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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
8,144
Triple dummy placebo for each treatment arm
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
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).
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.
Time frame: 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.
Time frame: 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, 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.
Time frame: 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
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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.
Coastal Clinical Research, Inc.
Mobile, Alabama, United States
NoesisPharma Research
Phoenix, Arizona, United States
Pharmacology Research Institute
Encino, California, United States
Synergy Clinical Research of Escondido
Escondido, California, United States
Sun Valley Research Center
Imperial, California, United States
Omega Clinical Trials
La Habra, California, United States
Pacific Treatment and Research Center UC San Diego Health System
La Jolla, California, United States
Pharmacology Research Institute
Los Alamitos, California, United States
David Geffen School of Medicine at University of California, Los Angeles
Los Angeles, California, United States
Pharmacology Research Institute
Newport Beach, California, United States
...and 146 more locations
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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?
Time frame: 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?
Time frame: 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?
Time frame: 24 Weeks