Comparative Effectiveness Study for Bipolar Disorder

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01331304
• Collaborator: Agency for Healthcare Research and Quality (AHRQ) (U.S. Fed)
• Enrollment: 482
• Locations: 11
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 43.8
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the effectiveness of lithium and quetiapine for the treatment of individuals with bipolar disorder.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder	Drug: Lithium; Drug: Quetiapine	Phase 4

Detailed Description

Mood stabilizers, medications that prevent future mood episodes, are the foundation for treatment of bipolar disorder. While all published bipolar disorder treatment guidelines recommend that pharmacotherapy should include mood stabilizers for long-term maintenance treatment, no randomized comparative effectiveness studies have examined the real-world advantages and disadvantages of the newer second generation antipsychotic (SGA) mood stabilizers compared to the classic mood stabilizers, such as lithium (Li). No studies have looked at the effectiveness of SGAs compared to mood stabilizers when used in the context of other medications required to manage bipolar patients, since bipolar disorder patients take a median of 3 medications for optimal outcomes. Quetiapine (QTP) is the most extensively studied, broadly efficacious and the most widely prescribed SGA for bipolar disorder. The classic mood stabilizer Li has the largest evidence base for treating bipolar disorder, but has been largely supplanted by the SGAs.

Thus, this study compares symptomatic benefits and adverse effect burden between a QTP foundation with adjunctive personalized treatments (QTP+APT) and a mood stabilizer foundation consisting of Li with APT (Li+APT). APT will include any other medication needed with the following exceptions: the QTP+APT cannot receive Li and the Li+APT group cannot receive an antipsychotic. If, however, participants clinically require a switch to, or the addition of any other SGA or mood stabilizer, then those medications can be added as a rescue strategy that will be carefully recorded. Consistent with an effectiveness trial, participants will be able to continue in the study if they require a rescue treatment. The specific plan is a randomized, open, two arm, comparative effectiveness study of QTP+APT vs. Li+APT treatment for 6 months across 10 sites.

In summary, this comparative effectiveness study compares fundamentally different acute and continuation treatments for bipolar disorder. The investigators address the key question of whether to use a prototypical mood stabilizing SGA (i.e., QTP) or the classical mood stabilizer Li as the foundational treatment in the context of other necessary adjunctive personalized treatments (APT).

Study Design

• Study Type: Interventional
• Actual Enrollment: 482 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer And a Classic Mood Stabilizer for Bipolar Disorder
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Other: Li + APT Study participants will take lithium in addition to any other medications recommended by the study physician.	Drug: Lithium; 600-900mg per day over 6 months; Other Names: Lithoboid, Eskalith
Other: QTP + APT Study participants will take quetiapine in addition to any other medications recommended by the study physician.	Drug: Quetiapine; 100-800mg a day over 6 months; Other Names: Seroquel

Outcome Measures

Primary Outcome Measures

1. Clinical Global Impression-Efficacy Index (CGI-EI) [Average 6 month score minus Average baseline score]

   The CGI-EI integrates benefits and harms and yields a score that can be compared across interventions. It is made up of 2 subscales: therapeutic effects and side effects. Each rating is on a scale from 1 to 4. To combine these two subscales into the CGI-EI we report as our primary outcome, we subtracted the side effects subscale from the therapeutic effects subscale. Thus, the CGI-EI we report ranges the integers from -3 to +3 (i.e. possible scores are -3,-2,-1,0,1,2,3). A score of -3 is the most burdensome side effect score (4) and the least therapeutic effect score (1) and a score of +3 is the least burdensome side effect score (1) and the highest therapeutic effect score (4). Higher CGI-EI signifies better outcome (minimal side effects, maximal therapeutic effect). Lower CGI-EI signifies worse outcome (maximal side effects, minimal therapeutic effect).To compute CGI-EI score, we subtract the side effect score from the therapeutic effect score.

2. Necessary Clinical Adjustments [6 Months]

   Necessary Clinical Adjustment (NCA): The Medication Recommendation Tracking Form was developed and successfully implemented in a previous study to capture recommended medication changes at each study visit 17. Clinicians record dosage changes, missed doses, new medications added or discontinued, and specify the reason for each change. Any change in psychotropic medications, or medications used to treat side effects, is coded along with the reason for the change. NCAs include those changes made for lack of effectiveness or intolerance, but not changes for planned dose titrations.

Secondary Outcome Measures

1. Risk of Cardiovascular Disease - Framingham Risk Score [Average baseline score minus Average 6 month score]

   The Framingham risk score captures the classic risk factors for cardiovascular disease, including age, sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, and smoking. The Framingham risk score is used as a simple predictive tool to determine 10-year (short term) risk for developing cardiovascular disease (CHD), with higher scores indicating higher risk. Established benchmarks exist for scores from 0 to 25--though it can exceed this value--that are meant to translate to the probability of developing heart disease.

2. Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT) [Average baseline score minus Average 6-month score]

   The LIFE-RIFT asses the extent to which psychopathology has impacted current functioning in work, household chores, interpersonal relationships with partner, family, and friends, recreational activities, and life, satisfaction, leisure activities and social relationships. Summary scores can range from 4 to 20, with higher scores indicating greater functional impairment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 68 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Meets DSM-IV criteria for BD I or II, which is the primary focus of treatment

2. Able to give written informed consent

3. Age > to 18 years and < 68 years

4. Women of child bearing potential must agree to use adequate contraception (e.g. oral contraceptives, intrauterine device, barrier methods, or total abstinence from intercourse; Depo Provera is acceptable if it is started 3 months prior to enrollment), inform their doctor at the earliest possible time of their plans to conceive, and to understand the risks of lithium and other study treatments to the fetus and infant

5. Currently symptomatic, as defined as a Clinical Global Impression - Bipolar Disorder Overall Severity (CGI-BP-S) score of at least 3 (mild)

6. If currently taking an SGA, participants would be required to be willing to either discontinue or switch to QTP

7. Willing to be randomized to either QTP+APT or Li+APT.

Exclusion Criteria:

1. Unwilling or unable to comply with study requirements

2. If maintained on thyroid medication must be euthyroid for at least 1 month before Visit 1

3. Patients who have had intolerable side effects with QTP or Li

4. Patients whose clinical status requires inpatient care

5. Drug/alcohol dependence within the past 30 days

6. Pregnancy as determined by urine pregnancy test or breastfeeding

7. History of nonresponse to Li at a serum level of ≥ 1.0 mEq/L ≥ 8 weeks

8. History of nonresponse to QTP at doses of at least 600 mg ≥ 8 weeks.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35205
2	Stanford University School of Medicine	Stanford	California	United States	94305
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
4	University of Michigan	Ann Arbor	Michigan	United States	48109
5	Weill Cornell Medical College	New York	New York	United States	10065
6	Case Western Reserve University School of Medicine	Cleveland	Ohio	United States	44106
7	The Lindner Center of HOPE	Mason	Ohio	United States	45040
8	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
9	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
10	Vanderbilt University	Nashville	Tennessee	United States	37212
11	The University of Texas Health Science Center	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• Massachusetts General Hospital
• Agency for Healthcare Research and Quality (AHRQ)

Investigators

• Principal Investigator: Andrew A Nierenberg, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Andrew A. Nierenberg, MD, Director of Research, Bipolar Clinic and Research Program, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01331304
• Other Study ID Numbers: 2010P001442; R01HS019371-01
• First Posted: Apr 8, 2011
• Last Update Posted: Apr 26, 2018
• Last Verified: Mar 1, 2018

• Keywords provided by Andrew A. Nierenberg, MD, Director of Research, Bipolar Clinic and Research Program, Massachusetts General Hospital: Bipolar disorder; Comparative effectiveness trial; Lithium; Quetiapine
• Additional relevant MeSH terms: Disease; Bipolar Disorder; Quetiapine Fumarate

Study Results

Participant Flow

Arm/Group Title	Li + APT	QTP + APT
Arm/Group Description	Study participants will take lithium in addition to any other medications recommended by the study physician. Lithium: 600-1200mg per day over 6 months	Study participants will take quetiapine in addition to any other medications recommended by the study physician. Quetiapine: 100-800mg a day over 6 months
Period Title: Overall Study
STARTED	240	242
COMPLETED	182	182
NOT COMPLETED	58	60

Baseline Characteristics

Arm/Group Title	Li + APT	QTP + APT	Total
Arm/Group Description	Study participants will take lithium in addition to any other medications recommended by the study physician. Lithium: 600-1200mg per day over 6 months	Study participants will take quetiapine in addition to any other medications recommended by the study physician. Quetiapine: 100-800mg a day over 6 months	Total of all reporting groups
Overall Participants	240	242	482
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	38.6 (12.1)	39.1 (12.2)	38.9 (12.1)
Sex: Female, Male (Count of Participants)
Female	140 58.3%	143 59.1%	283 58.7%
Male	100 41.7%	99 40.9%	199 41.3%
Region of Enrollment (participants) [Number]
United States	240 100%	242 100%	482 100%

Outcome Measures

1. Primary Outcome

Title	Clinical Global Impression-Efficacy Index (CGI-EI)
Description	The CGI-EI integrates benefits and harms and yields a score that can be compared across interventions. It is made up of 2 subscales: therapeutic effects and side effects. Each rating is on a scale from 1 to 4. To combine these two subscales into the CGI-EI we report as our primary outcome, we subtracted the side effects subscale from the therapeutic effects subscale. Thus, the CGI-EI we report ranges the integers from -3 to +3 (i.e. possible scores are -3,-2,-1,0,1,2,3). A score of -3 is the most burdensome side effect score (4) and the least therapeutic effect score (1) and a score of +3 is the least burdensome side effect score (1) and the highest therapeutic effect score (4). Higher CGI-EI signifies better outcome (minimal side effects, maximal therapeutic effect). Lower CGI-EI signifies worse outcome (maximal side effects, minimal therapeutic effect).To compute CGI-EI score, we subtract the side effect score from the therapeutic effect score.
Time Frame	Average 6 month score minus Average baseline score

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Li + APT	QTP + APT
Arm/Group Description	Study participants will take lithium in addition to any other medications recommended by the study physician. Lithium: 600-1200mg per day over 6 months	Study participants will take quetiapine in addition to any other medications recommended by the study physician. Quetiapine: 100-800mg a day over 6 months
Measure Participants	240	242
Mean (95% Confidence Interval) [Units on the scale]	1.58	1.52

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Li + APT, QTP + APT
	Comments	For the first co-primary aim, mixed-effects linear regression analyses compared the two intervention groups on the repeated assessments of the CGI-EI over 6 months.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.59
	Comments	Because this study has co-primary outcomes (CGI-EI and NCAs), the analyses of the treatment effect in the two primary hypotheses each involved a two-tailed alpha-level of 0.025.
	Method	Mixed Models Analysis
	Comments

2. Primary Outcome

Title	Necessary Clinical Adjustments
Description	Necessary Clinical Adjustment (NCA): The Medication Recommendation Tracking Form was developed and successfully implemented in a previous study to capture recommended medication changes at each study visit 17. Clinicians record dosage changes, missed doses, new medications added or discontinued, and specify the reason for each change. Any change in psychotropic medications, or medications used to treat side effects, is coded along with the reason for the change. NCAs include those changes made for lack of effectiveness or intolerance, but not changes for planned dose titrations.
Time Frame	6 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Li + APT	QTP + APT
Arm/Group Description	Study participants will take lithium in addition to any other medications recommended by the study physician. Lithium: 600-1200mg per day over 6 months	Study participants will take quetiapine in addition to any other medications recommended by the study physician. Quetiapine: 100-800mg a day over 6 months
Measure Participants	240	242
Mean (Standard Deviation) [Mean NCAs per month]	.8 (.8)	.9 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Li + APT, QTP + APT
	Comments	For the second co-primary, patient monthly rates of NCAs (determined by dividing total number of NCAs during follow-up by the length of follow-up - to account for attrition and resulting differential exposure time) for treatment groups were compared using a Wilcoxon rank-sum test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.118
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Risk of Cardiovascular Disease - Framingham Risk Score
Description	The Framingham risk score captures the classic risk factors for cardiovascular disease, including age, sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, and smoking. The Framingham risk score is used as a simple predictive tool to determine 10-year (short term) risk for developing cardiovascular disease (CHD), with higher scores indicating higher risk. Established benchmarks exist for scores from 0 to 25--though it can exceed this value--that are meant to translate to the probability of developing heart disease.
Time Frame	Average baseline score minus Average 6 month score

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Li + APT	QTP + APT
Arm/Group Description	Study participants will take lithium in addition to any other medications recommended by the study physician. Lithium: 600-900mg per day over 6 months	Study participants will take quetiapine in addition to any other medications recommended by the study physician. Quetiapine: 100-800mg a day over 6 months
Measure Participants	240	242
Mean (95% Confidence Interval) [units on a scale]	-0.26	0.17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Li + APT, QTP + APT
	Comments	Mixed-effects linear regression analyses compared the two intervention groups on the repeated collection of measures relevant to calculation of the Framingham Risk Score over 6 months
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments	Analysis of this secondary outcome was not corrected for multiple comparisons. Therefore, the a priori threshold for statistical significance was set at 0.05
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT)
Description	The LIFE-RIFT asses the extent to which psychopathology has impacted current functioning in work, household chores, interpersonal relationships with partner, family, and friends, recreational activities, and life, satisfaction, leisure activities and social relationships. Summary scores can range from 4 to 20, with higher scores indicating greater functional impairment.
Time Frame	Average baseline score minus Average 6-month score

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Li + APT	QTP + APT
Arm/Group Description	Study participants will take lithium in addition to any other medications recommended by the study physician. Lithium: 600-900mg per day over 6 months	Study participants will take quetiapine in addition to any other medications recommended by the study physician. Quetiapine: 100-800mg a day over 6 months
Measure Participants	240	242
Mean (95% Confidence Interval) [units on a scale]	-3.74	-3.61

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Li + APT, QTP + APT
	Comments	Mixed-effects linear regression analyses compared the two intervention groups on the repeated assessment of the LIFE-RIFT over 6 months
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments	Analysis of this secondary outcome was not corrected for multiple comparisons. Therefore, the a priori threshold for statistical significance was set at 0.05
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	Six months
Arm/Group Title	Li + APT		QTP + APT
Arm/Group Description	Study participants will take lithium in addition to any other medications recommended by the study physician. Lithium: 600-1200mg per day over 6 months		Study participants will take quetiapine in addition to any other medications recommended by the study physician. Quetiapine: 100-800mg a day over 6 months
All Cause Mortality
	Li + APT		QTP + APT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Li + APT		QTP + APT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/240 (15%)		27/242 (11.2%)
Cardiac disorders
Death	1/240 (0.4%)	1	0/242 (0%)	0
Gastrointestinal disorders
Gastrointestinal Issues	2/240 (0.8%)	2	0/242 (0%)	0
General disorders
Alcoholism Treatment	1/240 (0.4%)	1	0/242 (0%)	0
Heroin Overdose	1/240 (0.4%)	1	0/242 (0%)	0
Hospitalization reason unknown	0/240 (0%)	0	1/242 (0.4%)	1
Extreme Sedation Hospitalization	0/240 (0%)	0	1/242 (0.4%)	1
Study Medication Overdose	1/240 (0.4%)	1	2/242 (0.8%)	2
Dizziness	1/240 (0.4%)	1	0/242 (0%)	0
Hepatobiliary disorders
Biliary Cirrhosis	1/240 (0.4%)	1	0/242 (0%)	0
Infections and infestations
Flu Hospitalization	0/240 (0%)	0	1/242 (0.4%)	1
Staph Infection	0/240 (0%)	0	1/242 (0.4%)	1
Injury, poisoning and procedural complications
Car/Bike Accident	2/240 (0.8%)	2	1/242 (0.4%)	1
Broken Bones	0/240 (0%)	0	2/242 (0.8%)	2
Fall	0/240 (0%)	0	2/242 (0.8%)	2
Musculoskeletal and connective tissue disorders
Muscle Spasms Hospitalization	1/240 (0.4%)	1	0/242 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cyst	0/240 (0%)	0	1/242 (0.4%)	1
Nervous system disorders
Pseudoseizure	1/240 (0.4%)	1	0/242 (0%)	0
Pregnancy, puerperium and perinatal conditions
Pregnancy	3/240 (1.3%)	3	1/242 (0.4%)	1
Psychiatric disorders
Psychiatric Hospitalization	18/240 (7.5%)	23	14/242 (5.8%)	19
Suicide	1/240 (0.4%)	1	0/242 (0%)	0
Renal and urinary disorders
Kidney Infection	1/240 (0.4%)	1	0/242 (0%)	0
Skin and subcutaneous tissue disorders
Eczema Outbreak	1/240 (0.4%)	1	0/242 (0%)	0
Surgical and medical procedures
Laparoscopic Cholecystectomy	1/240 (0.4%)	1	0/242 (0%)	0
Other (Not Including Serious) Adverse Events
	Li + APT		QTP + APT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	210/240 (87.5%)		221/242 (91.3%)
Eye disorders
Blurred Vision	12/240 (5%)	15	6/242 (2.5%)	7
Gastrointestinal disorders
Nausea	58/240 (24.2%)	70	15/242 (6.2%)	17
Upset stomach/stomach pain/bloating	31/240 (12.9%)	36	12/242 (5%)	13
Diarrhea	32/240 (13.3%)	38	7/242 (2.9%)	10
Constipation	19/240 (7.9%)	23	22/242 (9.1%)	23
General disorders
Excessive sleepiness/daytime somnolence	68/240 (28.3%)	96	186/242 (76.9%)	249
Dry Mouth	29/240 (12.1%)	32	51/242 (21.1%)	58
Increased Weight	25/240 (10.4%)	31	45/242 (18.6%)	55
Increased Appetite	20/240 (8.3%)	22	55/242 (22.7%)	56
Increased Thirst	29/240 (12.1%)	32	4/242 (1.7%)	4
Restless/fidgety (akathisia)	7/240 (2.9%)	7	15/242 (6.2%)	17
Insomnia	12/240 (5%)	12	5/242 (2.1%)	7
Musculoskeletal and connective tissue disorders
Tremor	63/240 (26.3%)	69	13/242 (5.4%)	13
Stiffness/muscle aches	13/240 (5.4%)	14	14/242 (5.8%)	14
Weakness/muscle fatigue	11/240 (4.6%)	12	14/242 (5.8%)	15
Muscle twitching (myoclonus)	6/240 (2.5%)	6	14/242 (5.8%)	14
Nervous system disorders
Headache	48/240 (20%)	61	33/242 (13.6%)	43
Memory/concentration problems	27/240 (11.3%)	32	21/242 (8.7%)	25
Dizziness/Lightheaded	21/240 (8.8%)	24	23/242 (9.5%)	30
Renal and urinary disorders
Increased Urinary Frequency	32/240 (13.3%)	33	2/242 (0.8%)	3
Respiratory, thoracic and mediastinal disorders
Respiratory infection or other cold-like symptoms	12/240 (5%)	12	12/242 (5%)	12
Skin and subcutaneous tissue disorders
Hair Loss	16/240 (6.7%)	16	4/242 (1.7%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.