Sequential Multiple Assignment Treatment for Bipolar Disorder - Full Text View

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: Open Label Primary Purpose: Treatment
Official Title:	Sequential Multiple Assignment Randomized Treatment (SMART) for Bipolar Disorder

Resource links provided by NLM:

MedlinePlus related topics: Bipolar Disorder

Drug Information available for: Valproic acid Lithium carbonate Lithium citrate Lamotrigine Quetiapine Quetiapine fumarate

U.S. FDA Resources

Further study details as provided by The University of Texas Health Science Center at San Antonio:

Primary Outcome Measures:

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

Secondary Outcome Measures:

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:	December 2016
Estimated Primary Completion Date:	December 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: 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

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 (Adult)
Genders Eligible for Study:	Both
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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01588457

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
Study First Received:	February 29, 2012
Last Updated:	June 21, 2016
Health Authority:	United States: Institutional Review Board United States: Federal Government

Additional relevant MeSH terms:


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

ClinicalTrials.gov processed this record on September 29, 2016

Sequential Multiple Assignment Treatment for Bipolar Disorder (SMART)