Sequential Multiple Assignment Treatment for Bipolar Disorder (SMART)

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborator: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): Charles L. Bowden, The University of Texas Health Science Center at San Antonio

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Bipolar I Disorder; Bipolar II Disorder	Drug: Lithium/Lithium Carbonate; Drug: Divalproex; Drug: Lamotrigine; Drug: Quetiapine	Phase 4

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 110 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Sequential Multiple Assignment Randomized Treatment (SMART) for Bipolar Disorder
• Study Start Date: June 2011
• Actual Primary Completion Date: December 2016
• Actual Study Completion Date: December 2016

Arms and Interventions

Arm	Intervention/treatment
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: Depakote; Depakote ER
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: Depakote; Depakote ER; 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: Depakote; Depakote ER; 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

Outcome Measures

Primary Outcome Measures :

1. Bipolar Inventory of Symptoms Scale (BISS) [ Time Frame: Baseline and 26 weeks ]
   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

Secondary Outcome Measures :

1. Global Assessment of Functioning Scale (GAF) [ Time Frame: Baseline and 26 weeks ]
   Rating scale used to rate the social, occupational, and psychological functioning of adults.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Locations

United States, Ohio

Case Western Reserve University

Cleveland, Ohio, United States, 44106

United States, Texas

University of Texas Health Science Center

San Antonio, Texas, United States, 78229-3900

Sponsors and Collaborators

The University of Texas Health Science Center at San Antonio

National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Charles L. Bowden, M.D.; University of Texas
• Principal Investigator: Joseph R Calabrese, M.D.; Case Western Reserve University

More Information

• 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 ( U.S. NIH Grant/Contract )
• First Posted: May 1, 2012
• Last Update Posted: March 23, 2017
• Last Verified: March 2017

Additional relevant MeSH terms:

Disease; Bipolar Disorder; Pathologic Processes; Bipolar and Related Disorders; Mental Disorders; Lamotrigine; Valproic Acid; Quetiapine Fumarate; Lithium Carbonate; Anticonvulsants; Antidepressive Agents; Psychotropic Drugs; Antipsychotic Agents; Tranquilizing Agents; Central Nervous System Depressants; Physiological Effects of Drugs; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antimanic Agents; Calcium Channel Blockers; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Sodium Channel Blockers; GABA Agents; Neurotransmitter Agents