| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053325 |
| E.1.2 | Term | Smoking cessation therapy |
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| 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 |
The primary efficacy objective of this protocol is to compare 12 weeks of treatment with varenicline 1 mg BID to placebo for smoking cessation in the setting of a patient selfselected quit date (before Week 5 visit), and to evaluate continuous abstinence from smoking for 12 weeks after the treatment period.
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| E.2.2 | Secondary objectives of the trial |
| Additional secondary objectives of comparing treatments for urge to smoke, smoking satisfaction and the psychological reward over time in subjects in the United States will be accomplished by analyses of the results from the Minnesota Nicotine Withdrawal Scale (MNWS)7,8 (Appendix 3) and the Modified Cigarette Evaluation Questionnaire (mCEQ)9,10 (Appendix 4) questionnaires, respectively. The safety objective is to gather safety data for 12 weeks of treatment with varenicline 1 mg BID or placebo followed by 12 weeks of non-treatment follow-up, and to evaluate safety and tolerability when used in the setting of a subject self-selected quit date. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial:
1. Current cigarette smokers, male or female, who are between the ages of 18 and 75 years, inclusive, and who are motivated to stop smoking.
2. Subjects must have smoked an average of at least 10 cigarettes per day during the past year and during the month prior to the screening visit, with no continuous period of abstinence greater than 3 months in the past year.
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 of childbearing potential may be included provided that they are not pregnant, not nursing, and meet all of the following criteria:
4. Are instructed and agree to avoid pregnancy through 30 days after the last dose of study medication.
5. Have a negative serum pregnancy test (β-hCG) at screening; and.
6. Agree to use at least one of the birth control methods listed below:
7. An oral contraceptive, an Intrauterine Device (IUD), an implantable contraceptive, or an injectable contraceptive 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 drug or.
8. A barrier method of contraception, for example, condom and/or diaphragm (with spermicide) while participating in the study through at least 30 days after the last dose of study drug.
9. Subjects must have no serious or unstable disease within the past 6 months (See exclusion criteria).
10. Subjects must be outpatients, assessed in a clinic setting and be able and willing to comply with all study visits , treatment plan, laboratory tests, and other trial procedures during the treatment and non-treatment phases.
11. Subjects must provide a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the trial.
12. Only one subject per household may participate. |
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the trial:
1. Subjects currently suffering with depression, or who have been diagnosed with depression or treated with an anti-depressant for their depression within the past 12 months. Subjects should be excluded if their score at the screening or baseline administration of the Patient Health Questionnaire (PHQ-9) is ≥5, or if they have a score of >0 on item 9 regarding suicidal ideation or behavior.
2. Subjects with any history of suicidal ideation or suicidal behavior as assessed by the Columbia Suicide-Severity Rating Scale (C-SSRS)(Baseline Version) in the past 5 years, or at the time of the Baseline Visit (since Last Visit version)
3. Subjects with a past or present history of psychosis; subjects with panic attacks or anxiety disorders; or bipolar disorder.
4. Subjects with known severe Chronic Obstructive Pulmonary Disease (COPD).
5. Subjects with clinically unstable cardiovascular disease in the past 6 months. Examples of clinically unstable cardiovascular diseases include myocardial infarction, Coronary Artery Bypass Graft (CABG), Percutaneous Transluminal Coronary Angioplasty (PTCA), severe or unstable angina, serious arrhythmia, and clinically significant ECG conduction abnormalities (subjects with pacemakers may be included).
6. Subjects with a systolic blood pressure greater than 150 mmHg or a diastolic blood pressure greater than 95 mmHg at screening or baseline.
7. Subjects with clinically significant neurological disorders or cerebrovascular diseases (for example, stroke, transient ischemic attack, etc. with significant neurologic impairment in the past 6 months).
8. Subjects with a history of clinically significant or unstable endocrine disorders or gastrointestinal diseases, including insulin dependent diabetes, Type 2 diabetes mellitus with HgA1C ≥9, uncontrolled hyperthyroidism, and active peptic ulcer.
9. Subjects with clinically significant hepatic or renal impairment or other clinically significant abnormal laboratory test values.
• Subjects with an SGOT (AST) or SGPT (ALT) greater than 1.5 times the upper limit of normal (ULN) or total bilirubin greater than 1.1 times the ULN;
• Subjects with severe abnormalities of renal function (estimated creatinine clearance by Cockcroft-Gault equation <30 mL/min)
10. Subjects with a history of cancer (cured basal cell or squamous cell carcinoma of the skin allowed).
11. Subjects with evidence or history of serious or life-threatening allergic reactions to drugs (for example anaphylaxis or Stevens-Johnson syndrome).
12. Subjects with a history of drug (except nicotine) or alcohol abuse or dependence within the past 12 months.
13. Subjects with a positive urine drug screen for drugs of abuse/potential abuse not prescribed for the treatment of a medical condition.
14. Subjects with a body mass index (BMI) less than 15 or greater than 38 when wearing indoor clothing without shoes. No subject will be enrolled with a weight less than 45.5 kg.
15. Subjects who have previously taken varenicline.
16. Subjects who participated previously in this trial or participated in any other studies involving investigational or marketed products , concomitantly or within 30 days (or 5 half-lives, whichever is longer) prior to entry into this study. For subjects who have previously participated in smoking cessation studies see exclusion 19 below.
17. Subjects taking a concomitant medication that is prohibited by this protocol
18. Subjects requiring other medications during the study that might interfere with the evaluation of the study drug (for example, clonidine, nicotine replacement therapy, and bupropion).
19. Subjects who have used a nicotine replacement product, bupropion, clonidine, or nortriptyline for a quit attempt within the past 3 months, or have participated in a study with an experimental drug for smoking cessation within the past one year. Subjects who have recently used NRT for short intervals for management of craving and withdrawal during periods where smoking was prohibited, for example a plane trip, may be included.
20. Subjects who do not agree to completely abstain from using non-cigarette tobacco products (including, for example, pipe tobacco, cigars, snuff, nicotine replacement therapy, etc.) during study participation.
21. Subjects who donate blood or blood components while receiving study drug or within 1 month of the completion of the study treatment.
22. Subjects unable and/or unlikely to comprehend and follow the study protocol, including subjects unable and/or unwilling to participate in the non-treatment followup.
23. Subjects who in the investigator’s opinion will be unlikely to commit to the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the 4-week continuous abstinence rate (CAR) for Weeks 9 - 12 (ie, the proportion of subjects who are able to maintain complete abstinence from cigarette smoking and other nicotine use, with end-expiratory exhaled CO measurements ≤10 ppm, for the planned last 4 weeks of treatment). |
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| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 | Information not present in EudraCT |
| 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 |
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| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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