Sequential Multiple Assignment Randomized Trial for Bipolar Depression
- Conditions
- DepressionBipolar I Disorder
- Interventions
- Registration Number
- NCT06433635
- Lead Sponsor
- Massachusetts General Hospital
- Brief Summary
This is a sequential multiple assignment randomized trial for adults (ages \> 18) with a bipolar disorder type 1 diagnosis currently experiencing a depressive episode. It is a randomized pragmatic trial that will compare four commonly prescribed treatments for bipolar depression, which includes three FDA-approved medications (Cariprazine, Quetiapine and Lurasidone) and one antipsychotic/antidepressant combination (Aripiprazole/Escitalopram).
- Detailed Description
This is a comparative effectiveness study to address the critical questions of how best to treat people with bipolar disorder who have a major depressive episode: how to get them well, provide second-line treatment when they don't initially get well, and keep them well after they get well. This is a multisite Sequential Multiple Assignment Randomized Trial (SMART) comparative effectiveness design. Investigators will recruit 2726 participants who have BD with a current major depressive episode. In Stage 1, investigators will compare four treatment arms, including three FDA approved monotherapies and the most widely used, but understudied, treatment for BD major depressive episode (i.e., a non-FDA approved combination of an antipsychotic and antidepressant). In Stage 2, participants who do not remit will be re-randomized to treatments not used in Stage 1. Investigators will follow all participants for a total of 52 weeks. This study will be conducted in two phases, a feasibility phase and a full study phase. In the feasibility phase, investigators will recruit at 8 of the 19 study sites based on readiness and interest, to ensure the efficacy of the study design before launching the full study phase.
Feasibility Aim 1: To ensure that 8 of the 19 selected sites can recruit, randomize, and retain participants. During the feasibility phase, the selected sites will recruit 133 participants, administer baseline assessments, randomize the participants (at baseline and again at 6-weeks for non-remitters), and conduct follow-up assessments at the end of Stage 1 (6-weeks) and the end of Stage 2 (12-weeks) and end of study (52 weeks or end of feasibility phase, whichever is sooner) and all other scheduled visits.
Feasibility Aim 2: To refine and finalize all study standard operating procedures for the full-scale study. After Aim 1 is complete, any changes in standard operating procedures will be made as needed to be implemented in the full study phase.
Full Scale Study Full-Scale Study Aim 1: To compare the effectiveness, tolerability, and safety of the four treatments for BD major depressive episodes.
Hypothesis 1a: There will be significant differences across the Stage 1 treatments in the proportion of remitters at week 6 (primary endpoint, effectiveness) and in the average adverse event burden and suicidal ideation/behavior at week 6 (secondary endpoints, tolerability and safety).
Hypothesis 1b: Among non-remitters of a given Stage 1 treatment (i.e., participants who do not remit by week 6), there will be significant differences across the three remaining Stage 2 treatments in the proportion of remitters at week 12 (primary endpoint, effectiveness) and the average side effect burden and suicidal ideation/behavior at week 12 (secondary endpoints, tolerability and safety).
Full-Scale Study Aim 2: To characterize the effectiveness, tolerability, and safety of the 12 adaptive interventions for BD major depressive episodes embedded within the SMART design.
Hypothesis 2: On average, there will be significant differences across the 12 embedded adaptive interventions in the proportion of remitters at week 12 (primary endpoint, effectiveness) and in the average side effect burden and suicidal ideation/behavior at week 12 (secondary endpoints, tolerability and safety).
Full-Scale Study Aim 3: To determine individual-level characteristics that predict heterogeneity of treatment effect (HTE) across the 12 adaptive interventions for BD major depressive episodes embedded within the SMART design.
Hypothesis 3a: Individual-level characteristics and symptoms assessed at baseline as well as symptom changes and side effect profiles at week 6 will predict HTE at weeks 12 and 52. Hypothesis 3b: Investigators hypothesize that an optimal personalized adaptive intervention will perform significantly better than the best aggregate embedded adaptive intervention identified in Aim 2 in terms of the proportion of remitters at week 12 (primary endpoint, effectiveness) and the side effect burden and suicidal ideation/behavior at week 12 (secondary endpoints, tolerability and safety).
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 2726
- Aged between 18 years to 75 years
- Meets criteria for DSM-V Bipolar I disorder with a history of manic episodes and current major depressive episode lasting at least 6 weeks
- Can be managed as an outpatient and participate in the study
- Willing to be randomized; able to perform study assessments
- Women of childbearing potential must agree to use adequate contraception (e.g. oral contraceptives, intrauterine device, barrier methods, or total abstinence; Depo Provera is acceptable if it is started 3 months prior to enrollment), and inform staff of their plans to conceive.
- Meets current criteria for a manic episode, rapid cycling within the past year (history of 4 or more mood episodes per year)
- History of schizophrenia or other nonaffective psychosis
- Current substance use disorder that will interfere with participation in the study
- Currently taking the study medications or a history of serious adverse events to any of the study medications, to the extent that as determined by site PI, another trial would not be clinically indicated
- A history of non-response for depressive episodes, to any of the study medications, when given at adequate doses for at least 6 weeks
- Current acute suicidal risk that requires inpatient treatment
- Pregnancy or breastfeeding
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Aripiprazole /Escitalopram combination Aripiprazole/Escitalopram combination - Lurasidone Lurasidone - Quetiapine Quetiapine - Cariprazine Cariprazine -
- Primary Outcome Measures
Name Time Method The Remission from Depression Questionnaire Investigators will administer this measure every 2 weeks for the first 12 weeks (weeks:0,2,4,6,8,10,12), and then at each study visit during the follow up phase until they are discharged from the study (weeks:20,28,36,44,52 ). RDQ is a 41 items self report questionnaire used to assess the seven domains found in extensive previous research to be important to patients: depressive symptoms, anxiety, coping ability, positive mental health, functioning, life satisfaction and a general sense of well-being. Using a score of 27 as the cutoff, the RDQ scale has a sensitivity of 83.7% and specificity of 77.9% in predicting self-reported remission status. The RDQ has excellent internal consistency reliability (Cronbach's alpha of 0.97 for the total scale and above 0.80 for each of the 7 subscales with test-retest reliability of the total scale = 0.85 and \> 0.60 for each subscale). The primary outcome will be remission as defined by a RDQ score \< 27. This test will be administered in all assessment visits.
The RDQ scale ranges from 0-27 per domain, with higher scores indicating greater remission rates.
- Secondary Outcome Measures
Name Time Method Frequency and Intensity of Side Effects Ratings - Intensity Investigators will administer this measure every 2 weeks for the first 12 weeks (weeks:0,2,4,6,8,10,12), and then at each study visit during the follow up phase until they are discharged from the study (weeks:20,28,36,44,52 ). This subscale of the FIBSER scale is a reliable self-report measure of the intensity of side effects from medications in a population receiving treatment for depression. This scale measures the participants side effects intensity from the previous week and has them rate each on a scale from 0-6. The results will help the clinician determine the appropriate level of response.
The range is from 0-6, higher scores reflect an greater intensity in medication side effects.Frequency and Intensity of Side Effects Ratings - Frequency Investigators will administer this measure every 2 weeks for the first 12 weeks (weeks:0,2,4,6,8,10,12), and then at each study visit during the follow up phase until they are discharged from the study (weeks:20,28,36,44,52 ). This subscale of the FIBSER scale is a reliable and valid self-report measure on the frequency of medication side effects in a population receiving treatment for depression. This scale measures the participants side effects frequency from the previous week and has them rate each on a scale from 0-6. The results will help the clinician determine the appropriate level of response.
The range is from 0-6, higher scores reflect an greater frequency in medication side effects.Safety: Concise Health Risk Tracking Scale Investigators will administer this measure every 2 weeks for the first 12 weeks (weeks:0,2,4,6,8,10,12), and then at each study visit during the follow up phase until they are discharged from the study (weeks:20,28,36,44,52 ). CHRT is a 14 item self-report measure of suicidal ideation and behavior in individuals with mood disorders. The CHRT has excellent psychometric properties, with an internal consistency reliability (Cronbach's alpha) of 0.78 and a consistent factor structure with 3 independent factors (current suicidal thoughts and plans, perceived lack of social support, and hopelessness).
The range is from 14-70, higher scores reflect an increase in suicidality behaviors.Frequency and Intensity of Side Effects Ratings - Burden Investigators will administer this measure every 2 weeks for the first 12 weeks (weeks:0,2,4,6,8,10,12), and then at each study visit during the follow up phase until they are discharged from the study (weeks:20,28,36,44,52 ). This subscale of the FIBSER scale is a reliable self-report measure of the side effects burden of medications in a population receiving treatment for depression. This scale measures the participants side effects burden from the previous week and has them rate each on a scale from 0-6. The results will help the clinician determine the appropriate level of response.
The range is from 0-6, higher scores reflect an greater burden in medication side effects.
Trial Locations
- Locations (19)
McLean Hospital
🇺🇸Belmont, Massachusetts, United States
John Hopkins
🇺🇸Baltimore, Maryland, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
University of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
University of Toronto
🇨🇦Toronto, Ontario, Canada
New York University Grossman School of Medicine NYU
🇺🇸New York, New York, United States
Case Western Reserve University
🇺🇸Cleveland, Ohio, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
UT Health Houston Texas
🇺🇸Houston, Texas, United States
University of New Mexico Health Sciences Center Albuquerque
🇺🇸Albuquerque, New Mexico, United States
University of Texas at Austin
🇺🇸Austin, Texas, United States
University of Texas at Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
University of Alabama Birmingham
🇺🇸Birmingham, Alabama, United States
Montefiore Medical Center and Albert Einstein College of Medicine
🇺🇸New York, New York, United States
Sheppard Pratt Health System
🇺🇸Baltimore, Maryland, United States
University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
University of British Columbia
🇨🇦Vancouver, British Columbia, Canada