Sequential Multiple Assignment Treatment for Bipolar Disorder

Study Overview
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Brief Summary
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The purpose of this study is to compare which of the two mood stabilizers (drugs that help to steady/stabilize mood in patients with bipolar disorder (BD)), lithium and divalproex, is more effective in patients with bipolar disorder over 26 weeks. The study will also compare if lithium or divalproex used alone versus lithium or divalproex used with quetiapine versus lithium or divalproex used with lamotrigine is more effective when symptoms of depression develop.

Detailed Description
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This open methods advancement study will randomize BD patients with clinically significant symptoms to treatment with one of two mood stabilizers (MS), lithium [Li] or divalproex [Div]. Those who develop protocol defined depression will then be randomized to a MS alone, MS + quetiapine [QTP] or MS + lamotrigine [LTG]. A SMART strategy employs a rule for adding new treatments based on each patient's current illness state and response during the trial, mimicking the adaptive nature of treatment selection which occurs in clinical settings, but in a controlled way which allows application of causal inference. By using early indices of response to dynamically alter treatment decisions to improve outcome, SMART eliminates unmeasured confounders associated with treatment decisions that are not randomized, as occurs in data mining exercises and in other non-randomized decisions in studies which randomize one variable at baseline. This sequential adaptive design represents a methodological innovation in bipolar trial history which will have particular implications for effectiveness studies. Specific Aim A.1: Assess the feasibility of a SMART design in the conduct of an effectiveness study over 26 weeks in patients with BD (bipolar disorder). Aim A.2 Compare the effectiveness of Li to Div as a primary component of treatment for BD over 26 weeks. Aim A.3: Assess the effectiveness of MS + QTP and MS + LTG versus MS in subjects who develop depression. A4. Exploratory Aims: 1.Determine the effects of ethnicity, language facility, education and stress as moderators of treatment outcomes; 2. Explore the use of novel statistical methodologies to more informatively characterize illness trajectories in response to the interventions. In the aggregate these aims also will clarify whether the SMART confirms results provided by traditional, single point randomized controlled trials (RCTs).

Official Title
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Sequential Multiple Assignment Randomized Treatment (SMART) for Bipolar Disorder

Conditions
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Bipolar I Disorder, Bipolar II Disorder

Intervention / Treatment
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* Drug: Lithium
* Drug: Divalproex
* Drug: Lamotrigine
* Drug: Quetiapine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: DSM-IV TR (Diagnostic and Statistical Manual Edition IV Text Revision) diagnosis BD I or II as assessed by MINI PLUS (Mini International Neuropsychiatric Interview PLUS) Male or female ≥ 18 years old Currently symptomatic with a CGI-BP-S ≥3 for mania/hypomania &/or depression for ≥ 2 weeks One of the following indicators of recent active illness: a depressive or manic or hypomanic or mixed episode in the past 12 months If female of child bearing age must use effective birth control. Exclusion Criteria: Unwilling or unable to comply with study requirements Renal impairment (serum creatinine > 1.5 mg/dL) If maintained on thyroid medication must be euthyroid for at least 1 month before Visit 1 Patients who have had intolerable side effects to QTP, Li, Div, or LTG Patients whose clinical status requires inpatient care Drug/alcohol dependence within the past 30 days Pregnancy as determined by serum pregnancy test or breastfeeding History of poor response to Li at a serum Li of ≥ 0.5 mEq/L (milliequivalents per Liter) or Div at a serum level of ≥ 45 mg/dL for at least 2 weeks.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lithium<br>This open methods advancement study will randomize BD patients with clinically significant symptoms to treatment with one of two mood stabilizers, lithium [Li] at baseline. Lithium is one of these two mood stabilizers. The person may or may not stay solely on lithium throughout the study. | Drug: Lithium<br>* Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain Li of ≥0.5mEq/L (milliequivalents per liter).<br>* Other names: Lithium Carbonate;|
| Active Comparator: Divalproex<br>This open methods advancement study will randomize BD patients with clinically significant symptoms to treatment with one of two mood stabilizers, divalproex (DV)at baseline. Divalproex is one of these two mood stabilizers. The person may or may not stay solely on divalproex throughout the study. | Drug: Divalproex<br>* DV will be dosed to attain DV levels of ≥45mg/L.<br>* Other names: Depakote ER;|
| Active Comparator: Lithium plus Quetiapine<br>Those who develop protocol defined depression will then be randomized to a mood stabilizer (lithium) + quetiapine [QT]. | Drug: Lithium<br>* Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain Li of ≥0.5mEq/L (milliequivalents per liter).<br>* Other names: Lithium Carbonate;Drug: Quetiapine<br>* QT will be started at 50 mg/day and titrated up to 300 mg as tolerated. QT will be discontinued if not tolerated at 100mg/day and the patient will be treated according to guidelines.<br>* Other names: Seroquel;|
| Active Comparator: Lithium plus Lamotrigine<br>Those who develop protocol defined depression will then be randomized to a mood stabilizer (lithium) + lamotrigine (LM). | Drug: Lithium<br>* Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain Li of ≥0.5mEq/L (milliequivalents per liter).<br>* Other names: Lithium Carbonate;Drug: Lamotrigine<br>* LM will be incrementally dosed up to 400 mg/day, or, in combination with DV, 200 mg/day. Dosage may be reduced for adverse effects to one half of the target dose.<br>* Other names: Lamictal;|
| Active Comparator: Divalproex plus Quetiapine<br>Those who develop protocol defined depression will then be randomized to a mood stabilizer (divalproex) + quetiapine [QT]. | Drug: Divalproex<br>* DV will be dosed to attain DV levels of ≥45mg/L.<br>* Other names: Depakote ER;Drug: Quetiapine<br>* QT will be started at 50 mg/day and titrated up to 300 mg as tolerated. QT will be discontinued if not tolerated at 100mg/day and the patient will be treated according to guidelines.<br>* Other names: Seroquel;|
| Active Comparator: Divalproex plus Lamotrigine<br>Those who develop protocol defined depression will then be randomized to a mood stabilizer (divalproex) + lamotrigine (LM). | Drug: Divalproex<br>* DV will be dosed to attain DV levels of ≥45mg/L.<br>* Other names: Depakote ER;Drug: Lamotrigine<br>* LM will be incrementally dosed up to 400 mg/day, or, in combination with DV, 200 mg/day. Dosage may be reduced for adverse effects to one half of the target dose.<br>* Other names: Lamictal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bipolar Inventory of Symptoms Scale (BISS) | The BISS uses a structured interview to assess the full spectrum of symptoms associated with all primary clinical states in bipolar disorder, yielding a total severity, a depression, a mania, as well as dimensional scale scores. There are 42 items; each item is rated on a 0-4 scale. The BISS is a clinician-rated instrument. The Scale is rated as follows: 0 Not at all Slight Mild Moderate Severe Each of the 42 items is rated separately, with a score, based on the most recent 7 day period. The mean score is calculated from the total score, giving an overall score out of 4, where 0 is slight and 4 is the most severe symptoms. A negative score indicated an improvement from baseline to 26 weeks. | Change from Baseline to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global Assessment of Functioning | The Clinical Global Impression-Severity Scale (CGI-S) is used to assess global illness severity The CGI-S score change is measured from baseline to 26 weeks and is rated on a 7-point scale. The scale is read as follows: very much improved since the initiation of treatment much improved minimally improved no change from baseline (the initiation of treatment) minimally worse much worse very much worse since the initiation of treatment The score is calculated as a mean of all items, where 1 indicates improvement from inititation of visit, and 7 indicates the condition to be much worse since the inititation of treatment. A negative score indicates a change from worse to better. | Change from Baseline to 26 weeks | 
| Baseline Randomization Percentage of Bipolar Types | Percentages of Type I and Type II Bipolar Disorder included in Randomization groups | Baseline | 
| Demographic in Randomization 1 Group | Baseline demographic percentages of subject randomized to either Divalproex or Lithium at the first randomization | Baseline |