| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nicotine Addiction with the desire to quit smoking |
|
| E.1.1.1 | Medical condition in easily understood language |
| Nicotine Addiction with the desire to quit smoking |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behavioral Disciplines and Activities [F04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10053325 |
| E.1.2 | Term | Smoking cessation therapy |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Safety Objectives:
1. To characterize the neuropsychiatric safety profiles of varenicline and bupropion by estimating the differences from placebo in the incidence of the primary neuropsychiatric
AE endpoint for subjects:
a. With a diagnosis of psychiatric disorder;
b. Without a diagnosis of psychiatric disorder.
2. To characterize the differences in the neuropsychiatric safety profiles of varenicline and bupropion as compared with placebo between these sub-populations (cohorts).
Efficacy: Abstinence from Smoking
Main Efficacy Objective: To compare smoking abstinence rates of varenicline and bupropion relative to placebo for the last 4 weeks of treatment and continuously through Week 24, as measured by CO-confirmed continuous abstinence rate (CAR) CAR9-12 and CAR9-24, respectively, separately for subjects with and without a diagnosis of psychiatric disorder. |
|
| E.2.2 | Secondary objectives of the trial |
To assess if there is a difference between cohorts in the placebo adjusted relative abstinence rates (CAR9 12 and CAR9 24) of varenicline and bupropion, separately.
Another secondary objective of the study is to perform the following comparisons with respect to the primary safety and efficacy endpoints:
1. NRT vs. Placebo;
2. Varenicline vs. Bupropion;
3. Varenicline vs. NRT;
4. Bupropion vs NRT. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The following is an excerpt of the most critical Inclusion criteria in protocol A3051123. For a complete listing of all Inclusion criteria please refer to sections 4.1 and 4.2 of the protocol.
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the psychiatric or non psychiatric arm of the study:
1. Male or female cigarette smokers, 18 -75 years, motivated to stop smoking and considered suitable for a smoking cessation attempt.
2. 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.
3. Females who are not of childbearing potential (ie, who are surgically sterilized or at least 2 years postmenopausal) and who are not nursing may be included. Females who are of childbearing potential may be included provided that they are not pregnant, not nursing, and meet all of the following criteria:
• Are instructed and agree to avoid pregnancy through 30 days after the last dose of study medication;
• Have a negative pregnancy test (beta hCG) at Screening and Baseline and
• Agree to use at least one of the birth control methods listed below:
• An oral contraceptive agent, an intrauterine device (IUD), an implantable contraceptive (eg, Norplant), or an injectable contraceptive (eg, Depo Provera) for at least 1 month prior to entering the study and will continue its use through at least 30 days after the last dose of study medication or;
• A double barrier method of contraception, eg, condom and diaphragm with spermicide while participating in the study through at least 30 days after the last dose of study medication or abstinence.
4. A personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
5. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Additional Inclusion Criteria for Neuropsychiatric Cohort:
In addition to the criteria above, subjects to be included in the Neuropsychiatric cohort must also meet the following: All subjects will be screened for Axis I and II diagnosis (current and/or past) using DSM IV TR criteria based on clinical assessment and confirmed by SCID (administered by a clinician or a qualified person trained in clinical mental health, ie; a PhD level clinical psychologist, or an individual with master level training in related areas [masters level psychologist, social work] who have been trained to use the SCID ). A “current” diagnosis is defined as the subject meeting the established criteria in the prior month. A “past” diagnosis is also the same as a “lifetime” diagnosis where applicable. A past diagnosis can have occurred anytime in the past medical history. The four major diagnostic groups comprising the neuropsychiatric cohort are: Psychotic, Affective, Anxiety and Personality Disorders. The four diagnostic groups are further described below. Subjects will be included in the psychiatric cohort, if they are considered clinically stable and meet criteria, either current or lifetime diagnosis, for one or more of the DSM IV diagnoses listed below and have met diagnostic criteria before the initiation of study treatment.
a. Psychotic Disorders limited to:
• Schizophrenia;
• Schizoaffective.
b. Affective Disorders limited to:
• Major Depression;
c. Anxiety Disorders limited to:
• Panic Disorder with or without Agoraphobia;
• Post Traumatic Stress Disorder;
• Obsessive Compulsive Disorder;
• Social Phobia;
• Generalized Anxiety Disorder.
d. Personality Disorders limited to past history of:
• Borderline Personality Disorder.
All subjects with an Axis I or II diagnosis must be judged to be clinically stable including the following:
• No acute exacerbation of their condition in the preceding 6 months;
• If on treatment for their condition, must have been on stable treatment for a minimum of 3 months (eg, stable drug and dose greater than or equal 3 months);
• No change in treatment is anticipated for the duration of the study;
• In the opinion of the Investigator, the patient is not at high risk of self injury or suicidal behavior;
• In the event the Investigator is not a mental health professional (MHP), the subject should be evaluated by a MHP to confirm the SCID I or II diagnosis and determine if the subject is stable. A MHP must be a psychiatrist. A subject who requires new treatment or is judged not to be clinically stable cannot be randomized. |
|
| E.4 | Principal exclusion criteria |
The following is an excerpt of the most critical Exclusion criteria in protocol A3051123. For a complete listing of all Exclusion criteria please refer to sections 4.1 and 4.2 of the protocol.
Exclusion Criteria:
Subjects presenting with any of the following will not be included in the study:
6. 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);
d. All Factitious Disorders;
e. All Dissociative Disorders;
f. All Impulse Control Disorders;
g. Evidence of substance abuse/misuse or dependence severe enough to compromise the subject’s ability to comply with the study requirements;
h. Subjects with antisocial, schizotypal, or any other personality disorder severe enough to compromise the subject’s ability to comply with the study requirements.
7. Subjects with an Axis I diagnosis according to DSM IV TR criteria who have a rating of 5 or higher on the Clinical Global Impression Severity (CGI S).
8. Subjects who are believed to have a suicidal risk at screening, baseline, or after assessment by a qualified MHP-(Psychiatrist) if a risk assessment interview was required after screening or baseline using the Columbia Suicide Severity Rating Scale (C SSRS).
• Suicide ideation associated with actual intent and/or plan in the past year: Yes answers on item 5 of the C SSRS.
• Previous history of suicide behaviors in the past year.
9. Subjects who in the opinion of the Investigator display self injuring behaviors.
10. Subjects with a positive urine drug screen at screening or baseline.
11. Subjects taking an investigational drug within 30 days before the Baseline visit and at anytime during the study period.
12. Subjects who have taken varenicline, bupropion, or NRT within 30 days prior to Baseline visit.
13. Subjects for whom treatment with bupropion is not appropriate:
• Subjects with seizure disorder;
• Subjects undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines);
• Subjects with current or prior diagnosis of anorexia or bulimia nervosa;
• Subjects who have taken a monoamine oxidase (MAO) inhibitor within the past fourteen days (prior to the Baseline visit);
• Subjects who are taking the following narrow therapeutic range medications which are metabolized by CYP2D6; desipramine, nortriptyline, Type 1C antiarrhythmics (eg, propafenone, flecainide), thioridazine.
14. Subjects with severe chronic obstructive pulmonary disease (COPD) defined as any subject who fulfills any of the following criteria:
• History of repeated exacerbations of COPD (greater than or equal to 3 in 3 years);
• Requires systemic corticosteroid maintenance (eg, oral prednisolone) for management of chronic symptoms;
• Is maintained on oxygen therapy for management of chronic symptoms.
15. Subjects with clinically significant cardiovascular disease in the past 2 months. Examples of clinically significant cardiovascular disease include:
• Myocardial infarction;
• Coronary artery bypass graft (CABG);
• Percutaneous transluminal coronary angioplasty (PTCA);
• Severe or unstable angina;
• A serious arrhythmia;
• Clinically significant ECG conduction abnormalities;
• Hospitalizations for heart failure.
16. Subjects with clinically significant cerebrovascular disease in the past 2 months. Examples of clinically significant cerebrovascular disease include:
• Cerebrovascular accident (CVA), stroke;
• Documented transient ischemic attack (TIA).
17. Subjects who do not agree to abstain from using non cigarette tobacco products (including, eg, pipe tobacco, cigars, snuff, chewing tobacco, hookah, etc.) or marijuana during study participation.
18. Subjects who do not agree to abstain from using nicotine replacement therapy, bupropion, varenicline and other aids to smoking cessation during study participation (both the treatment phase and the post treatment follow up).
19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
20. Subjects with Bipolar I or Bipolar II disorders. These subjects are not allowed into the study even if they are concurrently diagnosed with an inclusionary diagnosis. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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. This endpoint is referred to as the Neuropsychiatric (NPS) AE endpoint.
The main efficacy endpoint is 4-week CO-confirmed continuous abstinence for Weeks 9 through 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Safety Endpoint: Week 0-24
Primary Efficacy Endpoint: Weeks 9-12 and 12-24 |
|
| E.5.2 | Secondary end point(s) |
Secondary Safety Endpoints:
- Occurrence of the components of the primary safety endpoint;
- Individual item responses, along with subscale scores and overall score (when applicable; specifics are stated in the Statistical Analysis Plan), for the following questionnaires:
- Hospital Anxiety and Depression Scale (HADS);
- Columbia Suicide Severity Rating Scale (C-SSRS);
- Clinical Global Impression of Improvement (CGI-I).
Secondary Efficacy Endpoints:
The secondary efficacy endpoint is CO-confirmed continuous abstinence from Week 9 through Week 24.
An additional secondary efficacy endpoint is the 7-day point prevalence of abstinence at each assessment visit. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Safety Endpoint: Weeks 9-24
Secondary Efficacy Endpoint: Weeks 9-12 and 12-24 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Czech Republic |
| Denmark |
| Egypt |
| Finland |
| France |
| Germany |
| Mexico |
| New Zealand |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of Trial in all participating countries is defined as last subject’s last visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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