Sequential Multiple Assignment Treatment for Bipolar Disorder

NCT ID: NCT01588457

Last Updated: 2020-08-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 112 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-06-30
• Study Completion Date: 2016-12-31

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).

Conditions

Bipolar I Disorder; Bipolar II Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Lithium

Intervention Type: DRUG

Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain Li of ≥0.5mEq/L (milliequivalents per liter).

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.

Group Type: ACTIVE_COMPARATOR

Divalproex

Intervention Type: DRUG

DV will be dosed to attain DV levels of ≥45mg/L.

Lithium plus Quetiapine

Those who develop protocol defined depression will then be randomized to a mood stabilizer (lithium) + quetiapine \[QT\].

Group Type: ACTIVE_COMPARATOR

Lithium

Intervention Type: DRUG

Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain Li of ≥0.5mEq/L (milliequivalents per liter).

Quetiapine

Intervention Type: DRUG

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.

Lithium plus Lamotrigine

Those who develop protocol defined depression will then be randomized to a mood stabilizer (lithium) + lamotrigine (LM).

Group Type: ACTIVE_COMPARATOR

Lithium

Intervention Type: DRUG

Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain Li of ≥0.5mEq/L (milliequivalents per liter).

Lamotrigine

Intervention Type: DRUG

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.

Divalproex plus Quetiapine

Those who develop protocol defined depression will then be randomized to a mood stabilizer (divalproex) + quetiapine \[QT\].

Group Type: ACTIVE_COMPARATOR

Divalproex

Intervention Type: DRUG

DV will be dosed to attain DV levels of ≥45mg/L.

Quetiapine

Intervention Type: DRUG

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.

Divalproex plus Lamotrigine

Those who develop protocol defined depression will then be randomized to a mood stabilizer (divalproex) + lamotrigine (LM).

Group Type: ACTIVE_COMPARATOR

Divalproex

Intervention Type: DRUG

DV will be dosed to attain DV levels of ≥45mg/L.

Lamotrigine

Intervention Type: DRUG

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.

Interventions

Lithium

Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain Li of ≥0.5mEq/L (milliequivalents per liter).

Intervention Type: DRUG

Divalproex

DV will be dosed to attain DV levels of ≥45mg/L.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Lithium Carbonate; Depakote; Depakote ER; Lamictal; Seroquel

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

The University of Texas Health Science Center at San Antonio

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Charles L. Bowden, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Texas

Joseph R Calabrese, M.D.

Role: PRINCIPAL_INVESTIGATOR

Case Western Reserve University

Locations

Case Western Reserve University

Cleveland, Ohio, United States

University of Texas Health Science Center

San Antonio, Texas, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 34523118 (View on PubMed)

Other Identifiers

1P30MH086045-01A2

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HSC20110361H

Identifier Type: -

Identifier Source: org_study_id