Trial Outcomes & Findings for Sequential Multiple Assignment Treatment for Bipolar Disorder (NCT NCT01588457)

Results Overview

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 1. Slight 2. Mild 3. Moderate 4. 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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

112 participants

Primary outcome timeframe

Change from Baseline to 26 weeks

Results posted on

2020-08-19

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Randomization to Lithium 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.	Randomization to Divalproex 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.	Monotherapy Li or Div Plus Quetiapine Subjects who were on Li or Div and developed symptoms of depression had Quetiapine added to their treatment regimen	Monotherapy Li or Div Plus Lamotrigine Subjects who were on monotherapy Li or Div who developed symptoms of depression had Lamotrigine added to their regimen
Randomization 1 STARTED	53	59	0	0
Randomization 1 COMPLETED	30	43	0	0
Randomization 1 NOT COMPLETED	23	16	0	0
Randomization 2 STARTED	21	31	17	18
Randomization 2 COMPLETED	1	3	12	13
Randomization 2 NOT COMPLETED	20	28	5	5

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Sequential Multiple Assignment Treatment for Bipolar Disorder

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Randomization to Divalproex n=59 Participants Subjects randomized to Divalproex at Randomization 1. Demographics were only tracked in the Randomization 1 phase.	Randomization to Lithium n=53 Participants Subjects randomized to Lithium at Randomization 1. Demographics were only tracked in the Randomization 1 phase.	Total n=112 Participants Total of all reporting groups
Age, Customized Subjects over 18 years old	59 Participants n=5 Participants	53 Participants n=7 Participants	112 Participants n=5 Participants
Sex: Female, Male Female	37 Participants n=5 Participants	32 Participants n=7 Participants	69 Participants n=5 Participants
Sex: Female, Male Male	22 Participants n=5 Participants	21 Participants n=7 Participants	43 Participants n=5 Participants
Race/Ethnicity, Customized Overall Total · African American	8 Participants n=5 Participants	7 Participants n=7 Participants	15 Participants n=5 Participants
Race/Ethnicity, Customized Overall Total · White (non Hispanic)	33 Participants n=5 Participants	26 Participants n=7 Participants	59 Participants n=5 Participants
Race/Ethnicity, Customized Overall Total · Hispanic	15 Participants n=5 Participants	19 Participants n=7 Participants	34 Participants n=5 Participants
Race/Ethnicity, Customized Overall Total · Asian/Asian American	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Overall Total · Other	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment United States	59 Participants n=5 Participants	53 Participants n=7 Participants	112 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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 1. Slight 2. Mild 3. Moderate 4. 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.

Outcome measures

Outcome measures
Measure	Divalproex After Randomization 1 n=59 Participants 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.	Lithium After Randomization 1 n=53 Participants 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.	Divalproex or Lithium Monotherapy n=17 Participants Group which continued monotherapy or divalproex after Randomization 2	Lithium or Divalproex Plus Quetiapine n=17 Participants Group which had Quetiapine added to Lithium of Divalproex	Lithium or Divalproex Plus Lamotrigine n=18 Participants Group which had Lamotrigine added to Lithium or Quetiapine
Bipolar Inventory of Symptoms Scale (BISS) Mania	-0.31 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.41 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	0.15 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.38 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.85 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.
Bipolar Inventory of Symptoms Scale (BISS) Depression	-0.71 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.20 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.18 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.61 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.95 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.
Bipolar Inventory of Symptoms Scale (BISS) Irritability	-0.50 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.39 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.27 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.66 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.96 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.
Bipolar Inventory of Symptoms Scale (BISS) Anxiety	-0.49 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.51 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	0.16 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.72 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.93 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.
Bipolar Inventory of Symptoms Scale (BISS) Psychosis	-0.14 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.25 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.27 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.14 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.	-0.16 calculated mean scale score Standard Deviation NA Standard deviation is unavailable since the PI and statistician have retired and the information is unavailable.

SECONDARY outcome

Timeframe: 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: 1. very much improved since the initiation of treatment 2. much improved 3. minimally improved 4. no change from baseline (the initiation of treatment) 5. minimally worse 6. much worse 7. 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.

Outcome measures

Outcome measures
Measure	Divalproex After Randomization 1 n=59 Participants 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.	Lithium After Randomization 1 n=53 Participants 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.	Divalproex or Lithium Monotherapy n=17 Participants Group which continued monotherapy or divalproex after Randomization 2	Lithium or Divalproex Plus Quetiapine n=17 Participants Group which had Quetiapine added to Lithium of Divalproex	Lithium or Divalproex Plus Lamotrigine n=18 Participants Group which had Lamotrigine added to Lithium or Quetiapine
Global Assessment of Functioning CGI-Depression	-1.11 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data	-0.32 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data	-0.09 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data	-0.99 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data	-1.24 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data
Global Assessment of Functioning CGI-Mania	-0.69 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data	-1.12 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data	-0.19 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data	-0.71 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data	-1.81 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data
Global Assessment of Functioning CGI-Overall	-1.28 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data	-0.55 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data	-0.11 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data	-0.99 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data	-1.64 calculated mean scale score Standard Deviation NA PI and statistician have retired and do not have access to the data

SECONDARY outcome

Timeframe: Baseline

Percentages of Type I and Type II Bipolar Disorder included in Randomization groups

Outcome measures

Outcome measures
Measure	Divalproex After Randomization 1 n=59 Participants 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.	Lithium After Randomization 1 n=53 Participants 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.	Divalproex or Lithium Monotherapy n=59 Participants Group which continued monotherapy or divalproex after Randomization 2	Lithium or Divalproex Plus Quetiapine n=53 Participants Group which had Quetiapine added to Lithium of Divalproex	Lithium or Divalproex Plus Lamotrigine Group which had Lamotrigine added to Lithium or Quetiapine
Baseline Randomization Percentage of Bipolar Types	70 percentage of participants	74.1 percentage of participants	30 percentage of participants	25.9 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline

Baseline demographic percentages of subject randomized to either Divalproex or Lithium at the first randomization

Outcome measures

Outcome measures
Measure	Divalproex After Randomization 1 n=59 Participants 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.	Lithium After Randomization 1 n=53 Participants 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.	Divalproex or Lithium Monotherapy Group which continued monotherapy or divalproex after Randomization 2	Lithium or Divalproex Plus Quetiapine Group which had Quetiapine added to Lithium of Divalproex	Lithium or Divalproex Plus Lamotrigine Group which had Lamotrigine added to Lithium or Quetiapine
Demographic in Randomization 1 Group Single never married	27.1 percentage of subjects	33.3 percentage of subjects	—	—	—
Demographic in Randomization 1 Group Married	55.9 percentage of subjects	37.0 percentage of subjects	—	—	—
Demographic in Randomization 1 Group Disrupted Marriage	17.0 percentage of subjects	29.6 percentage of subjects	—	—	—

Adverse Events

Divalproex

Serious events: 1 serious events

Other events: 19 other events

Deaths: 0 deaths

Lithium

Serious events: 1 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Divalproex n=59 participants at risk 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.	Lithium n=53 participants at risk 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.
Cardiac disorders Shortness of Breath	1.7% 1/59 • Number of events 1 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).	0.00% 0/53 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).
Nervous system disorders Neurological symptoms	0.00% 0/59 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).	1.9% 1/53 • Number of events 1 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).

Other adverse events

Other adverse events
Measure	Divalproex n=59 participants at risk 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.	Lithium n=53 participants at risk 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.
Gastrointestinal disorders Nausea and Vomiting	32.2% 19/59 • Number of events 19 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).	28.3% 15/53 • Number of events 15 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).

Additional Information

Charles Bowden, MD

UT Health San Antonio

Phone: 2105675393

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place