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    Summary
    EudraCT Number:2010-022914-15
    Sponsor's Protocol Code Number:A3051123
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-01-10
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2010-022914-15
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This study investigates the effects of various smoking cessation therapies on people with and without a history of psychiatric conditions
    A.3.2Name or abbreviated title of the trial where available
    EAGLES
    A.4.1Sponsor's protocol code numberA3051123
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPfizer Inc., 235 East 42nd Street, New York, NY 10017 US
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfizer Inc., 235 East 42nd Street, New York, NY 10017
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc
    B.5.2Functional name of contact pointClinical Trials.gov Call Center
    B.5.3 Address:
    B.5.3.1Street Address235 E 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18007181021
    B.5.5Fax number+13037391119
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Champix
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code CP-526,555
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVARENICLINE TARTRATE
    D.3.9.1CAS number 375815-87-5
    D.3.9.2Current sponsor codeCP-526,555
    D.3.9.3Other descriptive nameCAS Name: 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine-(2R,3R)-2,3-dihydroxybutanedioate (1:1)
    D.3.9.4EV Substance CodeSUB22601
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Champix
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code CP-526,555
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVARENICLINE TARTRATE
    D.3.9.1CAS number 375815-87-5
    D.3.9.2Current sponsor codeCP-526,555
    D.3.9.3Other descriptive nameCAS Name: 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine-(2R,3R)-2,3-dihydroxybutanedioate (1:1)
    D.3.9.4EV Substance CodeSUB22601
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Zyban Bupropion hydrochloride
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBUPROPION HYDROCHLORIDE
    D.3.9.1CAS number 31677-93-7
    D.3.9.2Current sponsor codeBupropion Hydrochloride
    D.3.9.3Other descriptive nameZyban
    D.3.9.4EV Substance CodeSUB00432MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name NiQuitin
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline Consumer Healthcare
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code Transdermal nicotine Patch (NRT)
    D.3.4Pharmaceutical form Transdermal patch
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPTransdermal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNicotine
    D.3.9.1CAS number 54-11-5
    D.3.9.2Current sponsor codeNRT
    D.3.9.4EV Substance CodeSUB14645MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number36
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name NiQuitin
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline Consumer Healthcare
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code Transdermal nicotine Patch (NRT)
    D.3.4Pharmaceutical form Transdermal patch
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPTransdermal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNicotine
    D.3.9.1CAS number 54-11-5
    D.3.9.2Current sponsor codeNRT
    D.3.9.4EV Substance CodeSUB14645MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number78
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name NiQuitin
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline Consumer Healthcare
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code Transdermal nicotine Patch (NRT)
    D.3.4Pharmaceutical form Transdermal patch
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPTransdermal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNicotine
    D.3.9.1CAS number 54-11-5
    D.3.9.2Current sponsor codeNRT
    D.3.9.4EV Substance CodeSUB14645MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number114
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 4
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTransdermal patch
    D.8.4Route of administration of the placeboTransdermal use
    D.8 Placebo: 5
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTransdermal patch
    D.8.4Route of administration of the placeboTransdermal use
    D.8 Placebo: 6
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTransdermal patch
    D.8.4Route of administration of the placeboTransdermal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Nicotine Addiction with the desire to quit smoking
    E.1.1.1Medical condition in easily understood language
    Nicotine Addiction with the desire to quit smoking
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Behavioral Disciplines and Activities [F04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10053325
    E.1.2Term Smoking cessation therapy
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study No
    E.3Principal 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.4Principal 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.5.1Primary 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.5.1.1Timepoint(s) of evaluation of this end point
    Primary Safety Endpoint: Week 0-24
    Primary Efficacy Endpoint: Weeks 9-12 and 12-24
    E.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA45
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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.8.7Trial 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.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 7544
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 456
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state400
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 2550
    F.4.2.2In the whole clinical trial 8000
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    not different from the expected normal treatment of that condition
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-04-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-04-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-01-13
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