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Mood Stabilizer (MS)+ Antidepressant vs MS + Placebo in Maintenance of Bipolar Disorder.

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ClinicalTrials.gov Identifier: NCT00958633
Recruitment Status : Recruiting
First Posted : August 13, 2009
Last Update Posted : October 24, 2018
Sponsor:
Collaborators:
Canadian Institutes of Health Research (CIHR)
GlaxoSmithKline
Lundbeck Canada Inc.
Information provided by (Responsible Party):
University of British Columbia

Tracking Information
First Submitted Date  ICMJE August 11, 2009
First Posted Date  ICMJE August 13, 2009
Last Update Posted Date October 24, 2018
Study Start Date  ICMJE November 2010
Estimated Primary Completion Date March 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 9, 2010)
Patients who respond to acute treatment with an antidepressant in combination with a mood stabilizer. [ Time Frame: 12 months ]
In patients with BD depression who respond to acute treatment with escitalopram or bupropion XL in combination with a mood stabilizing medication,does continuing antidepressant treatment for 12 months reduce the risk of relapse compared to discontinuing the antidepressant after 2 months? Open-Label Phase: Mean improvement in Montgomery-Asberg Depression Rating Scales (MADRS) from baseline to endpoint. Double-Blind Phase: The primary outcome for the double-blind phase is mean survival time in the study until the occurrence of any mood episode (manic, hypomanic, or depressive).
Original Primary Outcome Measures  ICMJE
 (submitted: August 12, 2009)
Does continuing antidepressant treatment for 12 months reduce the risk of relapse into any mood episode, including depression, mania, and hypomania, compared to discontinuing the antidepressant and substituting it with placebo after 2 months? [ Time Frame: 12 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 22, 2013)
Does continuing antidepressant treatment for 12 months increase the risk of developing a manic or hypomanic episode? [ Time Frame: 12 months ]
Open-Label Phase •Improvement in depression and anxiety scores; Rates of remission, treatment-emergent mania and hypomania; Overall psychiatric status improvement; Adverse events (AEs) and serious adverse events (SAEs). Double-Blind Phase • time to an episode, study discontinuation; intolerable side effects; percentage of patients who experience subsyndromal symptoms; Rates of adverse events and SAEs.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 12, 2009)
Does continuing antidepressant treatment for 12 months increase the risk of developing a manic or hypomanic episode? [ Time Frame: 12 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Mood Stabilizer (MS)+ Antidepressant vs MS + Placebo in Maintenance of Bipolar Disorder.
Official Title  ICMJE Mood Stabilizer Plus Antidepressant Versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder
Brief Summary

Patients with bipolar I disorder (BD) experience depression 3 times more frequently than mania, and antidepressants are prescribed as adjuncts to mood stabilizers in up to 70% of patients. However, no placebo-controlled trials have assessed the efficacy or safety of modern antidepressants in combination with mood stabilizers in the maintenance treatment of BD. The investigators propose a multicentre, randomized, double-blind clinical trial comparing mood stabilizer plus antidepressant (escitalopram or bupropion XL) to mood stabilizer plus placebo in the maintenance treatment of BD.

The investigators hypothesize that in clinically representative patients with bipolar disorder, who respond to acute treatment with a newer antidepressant medication in conjunction with a mood stabilizing medication, continuing the antidepressant for 12 months will reduce the risk of relapse into any mood episode, including depression, mania, and hypomania, compared to stopping the antidepressant after 8 weeks.

Detailed Description

Study Design:

The investigators propose a multicentre, randomized, double-blind, placebo-controlled trial in patients with BD who are currently experiencing a depressive episode. The trial will consist of two phases: an open-label acute treatment phase, and a double-blind maintenance treatment phase.

OPEN-LABEL ACUTE TREATMENT PHASE

Experimental Design Patients with BD depression who are receiving treatment with antimanic medication(s), defined as: 1) a mood stabilizer (lithium or divalproex ), 2) a second-generation antipsychotic (SGA) (risperidone, olanzapine, quetiapine, aripiprazole, or ziprasidone), or 3) combination anti-manic therapy (two mood stabilizers; or a mood stabilizer plus an SGA (the SGA asenapine will also be permitted if prescribed with a mood stabilizer); or a mood stabilizer or SGA plus lamotrigine), will have open-label escitalopram 10-30 mg/day or bupropion XL 150-450 mg/day added to their medication(s) for up to 16 weeks.Patients who complete at least 4 weeks of treatment and achieve remission from their index depression which is maintained for ≥ 2 weeks will be eligible to enter the double-blind study phase. The duration of treatment in the open-label phase will be 4-16 weeks, depending on the time required to achieve remission.

DOUBLE-BLIND MAINTENANCE TREATMENT PHASE

Patients who are in remission from their index depression for ≥ 2 weeks and ≤ 8 weeks are eligible to take part in the double-blind maintenance phase. There are two routes to enter the double-blind phase:

  • following completion of the open-label phase, or
  • following a period of clinical treatment, not exceeding 16 weeks, with the same medications used in the open-label phase. Patients who respond to clinical treatment with carbamazepine plus an antidepressant may also enter the double-blind phase.

Experimental Design

During the double-blind phase, all patients will continue treatment with their anti-manic medication(s) and will be randomized to one of two treatment arms for up to 52 weeks:

  • Patients randomized to the "8 week arm" will discontinue antidepressant treatment after 8 weeks, as recommended in current clinical practice guidelines..
  • Patients randomized to the "52 week arm" will continue treatment with their antidepressant medication for 52 weeks, or until withdrawal from the study.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Bipolar I Disorder
Intervention  ICMJE
  • Drug: Escitalopram

    Escitalopram will be prescribed in the dose range 10-30 mg daily.

    • In patients randomized to the "8-week group", escitalopram will be tapered, discontinued, and replaced with placebo over a period of 2 weeks, beginning at the week 6 study visit.
    • The dose of escitalopram (or matching placebo) may be decreased in 10 mg increments only in the case of intolerable side effects. The dose must remain within the protocol-defined range of 10-30 mg daily at all time points.
    Other Name: Lexapro/Cipralex
  • Drug: Wellbutrin XL

    Bupropion XL will be prescribed in the dosage range 150-450 mg daily.

    • In patients randomized to the "8-week group", bupropion XL will be tapered, discontinued, and replaced with placebo over a period of 2 weeks, beginning at the week 6 study visit.
    • The dose of bupropion XL (or matching placebo) may be decreased in 150 mg increments only in the case of intolerable side effects. The dose must remain within the protocol-defined range of 150-450 mg daily at all time points.
    Other Name: Wellbutrin
Study Arms  ICMJE
  • Active Comparator: 8 week arm

    During the double-blind phase, all patients will continue treatment with their anti-manic medication(s)and will be randomized to one of two treatment arms for up to 52 weeks:

    Group 1 patients randomized to the "8 week arm" will discontinue antidepressant treatment after 8 weeks, as recommended in current clinical practice guidelines. The antidepressant will be tapered in a double-blind manner beginning at 6 weeks, and will be substituted with placebo by 8 weeks.

    Escitalopram 10 - 30 mg Wellbutrin XL 150 - 450 mg

    Intervention: Drug: Escitalopram
  • Active Comparator: 52 week arm

    During the double-blind phase, all patients will continue treatment with their anti-manic medication(s) and will be randomized to one of two treatment arms for up to 52 weeks:

    Group 2 patients randomized to the "52 week arm" will continue treatment with their antidepressant medication for 52 weeks, or until withdrawal from the study.

    Escitalopram 10 - 30 mg Wellbutrin XL 150 - 450 mg

    Intervention: Drug: Wellbutrin XL
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 12, 2009)
216
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2020
Estimated Primary Completion Date March 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

OPEN-LABEL ACUTE TREATMENT PHASE

  1. Diagnosed with BD, current episode depressed, with a MADRS score ≥ 20 at both the screening and baseline assessments
  2. The duration of the current depressive episode is ≥ 2 weeks but ≤ 52 weeks
  3. Taking or initiating treatment with an anti-manic medication at a therapeutic dose. Anti-manic medications and therapeutic doses are: lithium, serum level 0.6-1.4 mEq/L; divalproex, serum level 350-700 mM; risperidone 1-6 mg/day; olanzapine 5-30 mg/day; quetiapine IR or XR 300-900 mg/day; aripiprazole 10-30 mg/day; and ziprasidone 80-160 mg/day. Combinations of these medications as outlined above, or the combination of any of them with lamotrigine 100-400 mg daily, or the combination of a mood stabilizer plus asenapine 5-20 mg/day, are also permitted.
  4. If taking any other psychoactive medication (other than lorazepam ≤ 4 mg/day or equivalent), is agreeable to tapering and discontinuing it over a period of ≤ 4 weeks
  5. If female and of childbearing potential, is using an adequate method of contraception.
  6. Aged 18-70 years, inclusive
  7. Fluent in English and capable of providing informed consent

DOUBLE-BLIND MAINTENANCE TREATMENT PHASE

• Patients meeting all of the following criteria will be eligible to be included in the double-blind study phase:

  1. Taking escitalopram 10-30 mg/day or bupropion XL 150-450 mg/day, in addition to their anti-manic medication.
  2. Has adequately tolerated the combination of antidepressant plus mood stabilizer, and is currently in remission for ≥ 2 weeks and ≤ 8 weeks
  3. If female and of childbearing potential, is using an adequate method of contraception

Exclusion Criteria:

OPEN-LABEL ACUTE TREATMENT PHASE

  1. Has a history of rapid cycling, defined as ≥ 4 mood episodes in the preceding 12 months
  2. Has current manic, hypomanic, or subsyndromal hypomanic symptoms, defined as a Young Mania Rating Scale (YMRS) score ≥ 8 at the screening or baseline visits
  3. Has previously been refractory to treatment with both escitalopram and bupropion XL, or has been unable to tolerate both medications due to intolerable side effects or an allergic reaction
  4. Is taking monoamine oxidase inhibitors, such as phenelzine or tranylcypromine
  5. Escitalopram is contraindicated in patients taking pimozide or ziprasidone. Patients on pimozide or ziprasidone can participate in the study and will be prescribed bupropion XL
  6. Bupropion XL is contraindicated in patients taking other preparations containing bupropion, in patients with active eating disorders, including anorexia nervosa and bulimia nervosa; and in patients with seizure disorders. Patients with any of these can still participate in the study and will be prescribed Escitalopram
  7. Has active substance dependence, other than caffeine or nicotine dependence, in the preceding 3 months. Otherwise, patients with comorbid substance abuse or other comorbid psychiatric illnesses will be eligible to participate in the study
  8. Is at high risk for suicide, as defined by a score of ≥ 4 on the suicide item of the MADRS, or in the opinion of the investigator
  9. Has an unstable medical illness, as defined by a change in medication or other treatment in the past 4 weeks, or in the opinion of the investigator
  10. Has significant abnormalities on an electrocardiogram
  11. Is pregnant or lactating

DOUBLE-BLIND MAINTENANCE TREATMENT PHASE

  1. Has a history of rapid cycling, defined as ≥ 4 mood episodes in the preceding 12 months
  2. Has current manic, hypomanic, or subsyndromal hypomanic symptoms, defined as a YMRS score ≥ 8 at the screening or baseline visits
  3. Has active substance dependence, other than caffeine or nicotine dependence, in the preceding 3 months. Otherwise, patients with comorbid substance abuse or other comorbid psychiatric illnesses will be eligible to participate in the study
  4. Is at high risk for suicide, as defined by a score of ≥ 4 on the suicide item of the MADRS, or in the opinion of the investigator
  5. Has an unstable medical illness, as defined by a change in medication or other treatment in the past 4 weeks, or in the opinion of the investigator.
  6. Has significant abnormalities on an electrocardiogram
  7. Is pregnant or lactating
  8. Has experienced an episode of mania, hypomania, or a mixed episode during antidepressant treatment of the acute depression, defined as a YMRS score of ≥ 16 at any open-label study visit, or in the opinion of the study psychiatrist
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nazlin Walji 604-822-7294 nazlin.walji@ubc.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00958633
Other Study ID Numbers  ICMJE H09-01017
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of British Columbia
Study Sponsor  ICMJE University of British Columbia
Collaborators  ICMJE
  • Canadian Institutes of Health Research (CIHR)
  • GlaxoSmithKline
  • Lundbeck Canada Inc.
Investigators  ICMJE
Principal Investigator: Lakshmi Yatham, Dr. University of British Columbia
Study Director: B. Frey, Dr. St. Joseph's Healthcare, Hamilton, Ont.
Study Director: S. Beaulieu, Dr. Douglas Mental Health University Institute, Montreal, Quebec
Study Director: A. Daigneault, Dr. Douglas Mental Health University Institute, Montreal, Quebec
Study Director: A. Ravindran, Dr. Centre for Addictions and Mental Health, Toronto, Ont.
Study Director: A. Schaffer, Dr. Sunnybrook Health Sciences Centre, Toronto, Ont.
Study Director: R. Milev, Dr. Queen's University, Kingston, Ontario
Study Director: P. Cervantes, Dr. McGill University Health Centre, Montreal, Que
Study Director: T. H. Ha, Dr. Seoul National University Bundang Hospital
Study Director: Y. M. Ahn, Dr. Seoul National University Hospital
Study Director: Y. H. Joo, Dr. Asan Medical Centre, Korea
Study Director: S. Won, Dr. Kyungpook National University Hospital, Korea
Study Director: J. Y. Reddy, Dr. National Institute of Mental Health and Neuro sciences, Bangalore, India
Study Director: P.S. Sharma, Dr. Kasturba Medical College, Manipal, India
Study Director: M.S. Reddy, Dr. Asha Hospital, Hyderabad, India
Study Director: R. B. Galgali, Dr. St. John's hospital, Bangalore, India
PRS Account University of British Columbia
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP