospitalization for acute myocardial infarction, unstable angina, stroke, cerebrovascular accident, or congestive heart failure. · Current uncontrolled hypertension (blood pressure ≥ 160 / 100mmHg). · Documented diagnosis of schizophrenia or bipolar psychosis, current psychosis, suicidal ideation / risk ("yes" to question 4 or question 5 or "yes" to the suicidal behavior question on the C-SSRS), or current symptoms of moderate to severe depression (HADS score ≥ 11). Renal impairment defined as creatinine clearance (CrCl) <60 mL / min (estimated by the Cockcroft-Gault formula). · Liver dysfunction defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 × upper limit of normal (ULN). Pregnant or breastfeeding women. Male or female subjects of childbearing potential who do not agree to use an acceptable method of contraception during the study treatment period. Participation in a clinical trial with an investigational drug within 4 weeks prior to randomization. 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. Use of non-tobacco and / or non-combustible nicotine products (pipe tobacco, cigars, snuff, smokeless tobacco, hookah, e-cigarettes / vaping) or smoking or vaping marijuana in the 2 weeks prior to randomization or planned use during the study period. Any other reason why the investigator believes the subject should not participate or would not be able to meet the requirements of the study.

[0249] 2.6 Existing and Concomitant Medications All subjects will continue to receive their existing prescribed medications, and efforts will be made to ensure that existing medication regimens remain stable for the duration of the study.

[0250] At the investigator's discretion, non-study medications (prescription or over-the-counter) may be permitted for use during the study if clinically indicated. Full details of any new medications will be recorded on the subject's Case Report Form (CRF).

[0251] All concomitant medications taken during the study and any changes (additions, deletions, dose changes) will be recorded on the CRF.

[0252] 2.7 Treatment Compliance Treatment compliance will be monitored throughout the 84-day (12-week) treatment period through a review of administration timing and study drug administration. Subjects will have a daily treatment diary to record the number of tablets taken and the time of administration. Subjects will be instructed to bring their own medication pack (blister pack) to each visit so that clinic staff can check the treatment diary and record the number of tablets taken and the number of tablets missed. In addition, an optional text messaging system will be implemented to provide each subject with a reminder text corresponding to the approximate time of administration.

[0253] 2.8 Test Procedure After providing signed informed consent, all subjects are evaluated for study inclusion within a 28-day screening period. Subjects who meet the inclusion criteria must provide a stop date, which must be within 5–7 days of treatment initiation, and agree to begin study treatment the day after randomization. Both the planned stop date and treatment start date are documented to confirm inclusion. Once all eligibility criteria are confirmed, randomization can occur. Study Day 1 is defined as the first day of treatment. Subjects complete visits at 2, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, and 86 days. Follow-up visits are scheduled at 16, 20, and 24 weeks.

[0254] 2.8.1 Procedure Schedule Table 15 provides a summary of the required study assessments. Screening assessments will occur within 28 days between the start of screening assessments and randomization. Subjects will begin study treatment the day after randomization, whereby study treatment will begin within 5-7 days of Day 1, but before Day 1, before the stop date. [Table 15] JPEG0007742832000017.jpg255170JPEG0007742832000018.jpg255170JPEG0007742832000019.jpg255170JPEG0007742832000020.jpg255170 [Table 16]

[0255] 2.8.2 Target journal A 7-day smoking diary will be collected during the screening period to obtain the number of cigarettes smoked each day for 7 consecutive days. This data will be used to calculate the average number of cigarettes smoked per day to support the second inclusion criterion.

[0256] In addition, a study treatment diary will be maintained by each subject to record the dates and timing of study drug administration during the treatment period. The diary will be organized into specific sections to support the above reporting by subjects.

[0257] 2.9 Efficacy Criteria This study follows general criteria applicable to past and current smoking cessation trials, with participants having a predetermined target cessation date and direct contact with investigators or clinic staff. Endpoint analyses for abstinence (4-week abstinence recorded in the last 4 weeks of treatment) and continued abstinence (continuously recorded through 24 weeks after randomization) include the following criteria: · Self-reported smoking cessation since the last visit at each clinic assessment. Biochemical verification of smoking cessation by exhaled CO at each visit. · Use of an "intention to treat" approach, in which data from all randomized smokers were included in the analysis. Subjects with unknown smoking status or lost to follow-up at the 6-, 12-, and 24-week assessments will be classified as having failed to quit. During the follow-up period (12 to 24 weeks) only, self-reported smoking cessation will follow the Russell Standard. Treatment assignment will remain blinded during follow-up data collection through week 24.

[0258] 2.9.1 Safety Assessment All subjects will be monitored for adverse events starting with screening (pre-screening), a phone call on Day 1, visits on Days 2 and 7 of Week 1, then weekly throughout the treatment period (Weeks 2 through 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 the Week 1, Week 6, and Week 12 visits.

[0259] Safety will be assessed by considering all adverse events reported or elicited by the subject, as well as abnormalities detected in hematology and serum chemistry tests. Worsening of other pre-existing medical conditions and any changes to concomitant medications / treatments will also be taken into account in this assessment.

[0260] 2.9.2 Examination Room Routine Laboratory Evaluation Routine laboratory safety samples will be analyzed by a central laboratory for each subject at screening and visits identified in Table 15. The determination of out-of-reference range results as clinically significant or not will be made by the investigator, and the report will be annotated accordingly. Clinically significant abnormalities that occur during the study will be recorded on the AE page. Reference ranges for laboratory parameters will also be entered into the database and filed in the investigator site file.

[0261] Hematology: Hemoglobin, red blood cells, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelets.

[0262] Chemistry: Total protein, albumin, total bilirubin, SGPT (ALT), SGOT (AST), alkaline phosphatase, glucose, sodium, potassium, calcium, creatinine, and urea.

[0263] Exhaled CO Exhaled CO is obtained using a calibrated device (e.g., Bedfont Micro+ Smokerlyzer®) provided and maintained by the clinical site. Each clinical site has documentation of the device used and current calibration. CO values ​​are reported in parts per million (ppm) weekly from weeks 2 through 12, and at weeks 16, 20, and 24.

[0264] Serum cotinine level Serum samples will be collected to determine cotinine levels at weeks 2, 4, 6, 8, 10, 12, 16, 20, and 24. Baseline cotinine testing will use frozen serum collected at Visit SV1 for randomized subjects. Cotinine levels will be determined at a central laboratory.

[0265] 2.9.3 Vital Signs Systolic and diastolic blood pressure, pulse rate, and oral temperature measurements will be recorded in a seated position. Weight will also be recorded. Height will be recorded at Screening Visit 1 for BMI calculation.

[0266] 2.9.4 Physical Examination A physical examination will be conducted by the investigator. The examination will include general appearance, head, ears, eyes, nose, throat, neck, skin, cardiovascular system, respiratory system, gastrointestinal system, central nervous system, lymph nodes, and musculoskeletal system. The investigator may examine other body systems as needed at their discretion.

[0267] 2.10 Primary Outcome of Interest The primary efficacy outcome for each subject (biochemically verified abstinence for the last 4 weeks of citisinicline treatment) is binary: success vs. failure. Success is defined as a subject reporting abstinence (no cigarettes since last visit) at each clinic assessment between weeks 3 and 6 (Group B) and between weeks 9 and 12 (Group C), with biochemical verification at each assessment. Biochemical verification is defined by an exhaled carbon monoxide concentration of less than 10 ppm. Similar time frames and analyses will be performed for Group A placebo subjects.

[0268] 2.11 Secondary outcomes of interest Secondary efficacy outcomes 1 and 2 (biochemically verified sustained abstinence through week 24) for each subject were binary: success vs. failure. Success was defined as a subject reporting abstinence since their last visit at week 6 (Group B) or at each clinic assessment from weeks 12 through 24 (Group C), with biochemical verification at each assessment. Biochemical verification was defined by an exhaled carbon monoxide concentration of less than 10 ppm. During the 12-week to 24-week follow-up abstinence assessment period, self-reported abstinence followed the Russell criteria.

[0269] Secondary efficacy outcome 3 is success with regard to freedom from relapse at week 24. Secondary efficacy outcome 3 (reduction in risk of relapse from week 6 to week 24 in Arm C vs. Arm B) will be assessed for each subject (both Arm C and Arm B). Subjects who have not quit smoking at week 6 are considered to have relapsed.

[0270] 2.12 Safety goals Safety assessments will include reported adverse events, clinical laboratory results, and vital signs. Safety variables will be summarized for the Safety Analysis Set (SAS), defined as all randomized subjects who receive at least one dose of study drug.

[0271] Adverse events are coded using the MedDRA dictionary. Coding includes system organ class (SOC) and preferred term (PT). Full verbatim descriptions and coded terms are listed for all AEs. Various embodiments of the present invention are presented in paragraphs 272-391 below.

[0272] 1. A method of treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, the method comprising administering cytisine to the subject provided in a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine three times daily.

[0273] The method of paragraph 272, wherein the subject does not experience an adverse event after receiving the cytisine treatment.

[0274] The method of paragraphs 272 and 273, wherein the adverse event is selected from the group consisting of a URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0275] The method of paragraphs 272-274, wherein the subject does not experience nausea after receiving the cytisine treatment.

[0276] The method of paragraphs 272-275, wherein cytisine is administered for about 6 weeks or about 12 weeks.

[0277] The method of paragraphs 272-276, wherein the unit dose of cytisine comprises: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine.

[0278] The method of paragraphs 272-277, wherein the subject is a treatment-refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation treatments.

[0279] The method of paragraphs 272-278, wherein the nicotine addiction or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0280] The method of paragraphs 272-279, wherein the subject (a) smoked 10 or more cigarettes per day prior to administration of cytisine, or (b) had an exhaled CO2 concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0281] The method of paragraphs 272-280, further comprising providing behavioral support to the subject.

[0282] 1. 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 treatments.

[0283] The method of paragraph 282, wherein the nicotine addiction or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0284] The method of paragraphs 282 and 283, wherein the cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times daily to a subject in need thereof.

[0285] The method of paragraphs 282-284, wherein the cytisine is provided in a unit dose of 3.0 mg of cytisine three times daily to a subject in need thereof.

[0286] The method of paragraphs 282-285, wherein the unit dose of cytisine comprises: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine.

[0287] The method of paragraphs 282-286, wherein cytisine is administered for about 6 weeks or about 12 weeks.

[0288] The method of paragraphs 282-287, wherein the subject does not experience an adverse event after receiving the cytisine treatment.

[0289] The method of paragraphs 282-288, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0290] The method of paragraphs 282-289, wherein the subject (a) smoked 10 or more cigarettes per day prior to administration of cytisine, or (b) had an exhaled CO2 concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0291] 1. 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 a unit dose of: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine.

[0292] The method of paragraph 291, wherein the cytisine is administered for about 6 weeks or about 12 weeks.

[0293] The method of paragraphs 291 and 292, wherein the subject does not experience an adverse event after receiving the cytisine treatment.

[0294] The method of paragraphs 291-293, wherein the adverse event is selected from the group consisting of a URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0295] The method of paragraphs 291-294, wherein the subject (a) smoked 10 or more cigarettes per day prior to administration of cytisine, or (b) had an exhaled CO2 concentration of about 10 ppm or greater prior to administration of cytisine, or (c) a combination of (a) and (b).

[0296] The method of paragraphs 291-295, wherein the subject is a treatment-refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation treatments.

[0297] The method of paragraphs 291-296, wherein the smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0298] 1. 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 selected from the group consisting of NRT, bupropion administration, varenicline administration, e-cigarettes, and vaping.

[0299] The method of paragraph 298, wherein the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, or (b) had an exhaled CO2 concentration of about 10 ppm or greater before administration of cytisine, or (c) a combination of (a) and (b).

[0300] The method of paragraphs 298-299, wherein the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine; and wherein the cytisine is administered for about 6 weeks or about 12 weeks.

[0301] The method of paragraphs 298-300, 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 the cytisine treatment.

[0302] 1. A pharmaceutical product comprising a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, wherein the pharmaceutical product is for oral administration to the subject three times daily.

[0303] The drug product of paragraph 302, wherein the subject does not experience an adverse event after receiving the cytisine treatment.

[0304] The medication of paragraphs 302 and 303, wherein the adverse event is selected from the group consisting of a URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0305] The pharmaceutical product of paragraphs 302-304, wherein the subject does not experience nausea after receiving the cytisine treatment.

[0306] The pharmaceutical product of paragraphs 302-305, wherein cytisine is administered for about 6 weeks or about 12 weeks.

[0307] The drug product of paragraphs 302-306, wherein the unit dose of cytisine comprises: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine.

[0308] The pharmaceutical product of paragraphs 302-307, wherein the subject is a treatment-refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation treatments.

[0309] The pharmaceutical product of paragraphs 302-308, wherein the nicotine addiction or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0310] The drug product of paragraphs 302-309, wherein the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, or (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytisine, or (c) a combination of (a) and (b).

[0311] The medication of paragraphs 302-310, further including providing behavioral support to the subject.

[0312] 1. A pharmaceutical product 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 pharmaceutical product is for oral administration to the subject three times daily.

[0313] The drug product of paragraph 312, wherein the nicotine addiction or nicotine dependence treatment includes NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof.

[0314] The pharmaceutical product of paragraphs 312-313, wherein the cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times daily to a subject in need thereof.

[0315] The drug product of paragraphs 312-314, wherein the cytisine is provided in a unit dose of 3.0 mg of cytisine three times daily to a subject in need thereof.

[0316] The drug product of paragraphs 312-315, wherein the unit dose of cytisine comprises: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine.

[0317] The pharmaceutical product of paragraphs 312-316, wherein the cytisine is administered for about 6 weeks or about 12 weeks.

[0318] The method of paragraphs 312-317, wherein the subject does not experience an adverse event after receiving the cytisine treatment.

[0319] The pharmaceutical agent of paragraphs 312-318, wherein the adverse event is selected from the group consisting of a URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0320] The drug product of paragraphs 312-319, wherein the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, or (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytisine, or (c) a combination of (a) and (b).

[0321] 1. A pharmaceutical product comprising a unit dose of cytisine in the form of: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine, for preventing relapse to smoking and / or vaping in a subject in need thereof, wherein the pharmaceutical product is for oral administration to the subject three times daily.

[0322] The medicine of paragraph 321, in which cytisine is administered for about 6 weeks or about 12 weeks.

[0323] The pharmaceutical product of paragraphs 321 and 322, wherein the subject does not experience an adverse event after receiving the cytisine treatment.

[0324] The pharmaceutical agent of paragraphs 321-323, wherein the adverse event is selected from the group consisting of a URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0325] The drug product of paragraphs 321-324, wherein the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytisine, or (c) a combination of (a) and (b).

[0326] The pharmaceutical product of paragraphs 321-325, wherein the subject is a treatment-refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation treatments.

[0327] The pharmaceutical product of paragraphs 321-326, wherein the smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0328] A pharmaceutical product comprising cytisine for preventing relapse to smoking and / or vaping in a subject who is a treatment-refractory patient who has failed treatment with one or more nicotine addiction treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, e-cigarettes, and vaping, wherein the pharmaceutical product is for oral administration to the subject three times daily.

[0329] The drug product of paragraph 328, wherein the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, or (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytisine, or (c) a combination of (a) and (b).

[0330] The pharmaceutical product of paragraphs 328-329, wherein the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine, and wherein the cytisine is administered for about 6 weeks or about 12 weeks.

[0331] The pharmaceutical agent of paragraphs 328-330, wherein the subject does not experience an adverse event selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving the cytisine treatment.

[0332] 1. Use of a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine to treat nicotine addiction, nicotine dependence, promote cessation of smoking and / or vaping, and / or promote a reduction in smoking and / or vaping in a subject in need thereof, wherein the cytisine is for oral administration to the subject three times daily.

[0333] The use of paragraph 332, wherein the subject does not experience an adverse event after receiving cytisine treatment.

[0334] The use of paragraphs 332 and 333, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0335] The use of paragraphs 332-334, wherein the subject does not experience nausea after receiving cytisine treatment.

[0336] The use of paragraphs 332-335, wherein cytisine is administered for about 6 weeks or about 12 weeks.

[0337] The use of paragraphs 332-336, wherein the unit dose of cytisine comprises: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine.

[0338] Use of paragraphs 332-337, where the subject is a treatment-refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation treatments.

[0339] The use of paragraphs 332-338, wherein the nicotine addiction or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0340] The use of paragraphs 332-339, wherein the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, or (b) had an exhaled CO concentration of about 10 ppm or greater before administration of cytisine, or (c) a combination of (a) and (b).

[0341] Use of paragraphs 332-340, further including providing behavioral support to the subject.

[0342] 1. Use of cytisine to treat 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.

[0343] The use of paragraph 342, wherein the nicotine addiction treatment includes NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof.

[0344] The use of paragraphs 342 and 343, wherein the cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times daily to a subject in need thereof.

[0345] The use of paragraphs 342-344, wherein the cytisine is provided in a unit dose of 3.0 mg of cytisine three times daily to a subject in need thereof.

[0346] The use of paragraphs 342-345, wherein the unit dose of cytisine comprises: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine.

[0347] The use of paragraphs 342-346, wherein cytisine is administered for about 6 weeks or about 12 weeks.

[0348] The use of paragraphs 342-347, wherein the subject does not experience an adverse event after receiving cytisine treatment.

[0349] The use of paragraphs 342-348, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0350] The use of paragraphs 342-349, wherein the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, or (b) had an exhaled CO concentration of about 10 ppm or greater before administration of cytisine, or (c) a combination of (a) and (b).

[0351] Use of a unit dose of cytisine in the form of: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each 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.

[0352] The use of paragraph 351, wherein the cytisine is administered for about 6 weeks or about 12 weeks.

[0353] The use of paragraphs 351 and 352, wherein the subject does not experience an adverse event after receiving the cytisine treatment.

[0354] The use of paragraphs 351-353, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0355] The use of paragraphs 351-354, wherein the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, or (b) had an exhaled CO concentration of about 10 ppm or greater before administration of cytisine, or (c) a combination of (a) and (b).

[0356] Use of paragraphs 351-355, wherein the subject is a treatment-refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation treatments.

[0357] The use of paragraphs 351-356, wherein the smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0358] 1. Use of a pharmaceutical product comprising cytisine for preventing relapse to smoking and / or vaping in a subject who is a treatment-refractory patient who has failed treatment with one or more nicotine addiction treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, e-cigarettes, and vaping, wherein the cytisine is for oral administration to the subject three times daily.

[0359] Use of paragraph 358, where the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, or (b) had an exhaled CO concentration of about 10 ppm or greater before administration of cytisine, or (c) a combination of (a) and (b).

[0360] The use of paragraphs 358 and 359, wherein the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine, and wherein the cytisine is administered for about 6 weeks or about 12 weeks.

[0361] The use of paragraphs 358-360, wherein the subject does not experience an adverse event selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving cytisine treatment.

[0362] 1. Use of a tablet containing about 1.0 mg or 1.5 mg of cytisine for oral administration of about 3.0 mg of cytisine three times daily to a subject to treat nicotine addiction, nicotine dependence, which promotes cessation of smoking and / or vaping and / or promotes a reduction in smoking and / or vaping in the subject.

[0363] The use of paragraph 362, wherein the subject does not experience an adverse event after receiving cytisine treatment.

[0364] The use of paragraphs 362 and 363, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0365] The use of paragraphs 362-364, wherein the subject does not experience nausea after receiving cytisine treatment.

[0366] The use of paragraphs 362-365, wherein cytisine is administered for about 6 weeks or about 12 weeks.

[0367] The use of paragraphs 362-366, wherein the unit dose of cytisine comprises: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine.

[0368] Use of paragraphs 362-367, where the subject is a treatment-refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation treatments.

[0369] The use of paragraphs 362-368, wherein the nicotine addiction or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0370] The use of paragraphs 362-369, wherein the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, or (b) had an exhaled CO concentration of about 10 ppm or greater before administration of cytisine, or (c) a combination of (a) and (b).

[0371] Use of paragraphs 362-370, further including providing behavioral support to the subject.

[0372] 1. Use of tablets containing about 1.0 mg or 1.5 mg of cytisine for oral administration of about 3.0 mg of cytisine three times daily to a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments, to treat nicotine addiction and / or nicotine dependence in the subject.

[0373] The use of paragraph 372, wherein the nicotine addiction treatment includes NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or a combination thereof.

[0374] The use of paragraphs 372 and 373, wherein the cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times daily to a subject in need thereof.

[0375] The use of paragraphs 372-374, wherein the cytisine is provided in a unit dose of 3.0 mg of cytisine three times daily to a subject in need thereof.

[0376] Use of paragraphs 372-375, wherein the unit dose of cytisine comprises either (a) two tablets, each containing 1.5 mg of cytisine, or (b) a single tablet containing 3.0 mg of cytisine.

[0377] The use of paragraphs 372-376, wherein cytisine is administered for about 6 weeks or about 12 weeks.

[0378] The use of paragraphs 372-377, wherein the subject does not experience an adverse event after receiving cytisine treatment.

[0379] The use of paragraphs 372-378, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0380] The use of paragraphs 372-379, wherein the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, or (b) had an exhaled CO concentration of about 10 ppm or greater before administration of cytisine, or (c) a combination of (a) and (b).

[0381] 1. Use of a tablet containing 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 to prevent relapse to smoking and / or vaping in the subject.

[0382] The use of paragraph 381, wherein the cytisine is administered for about 6 weeks or about 12 weeks.

[0383] The use of paragraphs 381 and 382, ​​wherein the subject does not experience an adverse event after receiving the cytisine treatment.

[0384] The use of paragraphs 381-383, wherein the adverse event is selected from the group consisting of upper respiratory tract infection (URTI), abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0385] The use of paragraphs 381-384, wherein the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, or (b) had an exhaled CO concentration of about 10 ppm or greater before administration of cytisine, or (c) a combination of (a) and (b).

[0386] Use of paragraphs 381-385, wherein the subject is a treatment-refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation treatments.

[0387] The use of paragraphs 381-386, wherein the smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0388] 1. Use of tablets containing about 1.0 mg or about 1.5 mg of cytisine for oral administration of about 3.0 mg of cytisine three times daily in a subject who has failed treatment with one or more nicotine addiction treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, e-cigarettes, and vaping to prevent smoking relapse in the subject.

[0389] Use of paragraph 388, where the subject (a) smoked 10 or more cigarettes per day before administration of cytisine, or (b) had an exhaled CO concentration of about 10 ppm or greater before administration of cytisine, or (c) a combination of (a) and (b).

[0390] The use of paragraphs 388 and 389, wherein the unit dose of cytisine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine, and wherein the cytisine is administered for about 6 weeks or about 12 weeks.

[0391] The use of paragraphs 388-390, wherein the subject does not experience an adverse event selected from the group consisting of URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving cytisine treatment. The present application provides the following aspects of the invention. (Aspect 1) 1. A method of treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof, said method comprising administering to said subject cytisine provided in a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine three times daily. (Aspect 2) 1. A method of 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 a unit dose of: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine. (Aspect 3) 1. A method of treating nicotine addiction and / or nicotine dependence in a subject in need thereof, said method comprising administering cytisine to said subject, wherein said subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments. (Aspect 4) 1. A method of preventing smoking relapse and / or vaping relapse 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 selected from the group consisting of nicotine replacement therapy, bupropion administration, varenicline administration, e-cigarettes, and vaping. (Aspect 5) 5. The method of embodiment 3 or 4, wherein cytisine is provided to said subject in a unit dose of about 1.0 mg to about 6.0 mg of cytisine given to said subject three to six times per day, or in a unit dose of 3.0 mg of cytisine given to said subject three times per day. (Aspect 6) 6. The method of any one of embodiments 1 and 3-5, wherein the cytisine is provided in a unit dose comprising: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine. (Aspect 7) The method of any one of aspects 1, 2, 5, and 6, wherein said subject is a refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation treatments. (Aspect 8) The method of aspect 3 or 7, wherein the nicotine addiction or smoking cessation treatment is selected from nicotine replacement therapy, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. (Aspect 9)

[0023] Aspect 10. The method of any one of the preceding aspects, wherein the subject, after administration of cytisine, does not experience an adverse event selected from the group of adverse events consisting of upper respiratory tract infection, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. (Aspect 10)

[0023] Aspect 14. The method of any one of the preceding aspects, wherein the cytisine is administered for about 6 weeks or about 12 weeks. (Aspect 11)

[0023] The method of any one of the preceding aspects, wherein the subject (a) smoked 10 or more cigarettes per day prior to said administration of cytisine; (b) had an exhaled CO2 level of about 10 ppm or greater prior to said administration of cytisine; or (c) a combination of (a) and (b). (Aspect 12) 1. Use of a 3.0 mg, 1.5 mg, or 1.0 mg unit dose of cytisine to treat nicotine addiction, nicotine dependence, promote cessation of smoking and / or vaping, and / or promote a reduction in smoking and / or vaping in a subject in need thereof, wherein the cytisine is for oral administration to the subject three times daily. (Aspect 13) 1. Use of a unit dose of cytisine in the form of: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each 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. (Aspect 14) 1. Use of cytisine to treat 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. (Aspect 15) 1. Use of cytisine to prevent relapse to smoking and / or vaping in a subject who is a treatment-refractory patient who has failed treatment with one or more nicotine addiction treatments selected from the group consisting of nicotine replacement therapy, bupropion administration, varenicline administration, e-cigarettes, and vaping, wherein the cytisine is for oral administration to the subject three times daily. (Aspect 16) 1. Use of a tablet containing about 1.0 mg or 1.5 mg of cytisine for oral administration of about 3.0 mg of cytisine three times daily to a subject to treat nicotine addiction, nicotine dependence, which promotes cessation of smoking and / or vaping and / or promotes a reduction in smoking and / or vaping in said subject. (Aspect 17) 1. Use of tablets containing about 1.0 mg or 1.5 mg of cytisine for oral administration of about 3.0 mg of cytisine three times daily to a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments, to treat nicotine addiction and / or nicotine dependence in said subject. (Aspect 18) 1. Use of a tablet containing 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 to prevent relapse to smoking and / or vaping in the subject. (Aspect 19) 1. Use of a tablet containing 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 prevent relapse to smoking in a subject who has failed treatment with one or more nicotine addiction treatments selected from the group consisting of nicotine replacement therapy, bupropion administration, varenicline administration, e-cigarettes, and vaping. (Aspect 20) 16. The use of any one of embodiments 12, 14, and 15, wherein the cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine given three to six times per day to a subject in need thereof, or in a unit dose of 3.0 mg of cytisine given three times per day to a subject in need thereof. (Aspect 21) 21. The use of any one of aspects 14-20, wherein the unit dose of cytisine comprises: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine; (b) a single tablet, each containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine. (Aspect 22) The use of any one of aspects 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 treatments. (Aspect 23) The use of any one of aspects 12-14, 16-18, or 20-22, wherein the nicotine addiction or smoking cessation treatment is selected from nicotine replacement therapy, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. (Aspect 24) 24. The use of any one of aspects 12-23, wherein the subject, after administration of cytisine, does not experience an adverse event selected from the group of adverse events consisting of upper respiratory tract infection, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. (Aspect 25) 25. The use according to any one of aspects 12 to 24, wherein cytisine is administered for about 6 weeks or about 12 weeks. (Aspect 26) 26. The use of any one of aspects 12-25, wherein the subject (a) smoked 10 or more cigarettes per day prior to said administration of cytisine, or (b) had an exhaled CO2 level of about 10 ppm or greater prior to said administration of cytisine, or (c) a combination of (a) and (b). (Aspect 27) 27. The use of any one of embodiments 12, 13, and 20-26, wherein the unit dose of cytisine comprises either (a) two tablets, each containing 1.5 mg of cytisine, or (b) a single tablet containing 3.0 mg of cytisine.

Claims

1. A pharmaceutical composition comprising 1.5 mg of cytisine for use in treating nicotine addiction and / or nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments or smoking cessation therapies, comprising: The pharmaceutical composition, wherein the pharmaceutical composition is for oral administration to the subject three times daily for a period of at least three weeks.

2. A pharmaceutical composition comprising 3.0 mg of cytisine for use in treating nicotine addiction and / or nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments or smoking cessation therapies, comprising: The pharmaceutical composition, wherein the pharmaceutical composition is for oral administration to the subject three times daily for a period of at least three weeks.

3. A pharmaceutical composition comprising 1.5 mg of cytisine for use in preventing relapse to smoking and / or vaping in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments or smoking cessation therapies, comprising: The pharmaceutical composition, wherein the pharmaceutical composition is for oral administration to the subject three times daily for a period of at least three weeks.

4. A pharmaceutical composition comprising 3.0 mg of cytisine for use in preventing relapse to smoking and / or vaping in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments or smoking cessation therapies, comprising: The pharmaceutical composition, wherein the pharmaceutical composition is for oral administration to the subject three times daily for a period of at least three weeks.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the smoking cessation therapy is selected from the group consisting of nicotine replacement therapy, varenicline administration, and bupropion administration.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the subject has been smoking for at least about 20 years.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the subject has been smoking for at least about 25 years.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the subject has been smoking for at least about 30 years.

9. The object is (a) smoking 10 or more cigarettes per day prior to administration of cytisine; (b) having an exhaled CO2 concentration of about 10 ppm or greater prior to administration of said cytisine; or The pharmaceutical composition of any one of claims 1 to 8, which is a combination of (c) (a) and (b).

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the subject is provided with behavioral support.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein cytisine is administered for at least 6 weeks, or at least 12 weeks.

12. A tablet comprising 1.5 mg of cytisine for oral administration three times daily to a subject for a period of at least three weeks, the tablet is for use in treating nicotine addiction and / or nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping; The tablet, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments or smoking cessation therapies.

13. A tablet comprising 3.0 mg of cytisine for oral administration three times daily to a subject for a period of at least three weeks, the tablet is for use in treating nicotine addiction and / or nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping; The tablet, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments or smoking cessation therapies.

14. 14. The tablet of claim 12 or 13, wherein the smoking cessation therapy is selected from the group consisting of nicotine replacement therapy, varenicline administration, and bupropion administration.

15. The tablet of any one of claims 12 to 14, wherein the subject has been smoking for at least about 20 years.

16. The tablet of any one of claims 12 to 15, wherein the subject has been smoking for at least about 25 years.

17. The tablet of any one of claims 12 to 16, wherein the subject has been smoking for at least about 30 years.

18. The object is (a) smoking 10 or more cigarettes per day prior to administration of cytisine; (b) having an exhaled CO2 concentration of about 10 ppm or greater prior to administration of said cytisine; or The tablet of any one of claims 12 to 17, wherein (c) is a combination of (a) and (b).

19. The tablet of any one of claims 12 to 18, wherein the subject is provided with behavioral support.

20. 20. The tablet of any one of claims 12 to 19, wherein cytisine is administered for at least 6 weeks, or at least 12 weeks.

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