Study Evaluating The Safety And Efficacy Of Varenicline and Bupropion For Smoking Cessation In Subjects With And Without A History Of Psychiatric Disorders

Study Overview
=================
Brief Summary
-----------------
This study is being conducted to assess varenicline and bupropion as aids to smoking cessation treatment in subjects with and without an established diagnosis of major psychiatric disorder and to characterize the neuropsychiatric safety profile (pre-specified adverse events (AEs) in both of these populations).

Official Title
-----------------
A Phase 4, Randomized, Double-blind, Active And Placebo-controlled, Multicenter Study Evaluating The Neuropsychiatric Safety And Efficacy Of 12 Weeks Varenicline Tartrate 1mg Bid And Bupropion Hydrochloride 150mg Bid For Smoking Cessation In Subjects With And Without A History Of Psychiatric Disorders

Conditions
-----------------
Smoking Cessation

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: varenicline tartrate
* Drug: bupropion hydrochloride
* Drug: Nicotine Replacement Therapy Patch


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female cigarette smokers, 18- 75 years, motivated to stop smoking and considered suitable for a smoking cessation attempt. Smoked an average of at least 10 cigarettes per day during past year and during the month prior to the screening visit, and exhaled carbon monoxide (CO) >10 ppm at screening. For Neuropsychiatric cohort- subjects must have proper diagnosis as outlined in protocol. Exclusion Criteria: Subjects with a past or current diagnosis of one of the following disorders: a. Psychotic Disorders: Schizophreniform Delusional Disorder Psychotic Disorder NOS b. All Delirium, Dementia, and Amnestic and Other Cognitive Disorders c. All Substance Induced Disorders (Other than nicotine)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>Subjects randomized to placebo will receive placebo treatments for all three study drugs. Blinded placebo will be provided for varenicline, bupropion hydrochloride and transdermal nicotine patch (NRT). In addition, subjects will receive blinded placebo treatments for the study drugs they are not randomized to receive. | Drug: Placebo<br>* Triple dummy placebo for each treatment arm<br>|
| Active Comparator: varenicline<br> | Drug: varenicline tartrate<br>* Subjects will be titrated to the full dose during the first week in the following manner: 0.5 mg (tablet form) once a day for 3 days, 0.5 mg twice a day for 4 days, then 1 mg twice a day for 11 weeks<br>* Other names: Chantix; Champix;|
| Active Comparator: bupropion<br> | Drug: bupropion hydrochloride<br>* Subjects will receive 150 mg (tablet form) once a day for 3 days and then will take 150 mg twice a day for the remainder of the treatment period (11 weeks and 4 days).<br>|
| Active Comparator: Nicotine Replacement Therapy Patch<br> | Drug: Nicotine Replacement Therapy Patch<br>* Subjects will start active dosing the morning of the Week 1 visit and will receive a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment.<br>* Other names: NRT;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Neuropsychiatric (NPS) Adverse Events (AE) - the Primary Study Endpoint | The primary safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. | Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. | 
| Estimated NPS AE Rate (%), by Cohort | The primary safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Estimated NPS AE rate (%) was calculated based on least-squares means analysis. | Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort | The safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Each of these 16 components is reported below. | Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. | 
| Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort | The safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Each of these 16 components is reported below. | Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. | 
| Occurrence of the Components of NPS AE Primary Endpoint (Overall) | The NPS AE composite results (as previously described) are for the two cohorts combined and are presented below. | Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. | 
| Occurrence of Severe-only NPS AEs in the Primary Endpoint, by Cohort | The primary safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint. | Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. | 
| Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort | The safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint. | Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. | 
| Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort | The safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint. | Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. | 
| Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) | The NPS AE endpoint was the occurrence of at least 1 treatment-emergent severe AE of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least 1 treatment-emergent severe AE of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint. | Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. | 
| Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort | The HADS is a subject self-reporting scale completed in person at clinic visits at Baseline and Weeks 1 through 6, 8, 10, 12, 13, 16, 20, and 24. It contains 14 individual item responses ranging in increasing severity from 0 (normal) to 3 (most severe) for a total range of 0 to 42. Of the 14 items, 7 assess anxiety and 7 assess depression, providing 2 subscales with ranges of 0 to 21. For each subscale, 0 to 7 is considered normal, while 15 to 21 represents severe symptoms. | Baseline to Week 24 | 
| HADS Total Score, Psychiatric History Cohort | The HADS is a subject self-reporting scale completed in person at clinic visits at Baseline and Weeks 1 through 6, 8, 10, 12, 13, 16, 20, and 24. It contains 14 individual item responses ranging in increasing severity from 0 (normal) to 3 (most severe) for a total range of 0 to 42. Of the 14 items, 7 assess anxiety and 7 assess depression, providing 2 subscales with ranges of 0 to 21. For each subscale, 0 to 7 is considered normal, while 15 to 21 represents severe symptoms. | Baseline to Week 24 | 
| HADS Total Score (Overall) | The HADS is a subject self-reporting scale completed in person at clinic visits at Baseline and Weeks 1 through 6, 8, 10, 12, 13, 16, 20, and 24. It contains 14 individual item responses ranging in increasing severity from 0 (normal) to 3 (most severe) for a total range of 0 to 42. Of the 14 items, 7 assess anxiety and 7 assess depression, providing 2 subscales with ranges of 0 to 21. For each subscale, 0 to 7 is considered normal, while 15 to 21 represents severe symptoms. | Baseline to Week 24 | 
| Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Non-psychiatric History Cohort | The C-SSRS is a semi-structured interview designed to evaluate an individual's degree of suicidal ideation, preparatory acts or behavior to actual attempt, ranging from wish to be dead to active suicidal ideation with specific plan and intent. Answers at screening are for lifetime history. Answers for all other visits are since last visit.The scale is also used to record any completed suicides. | Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. | 
| Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Psychiatric History Cohort | The C-SSRS is a semi-structured interview designed to evaluate an individual's degree of suicidal ideation, preparatory acts or behavior to actual attempt, ranging from wish to be dead to active suicidal ideation with specific plan and intent. Answers at screening are for lifetime history. Answers for all other visits are since last visit. The scale is also used to record any completed suicides. | Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. | 
| Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Overall | The C-SSRS is a semi-structured interview designed to evaluate an individual's degree of suicidal ideation, preparatory acts or behavior to actual attempt, ranging from wish to be dead to active suicidal ideation with specific plan and intent. Answers at screening are for lifetime history. Answers for all other visits are since last visit. The scale is also used to record any completed suicides. | Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. | 
| Clinical Global Impression of Improvement (CGI-I), No Change Rating by Visit | The CGI-I is a clinician rated instrument that measures change in participant's psychiatric condition (or lack thereof in the stratum without psychiatric disorders) on a 7 point scale ranging from 1 (very much improved) to 7 (very much worse), with 4 = no change. The ratings were applicable even to those without psychiatric diagnoses (eg, those with no psychiatric symptoms would be rated as normal, not at all ill on the CGI-S at baseline and assuming no psychiatric symptoms emerge during the trial, would be rated as no change on the CGI-I at follow-up visits). For those participants with a psychiatric diagnosis, the clinician should rate the severity of the mental illness with respect to the clinician's experience with the psychiatric population to which the participant belongs. | Baseline to Week 24 | 
| CO-Confirmed Continuous Abstinence for Weeks 9 Through 12, Non-psychiatric History Cohort | A responder to this endpoint requires the answer no to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 12 (inclusive). | Week 9 through Week 12 | 
| CO-Confirmed Continuous Abstinence for Weeks 9 Through 12, Psychiatric History Cohort | A responder to this endpoint requires the answer no to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 12 (inclusive). | Week 9 through Week 12 | 
| CO-Confirmed Continuous Abstinence for Weeks 9 Through 12 (Overall) | A responder to this endpoint requires the answer no to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 12 (inclusive). | Week 9 through Week 12 | 
| CO-confirmed Continuous Abstinence From Week 9 Through Week 24, Non-psychiatric History Cohort | A responder to this endpoint requires the answer no to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 24 (inclusive). | Week 9 through Week 24 | 
| CO-confirmed Continuous Abstinence From Week 9 Through Week 24, Psychiatric History Cohort | A responder to this endpoint requires the answer no to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 24 (inclusive). | Week 9 through Week 24 | 
| CO-confirmed Continuous Abstinence From Week 9 Through Week 24 (Overall) | A responder to this endpoint requires the answer no to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 24 (inclusive). | Week 9 through Week 24 | 
| 7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort | A responder to this endpoint requires the answer no to both questions 3 and 6 on the nicotine use inventory at that specific visit. NUI Question 3 (Baseline through Week 24): Has the subject smoked any cigarettes (even a puff) in the last 7 days? NUI Question 6 (Baseline through Week 12): Has the subject used any other nicotine containing products in the last 7 days? NUI Question 6 (Week 13 through Week 24): Has the subject used any other tobacco products in the last 7 days? | 24 Weeks | 
| 7-Day Point Prevalence of Abstinence, Psychiatric History Cohort | A responder to this endpoint requires the answer no to both questions 3 and 6 on the nicotine use inventory at that specific visit. NUI Question 3 (Baseline through Week 24): Has the subject smoked any cigarettes (even a puff) in the last 7 days? NUI Question 6 (Baseline through Week 12): Has the subject used any other nicotine containing products in the last 7 days? NUI Question 6 (Week 13 through Week 24): Has the subject used any other tobacco products in the last 7 days? | 24 Weeks | 
| 7-Day Point Prevalence of Abstinence (Overall) | A responder to this endpoint requires the answer no to both questions 3 and 6 on the nicotine use inventory at that specific visit. NUI Question 3 (Baseline through Week 24): Has the subject smoked any cigarettes (even a puff) in the last 7 days? NUI Question 6 (Baseline through Week 12): Has the subject used any other nicotine containing products in the last 7 days? NUI Question 6 (Week 13 through Week 24): Has the subject used any other tobacco products in the last 7 days? | 24 Weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
smoking cessation, psychiatric disease