Sequential Multiple Assignment Treatment for Bipolar Disorder (SMART)
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Bipolar I Disorder Bipolar II Disorder |
Drug: Lithium/Lithium Carbonate Drug: Divalproex Drug: Lamotrigine Drug: Quetiapine |
Phase 4 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Single Blind (Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | Sequential Multiple Assignment Randomized Treatment (SMART)for Bipolar Disorder |
- Bipolar Inventory of Symptoms Scale (BISS) [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]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
- Global Assessment of Functioning Scale (GAF) [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]Rating scale used to rate the social, occupational, and psychological functioning of adults.
| Estimated Enrollment: | 200 |
| Study Start Date: | June 2011 |
| Estimated Study Completion Date: | April 2016 |
| Estimated Primary Completion Date: | April 2016 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: Lithium
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/Lithium Carbonate
Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain LI of ≥0.5mEq/L.
Other Name: Lithium Carbonate
|
|
Active Comparator: Divalproex
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
DV will be dosed to attain DV levels of ≥45mg/L.
Other Names:
|
|
Active Comparator: Lithium plus Quetiapine
Those who develop protocol defined depression will then be randomized to a mood stabilizer (lithium) + quetiapine [QT].
|
Drug: Lithium/Lithium Carbonate
Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain LI of ≥0.5mEq/L.
Other Name: Lithium Carbonate
Drug: Quetiapine
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.
Other Name: Seroquel
|
|
Active Comparator: Lithium plus Lamotrigine
Those who develop protocol defined depression will then be randomized to a mood stabilizer (lithium) + lamotrigine (LM).
|
Drug: Lithium/Lithium Carbonate
Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain LI of ≥0.5mEq/L.
Other Name: Lithium Carbonate
Drug: Lamotrigine
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.
Other Name: Lamictal
|
|
Active Comparator: Divalproex plus Quetiapine
Those who develop protocol defined depression will then be randomized to a mood stabilizer (divalproex) + quetiapine [QT].
|
Drug: Divalproex
DV will be dosed to attain DV levels of ≥45mg/L.
Other Names:
Drug: Quetiapine
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.
Other Name: Seroquel
|
|
Active Comparator: Divalproex plus Lamotrigine
Those who develop protocol defined depression will then be randomized to a mood stabilizer (divalproex) + lamotrigine (LM).
|
Drug: Divalproex
DV will be dosed to attain DV levels of ≥45mg/L.
Other Names:
Drug: Lamotrigine
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.
Other Name: Lamictal
|
Detailed Description:
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 [DV]. Those who develop protocol defined depression will then be randomized to a MS alone, MS + quetiapine [QT] or MS + lamotrigine [LM]. 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.
Aim A.2 Compare the effectiveness of LI to DV as a primary component of treatment for BD over 26 weeks.
Aim A.3: Assess the effectiveness of MS + QT and MS + LM 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).
Eligibility| Ages Eligible for Study: | 18 Years to 65 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- DSM-IV TR diagnosis BD I or II as assessed by MINI 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 QT, LI, DV, or LM
- 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 or DV at a serum level of ≥ 45 mg/dL for at least 2 weeks.
Contacts and Locations| Contact: Martha L. Dahl, RN | 210-567-0996 | dahlml@uthscsa.edu |
| Contact: Melissa A Hernandez, MA | 210-567-0956 | hernandezma0@uthscsa.edu |
| United States, Ohio | |
| Case Western Reserve University | Recruiting |
| Cleveland, Ohio, United States, 44106 | |
| Contact: Carla Conroy 216-844-2871 carla.conroy@uhhospitals.org | |
| Principal Investigator: Joseph Calabrese, M.D. | |
| United States, Texas | |
| University of Texas Health Science Center | Recruiting |
| San Antonio, Texas, United States, 78229-3900 | |
| Contact: Martha L. Dahl, RN 210-567-0956 dahlml@uthscsa.edu | |
| Sub-Investigator: Mauricio Tohen, M.D. | |
| Sub-Investigator: Peter Thompson, M.D. | |
| Sub-Investigator: Marlon Quinones, M.D. | |
| Principal Investigator: | Charles L. Bowden, M.D. | University of Texas |
| Principal Investigator: | Joseph R Calabrese, M.D. | Case Western Reserve University |
| Principal Investigator: | Vivek Singh, M.D. | University of Texas |
More Information
No publications provided
| Responsible Party: | Charles L. Bowden, Professor/Clinical Psychiatry, The University of Texas Health Science Center at San Antonio |
| ClinicalTrials.gov Identifier: | NCT01588457 History of Changes |
| Other Study ID Numbers: | HSC20110361H, 1P30MH086045-01A2 |
| Study First Received: | February 29, 2012 |
| Last Updated: | November 19, 2012 |
| Health Authority: | United States: Institutional Review Board United States: Federal Government |
Additional relevant MeSH terms:
|
Bipolar Disorder Affective Disorders, Psychotic Mood Disorders Mental Disorders Lamotrigine Valproic Acid Lithium Carbonate Lithium Quetiapine Anticonvulsants Central Nervous System Agents Therapeutic Uses Pharmacologic Actions Enzyme Inhibitors |
Molecular Mechanisms of Pharmacological Action GABA Agents Neurotransmitter Agents Physiological Effects of Drugs Antimanic Agents Tranquilizing Agents Central Nervous System Depressants Psychotropic Drugs Antipsychotic Agents Antidepressive Agents Calcium Channel Blockers Membrane Transport Modulators Cardiovascular Agents |
ClinicalTrials.gov processed this record on May 19, 2013