Clinical trial NCT01588457: Sequential Multiple Assignment Treatment for Bipolar Disorder
Official title: Sequential Multiple Assignment Randomized Treatment (SMART) for Bipolar Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Bipolar I Disorder
Bipolar II Disorder
Lead sponsor: The University of Texas Health Science Center at San Antonio
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2012-05-01
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 \[Div\]. 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Bipolar Inventory of Symptoms Scale (BISS)
timeFrame: Change from Baseline to 26 weeks
Secondary outcomes:
measure: Global Assessment of Functioning
timeFrame: Change from Baseline to 26 weeks
measure: Baseline Randomization Percentage of Bipolar Types
timeFrame: Baseline
measure: Demographic in Randomization 1 Group
timeFrame: Baseline
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: San Antonio
country: United States
facility: University of Texas Health Science Center
state: Texas
Study officials:
affiliation: University of Texas
name: Charles L. Bowden, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Western Reserve University
name: Joseph R Calabrese, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hashimoto Y, Kotake K, Watanabe N, Fujiwara T, Sakamoto S. Lamotrigine in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev. 2021 Sep 15;9(9):CD013575. doi: 10.1002/14651858.CD013575.pub2.