Bipolar I DisorderPhase 4SMARTNCT01588457

Sequential Multiple Assignment Treatment for Bipolar Disorder

A Phase 4 study testing Lithium, Divalproex and Lamotrigine in people with Bipolar I Disorder and Bipolar II Disorder, run by The University of Texas Health Science Center at San Antonio at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Bipolar I Disorder, Bipolar II Disorder
What is being tested?: Lithium, Divalproex and Lamotrigine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 112 participants
Where: 2 sitesUnited States
Study dates: Jun 2011to Dec 2016
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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.

Who cannot join

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.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

Case Western Reserve University
Cleveland, Ohio, 44106
University of Texas Health Science Center
San Antonio, Texas, 78229-3900

Other trials in United States

About this study

Official title: Sequential Multiple Assignment Randomized Treatment (SMART) for Bipolar Disorder

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.

Read the 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
Being tested: Lithium, Divalproex, Lamotrigine, Quetiapine
Medical subject headings: Bipolar Disorder

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

LithiumDrug
Also called Lithium Carbonate
Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain Li of ≥0.5mEq/L (milliequivalents per liter).
DivalproexDrug
Also called Depakote, Depakote ER
DV will be dosed to attain DV levels of ≥45mg/L.
LamotrigineDrug
Also called Lamictal
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.
QuetiapineDrug
Also called Seroquel
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.

Study groups in NCT01588457
Study group	Role	What they receive
Lithium	Active comparator	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. Receives: Drug: Lithium
Divalproex	Active comparator	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. Receives: Drug: Divalproex
Lithium plus Quetiapine	Active comparator	Those who develop protocol defined depression will then be randomized to a mood stabilizer (lithium) + quetiapine [QT]. Receives: Drug: Lithium; Drug: Quetiapine
Lithium plus Lamotrigine	Active comparator	Those who develop protocol defined depression will then be randomized to a mood stabilizer (lithium) + lamotrigine (LM). Receives: Drug: Lithium; Drug: Lamotrigine
Divalproex plus Quetiapine	Active comparator	Those who develop protocol defined depression will then be randomized to a mood stabilizer (divalproex) + quetiapine [QT]. Receives: Drug: Divalproex; Drug: Quetiapine
Divalproex plus Lamotrigine	Active comparator	Those who develop protocol defined depression will then be randomized to a mood stabilizer (divalproex) + lamotrigine (LM). Receives: Drug: Divalproex; Drug: Lamotrigine

What is being measured

The primary outcome is the main question the study is designed to answer.

Bipolar Inventory of Symptoms Scale (BISS)
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.
Measured: Change from Baseline to 26 weeks

Secondary outcomes (3)

Global Assessment of Functioning
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.
Measured: Change from Baseline to 26 weeks
Baseline Randomization Percentage of Bipolar Types
Percentages of Type I and Type II Bipolar Disorder included in Randomization groups
Measured: Baseline
Demographic in Randomization 1 Group
Baseline demographic percentages of subject randomized to either Divalproex or Lithium at the first randomization
Measured: Baseline

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jun 2011Dec 2016

First posted1 May 2012 (estimated)
Study startJun 2011
Primary completionDec 2016
Study completionDec 2016

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Bipolar I DisorderStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 112 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01588457
Sponsor's protocol ID: HSC20110361H
Other IDs: 1P30MH086045-01A2
Acronym: SMART
Status last verified: Aug 2020
First submitted: 29 Feb 2012
Last updated: 19 Aug 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

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.
PubMed 34523118

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

Enrolling by invitationObservational study
Digital Phenotypes for Predicting Depression_Validation
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A Study to Assess the Long-term Safety of KarXT for the Treatment of Manic Episodes in Bipolar-I Disorder (BALSAM-3)
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RecruitingPhase 3
A Study to Evaluate the Efficacy and Safety of KarXT for the Treatment of Manic Episodes in Bipolar-I Disorder
Bipolar-I Disorder With Mania or Mania With Mixed Features
RecruitingPhase 2
NMDA Receptor Modulation for the Treatment of Bipolar I Disorder
Bipolar I Disorder
RecruitingPhase 3
A Study to Evaluate the Efficacy and Safety of KarXT for the Treatment of Manic Episodes in Bipolar-I Disorder (BALSAM-2)
Bipolar Disorder Type I With Mania or Mania With Mixed Features

All Bipolar I Disorder trials

Study at a glance

From the registry record, last updated by the sponsor on 19 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Sequential Multiple Assignment Randomized Treatment (SMART) for Bipolar Disorder
ClinicalTrials.gov ID: NCT01588457
Acronym / sponsor ID: SMART / HSC20110361H
Conditions: Bipolar I Disorder, Bipolar II Disorder
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 112 participants (actual)
Lead sponsor: The University of Texas Health Science Center at San AntonioUniversity, hospital or other
Collaborators: National Institute of Mental Health (NIMH)
Study start: Jun 2011
Primary completion: Dec 2016 (actual)
Study completion: Dec 2016 (actual)
First posted: 1 May 2012 (estimated)
Results: Posted 14 Aug 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

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.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 6

Arm	Type	Receives
Lithium	Active comparator	Drug: LithiumThis 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.
Divalproex	Active comparator	Drug: DivalproexThis 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.
Lithium plus Quetiapine	Active comparator	Drug: Lithium, Drug: QuetiapineThose who develop protocol defined depression will then be randomized to a mood stabilizer (lithium) + quetiapine [QT].
Lithium plus Lamotrigine	Active comparator	Drug: Lithium, Drug: LamotrigineThose who develop protocol defined depression will then be randomized to a mood stabilizer (lithium) + lamotrigine (LM).
Divalproex plus Quetiapine	Active comparator	Drug: Divalproex, Drug: QuetiapineThose who develop protocol defined depression will then be randomized to a mood stabilizer (divalproex) + quetiapine [QT].
Divalproex plus Lamotrigine	Active comparator	Drug: Divalproex, Drug: LamotrigineThose who develop protocol defined depression will then be randomized to a mood stabilizer (divalproex) + lamotrigine (LM).

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

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.

Key exclusion criteria (8 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
LithiumAlso: Lithium CarbonateTherapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain Li of ≥0.5mEq/L (milliequivalents per liter).	Drug	Lithium, Lithium plus Lamotrigine, Lithium plus Quetiapine
DivalproexAlso: Depakote, Depakote ERDV will be dosed to attain DV levels of ≥45mg/L.	Drug	Divalproex, Divalproex plus Lamotrigine, Divalproex plus Quetiapine
LamotrigineAlso: LamictalLM 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.	Drug	Divalproex plus Lamotrigine, Lithium plus Lamotrigine
QuetiapineAlso: SeroquelQT 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.	Drug	Divalproex plus Quetiapine, Lithium plus Quetiapine

Primary outcome

Bipolar Inventory of Symptoms Scale (BISS)
Time frame: 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.

3 secondary outcomes

Global Assessment of Functioning
Time frame: Change from Baseline to 26 weeks
Baseline Randomization Percentage of Bipolar Types
Time frame: Baseline
Demographic in Randomization 1 Group
Time frame: Baseline

Results and safety

Results posted to the registry on 14 Aug 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Randomization to Lithium	53	30
Randomization to Divalproex	59	43
Monotherapy Li or Div Plus Quetiapine	0	0
Monotherapy Li or Div Plus Lamotrigine	0	0

Primary outcome: Bipolar Inventory of Symptoms Scale (BISS)

Time frame: Change from Baseline to 26 weeks. Mean (Standard Deviation). Unit: calculated mean scale score

Measure	Divalproex After Randomization 1 n = 59	Lithium After Randomization 1 n = 53	Divalproex or Lithium Monotherapy n = 17	Lithium or Divalproex Plus Quetiapine n = 17	Lithium or Divalproex Plus Lamotrigine n = 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)

3 secondary outcomes are reported in the full results.

Adverse events

Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Divalproex	1 of 59 (1.7%)	19 of 59 (32.2%)	Not reported
Lithium	1 of 53 (1.9%)	15 of 53 (28.3%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 19 Aug 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 34523118Hashimoto 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.

Related trials for Bipolar I Disorder

Enrolling by invitationObservational study
Digital Phenotypes for Predicting Depression_Validation
Major Depressive Disorder, Bipolar I Disorder
RecruitingPhase 3
A Study to Assess the Long-term Safety of KarXT for the Treatment of Manic Episodes in Bipolar-I Disorder (BALSAM-3)
Bipolar Disorder Type I With Mania
RecruitingPhase 3
A Study to Evaluate the Efficacy and Safety of KarXT for the Treatment of Manic Episodes in Bipolar-I Disorder
Bipolar-I Disorder With Mania or Mania With Mixed Features
RecruitingPhase 2
NMDA Receptor Modulation for the Treatment of Bipolar I Disorder
Bipolar I Disorder
RecruitingPhase 3
A Study to Evaluate the Efficacy and Safety of KarXT for the Treatment of Manic Episodes in Bipolar-I Disorder (BALSAM-2)
Bipolar Disorder Type I With Mania or Mania With Mixed Features

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Charles L. Bowden, M.D. principal investigator

University of Texas

Joseph R Calabrese, M.D. principal investigator

Case Western Reserve University

2 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 14 Aug 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Bipolar Inventory of Symptoms Scale (BISS) (time frame: Change from Baseline to 26 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01588457, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Aug 2020.