SMART: Sequential Multiple Assignment Treatment for Bipolar Disorder
Study Details
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 |
|---|---|---|
| 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 [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).
Study Design
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
Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain Li of ≥0.5mEq/L (milliequivalents per liter).
Other Names:
|
| 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:
|
| Active Comparator: Lithium plus Quetiapine Those who develop protocol defined depression will then be randomized to a mood stabilizer (lithium) + quetiapine [QT]. |
Drug: 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).
Other Names:
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 Names:
|
| Active Comparator: Lithium plus Lamotrigine Those who develop protocol defined depression will then be randomized to a mood stabilizer (lithium) + lamotrigine (LM). |
Drug: 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).
Other Names:
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 Names:
|
| 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:
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 Names:
|
| 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:
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 Names:
|
Outcome Measures
Primary Outcome Measures
- Bipolar Inventory of Symptoms Scale (BISS) [Change from Baseline to 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. There are 42 items; each item is rated on a 0-4 scale. The BISS is a clinician-rated instrument. The Scale is rated as follows: 0 Not at all Slight Mild Moderate Severe Each of the 42 items is rated separately, with a score, based on the most recent 7 day period. The mean score is calculated from the total score, giving an overall score out of 4, where 0 is slight and 4 is the most severe symptoms. A negative score indicated an improvement from baseline to 26 weeks.
Secondary Outcome Measures
- Global Assessment of Functioning [Change from Baseline to 26 weeks]
The Clinical Global Impression-Severity Scale (CGI-S) is used to assess global illness severity The CGI-S score change is measured from baseline to 26 weeks and is rated on a 7-point scale. The scale is read as follows: very much improved since the initiation of treatment much improved minimally improved no change from baseline (the initiation of treatment) minimally worse much worse very much worse since the initiation of treatment The score is calculated as a mean of all items, where 1 indicates improvement from inititation of visit, and 7 indicates the condition to be much worse since the inititation of treatment. A negative score indicates a change from worse to better.
- Baseline Randomization Percentage of Bipolar Types [Baseline]
Percentages of Type I and Type II Bipolar Disorder included in Randomization groups
- Demographic in Randomization 1 Group [Baseline]
Baseline demographic percentages of subject randomized to either Divalproex or Lithium at the first randomization
Eligibility Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Case Western Reserve University | Cleveland | Ohio | United States | 44106 |
| 2 | 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
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- HSC20110361H
- 1P30MH086045-01A2
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | After a washout period of up to 1 week, subjects will be openly randomized to treatment with Lithium (Li) or Divalproex (Div) for 2 weeks. Subjects who become intolerant to lithium or divalproex at any point will be crossed over to the other mood stabilizer and continued in the study, or terminate early. |
| Arm/Group Title | Randomization to Lithium | Randomization to Divalproex | Monotherapy Li or Div Plus Quetiapine | Monotherapy Li or Div Plus Lamotrigine |
|---|---|---|---|---|
| Arm/Group Description | Subjects enrolled will be randomized to one of two mood stabilizers, Lithium (Li) or Divalproex (Div) in Randomization 1. If subjects show no symptoms, they will complete at the end of this phase of treatment. | Subjects enrolled will be randomized to one of two mood stabilizers, Lithium (Li) or Divalproex (Div) in Randomization 1. If subjects show no symptoms, they will complete at the end of this phase of treatment. | Subjects who were on Li or Div and developed symptoms of depression had Quetiapine added to their treatment regimen | Subjects who were on monotherapy Li or Div who developed symptoms of depression had Lamotrigine added to their regimen |
| Period Title: Randomization 1 | ||||
| STARTED | 53 | 59 | 0 | 0 |
| COMPLETED | 30 | 43 | 0 | 0 |
| NOT COMPLETED | 23 | 16 | 0 | 0 |
| Period Title: Randomization 1 | ||||
| STARTED | 21 | 31 | 17 | 18 |
| COMPLETED | 1 | 3 | 12 | 13 |
| NOT COMPLETED | 20 | 28 | 5 | 5 |
Baseline Characteristics
| Arm/Group Title | Randomization to Divalproex | Randomization to Lithium | Total |
|---|---|---|---|
| Arm/Group Description | Subjects randomized to Divalproex at Randomization 1. Demographics were only tracked in the Randomization 1 phase. | Subjects randomized to Lithium at Randomization 1. Demographics were only tracked in the Randomization 1 phase. | Total of all reporting groups |
| Overall Participants | 59 | 53 | 112 |
| Age, Customized (Count of Participants) | |||
| Subjects over 18 years old |
59
100%
|
53
100%
|
112
100%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
37
62.7%
|
32
60.4%
|
69
61.6%
|
| Male |
22
37.3%
|
21
39.6%
|
43
38.4%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| African American |
8
13.6%
|
7
13.2%
|
15
13.4%
|
| White (non Hispanic) |
33
55.9%
|
26
49.1%
|
59
52.7%
|
| Hispanic |
15
25.4%
|
19
35.8%
|
34
30.4%
|
| Asian/Asian American |
1
1.7%
|
1
1.9%
|
2
1.8%
|
| Other |
2
3.4%
|
0
0%
|
2
1.8%
|
| Region of Enrollment (Count of Participants) | |||
| United States |
59
100%
|
53
100%
|
112
100%
|
Outcome Measures
| Title | Bipolar Inventory of Symptoms Scale (BISS) |
|---|---|
| Description | 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. There are 42 items; each item is rated on a 0-4 scale. The BISS is a clinician-rated instrument. The Scale is rated as follows: 0 Not at all Slight Mild Moderate Severe Each of the 42 items is rated separately, with a score, based on the most recent 7 day period. The mean score is calculated from the total score, giving an overall score out of 4, where 0 is slight and 4 is the most severe symptoms. A negative score indicated an improvement from baseline to 26 weeks. |
| Time Frame | Change from Baseline to 26 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Divalproex After Randomization 1 | Lithium After Randomization 1 | Divalproex or Lithium Monotherapy | Lithium or Divalproex Plus Quetiapine | Lithium or Divalproex Plus Lamotrigine |
|---|---|---|---|---|---|
| Arm/Group Description | After a washout period of up to 1 week, subjects will be openly randomized to treatment Divalproex for 2 weeks. Subjects who become intolerant to or divalproex at any point will be crossed over to the other mood stabilizer (Lithium) and continued in the study. | After a washout period of up to 1 week, subjects will be openly randomized to treatment Lithium for 2 weeks. Subjects who become intolerant to or Lithium at any point will be crossed over to the other mood stabilizer (Divalproex) and continued in the study. | Group which continued monotherapy or divalproex after Randomization 2 | Group which had Quetiapine added to Lithium of Divalproex | Group which had Lamotrigine added to Lithium or Quetiapine |
| Measure Participants | 59 | 53 | 17 | 17 | 18 |
| Mania |
-0.31
(NA)
|
-0.41
(NA)
|
0.15
(NA)
|
-0.38
(NA)
|
-0.85
(NA)
|
| Depression |
-0.71
(NA)
|
-0.20
(NA)
|
-0.18
(NA)
|
-0.61
(NA)
|
-0.95
(NA)
|
| Irritability |
-0.50
(NA)
|
-0.39
(NA)
|
-0.27
(NA)
|
-0.66
(NA)
|
-0.96
(NA)
|
| Anxiety |
-0.49
(NA)
|
-0.51
(NA)
|
0.16
(NA)
|
-0.72
(NA)
|
-0.93
(NA)
|
| Psychosis |
-0.14
(NA)
|
-0.25
(NA)
|
-0.27
(NA)
|
-0.14
(NA)
|
-0.16
(NA)
|
| Title | Global Assessment of Functioning |
|---|---|
| Description | The Clinical Global Impression-Severity Scale (CGI-S) is used to assess global illness severity The CGI-S score change is measured from baseline to 26 weeks and is rated on a 7-point scale. The scale is read as follows: very much improved since the initiation of treatment much improved minimally improved no change from baseline (the initiation of treatment) minimally worse much worse very much worse since the initiation of treatment The score is calculated as a mean of all items, where 1 indicates improvement from inititation of visit, and 7 indicates the condition to be much worse since the inititation of treatment. A negative score indicates a change from worse to better. |
| Time Frame | Change from Baseline to 26 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Divalproex After Randomization 1 | Lithium After Randomization 1 | Divalproex or Lithium Monotherapy | Lithium or Divalproex Plus Quetiapine | Lithium or Divalproex Plus Lamotrigine |
|---|---|---|---|---|---|
| Arm/Group Description | After a washout period of up to 1 week, subjects will be openly randomized to Divalproex. Subjects who become intolerant to Divalproex at any point will be crossed over to the other mood stabilizer (Lithium) and continued in the study. | After a washout period of up to 1 week, subjects will be openly randomized to Lithium. Subjects who become intolerant to or lithium at any point will be crossed over to the other mood stabilizer (divalproex) and continued in the study. | Group which continued monotherapy on Divalproex or Lithium | Group which had Quetiapine added to Lithium or Divalproex | Group which had Lamotrigine added to Lithium or Divalproex |
| Measure Participants | 59 | 53 | 17 | 17 | 18 |
| CGI-Depression |
-1.11
(NA)
|
-0.32
(NA)
|
-0.09
(NA)
|
-0.99
(NA)
|
-1.24
(NA)
|
| CGI-Mania |
-0.69
(NA)
|
-1.12
(NA)
|
-0.19
(NA)
|
-0.71
(NA)
|
-1.81
(NA)
|
| CGI-Overall |
-1.28
(NA)
|
-0.55
(NA)
|
-0.11
(NA)
|
-0.99
(NA)
|
-1.64
(NA)
|
| Title | Baseline Randomization Percentage of Bipolar Types |
|---|---|
| Description | Percentages of Type I and Type II Bipolar Disorder included in Randomization groups |
| Time Frame | Baseline |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Bipolar Type 1 Divalproex Group | Bipolar Type II Divalproex Group | Bipolar Type 1 Lithium Group | Bipolar Type II Lithium Group |
|---|---|---|---|---|
| Arm/Group Description | Percentage of Bipolar Type 1 included in Randomization 1 | Percentage of Bipolar Type II included in Randomization 1 | Percentage of Bipolar Type 1 included in Randomization 1 | Percentage of Bipolar Type II included in Randomization 1 |
| Measure Participants | 59 | 53 | 59 | 53 |
| Number [percentage of participants] |
70
118.6%
|
74.1
139.8%
|
30
26.8%
|
25.9
NaN
|
| Title | Demographic in Randomization 1 Group |
|---|---|
| Description | Baseline demographic percentages of subject randomized to either Divalproex or Lithium at the first randomization |
| Time Frame | Baseline |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Divalproex | Lithium |
|---|---|---|
| Arm/Group Description | Subjects randomized to Divalproex at the first randomization | Subjects randomized to Lithium at the first randomization. |
| Measure Participants | 59 | 53 |
| Single never married |
27.1
|
33.3
|
| Married |
55.9
|
37.0
|
| Disrupted Marriage |
17.0
|
29.6
|
Adverse Events
| Time Frame | ||||
|---|---|---|---|---|
| Adverse Event Reporting Description | Adverse events were only collected for Lithium and Divalproex interventions. Adverse events were not tracked for monotherapy plus QTP or LTG (in Randomization 2 of the study). | |||
| Arm/Group Title | Divalproex | Lithium | ||
| Arm/Group Description | After a washout period of up to 1 week, subjects will be openly randomized to treatment Divalproex for 2 weeks. Subjects who become intolerant to or divalproex at any point will be crossed over to the other mood stabilizer (Lithium) and continued in the study. Adverse events were not collected for Randomization 2. | After a washout period of up to 1 week, subjects will be openly randomized to treatment Lithium for 2 weeks. Subjects who become intolerant to or Lithium at any point will be crossed over to the other mood stabilizer (Divalproex) and continued in the study. Adverse events were not collected for Randomization 2. | ||
All Cause Mortality |
||||
| Divalproex | Lithium | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Divalproex | Lithium | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/59 (1.7%) | 1/53 (1.9%) | ||
| Cardiac disorders | ||||
| Shortness of Breath | 1/59 (1.7%) | 1 | 0/53 (0%) | 0 |
| Nervous system disorders | ||||
| Neurological symptoms | 0/59 (0%) | 0 | 1/53 (1.9%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Divalproex | Lithium | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 19/59 (32.2%) | 15/53 (28.3%) | ||
| Gastrointestinal disorders | ||||
| Nausea and Vomiting | 19/59 (32.2%) | 19 | 15/53 (28.3%) | 15 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Charles Bowden, MD |
|---|---|
| Organization | UT Health San Antonio |
| Phone | 2105675393 |
| bowdenc@uthscsa.edu |
- HSC20110361H
- 1P30MH086045-01A2