Double-blind, Placebo-Controlled Divalproex Sodium ER in Bipolar I or Bipolar II Depression

• Sponsor: University Hospitals Cleveland Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00194116
• Collaborator: Abbott (Industry)
• Enrollment: 54
• Location: 1
• Arms: 2
• Duration (Months): 41
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

Double-Blind, Placebo-Controlled Divalproex Sodium ER in Bipolar I or Bipolar II Depression Previously Diagnosed and Treated as Recurrent Major Depression: This study recruits males and females aged 18 - 70 who currently meet diagnostic criteria for bipolar I or bipolar II disorder and are currently experiencing an episode of major depression. Patients are randomized to double-blind treatment with divalproex sodium ER or placebo and remain in the study for up to six weeks. This six-week double-blind treatment period is followed by an open-label treatment period of six months duration. This study is sponsored by Abbott Laboratories.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder	Drug: Divalproex Sodium ER; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Double-blind, Placebo-Controlled Divalproex Sodium ER in Bipolar I or Bipolar II Depression
• Study Start Date: Sep 1, 2004
• Actual Primary Completion Date: Oct 1, 2007
• Actual Study Completion Date: Feb 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Divalproex Sodium ER	Drug: Divalproex Sodium ER; Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.; Other Names: Depakote ER
Placebo Comparator: Placebo	Drug: Placebo; . Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.

Outcome Measures

Primary Outcome Measures

1. Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score [Acute phase (week0-week6)]

   MADRS total scores range from 0-60, where higher scores are indicative of more depression.

Secondary Outcome Measures

1. Change in Young Mania Rating Scale (YMRS) Total Score [Acute phase (week0-week6)]

   YMRS Scores range from 0 to 60 where higher scores are indicative of more mania.

2. Change in General Behavior Inventory (GBI) Depression Scale Score [Acute phase (week0-week6)]

   GBI Depression Scale Scores range from 46-184, where higher scores are indicative of more depression.

3. Change in General Behavior Inventory (GBI) Hypomanic/Biphasic Scale Score [Acute phase (week0-week6)]

   GBI Hypomanic/Biphasic Scale scores range from 28-112, where higher scores are indicative of more hypomanic/manic symptoms.

4. Change in Short Form Health Survey (SF-36) Physical Component Summary Score [Acute phase (week0-week6)]

   SF-36 Physical Component Summary scores range from 0-100, with a higher score indicating better physical health.

5. Change in Short Form Health Survey (SF-36) Mental Component Summary Score [Acute phase (week0-week6)]

   SF-36 Mental Component Summary scores range from 0-100, with a higher score indicating better mental health.

6. Change in Hamilton Anxiety Rating Scale (HAMA) Total Score [Acute phase (week0-week6)]

   HAMA Scores range from 0 to 56 where higher scores are indicative of more anxiety.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subject must give consent to participate in the study and sign and date the IRB approved written informed consent form prior to the initiation of any study procedures

• Subject must be between the ages of 18 and 70

• Subject must have a diagnosis of bipolar I or II.

• Subject must be currently depressed as confirmed by the Mini-International Neuropsychiatric Interview (MINI)

• Subject must have a baseline Montgomery-Asberg Depression Scale (MADRS) score of >19 and Young Mania Rating Scale (YMRS) score of <12

• Women of childbearing potential must be nonpregnant/nonlactating and using adequate contraception if sexually active

• Subject must not be using any concomitant psychotropic medications during the acute phase except prn benzodiazepines

Exclusion Criteria:

• Subjects lacks the capacity to provide informed consent

• Subject has currently or previously used divalproex or Dvpx-ER

• Subject is a serious suicide risk or has medically unstable conditions as judged by the investigators

• Subject has any alcohol, cocaine, or cannabis dependence within 3 months of study entry

• Subject has any cocaine, hallucinogens, opiates, crystal methamphetamine, or MMDA abuse within 3 months of study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106

Sponsors and Collaborators

• University Hospitals Cleveland Medical Center
• Abbott

Investigators

• Principal Investigator: Keming Gao, MD, PhD, Case Western Reserve University / University Hospitals of Cleveland

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Keming Gao, Director, Mood and Anxiety Clinic, University Hospitals Cleveland Medical Center
• ClinicalTrials.gov Identifier: NCT00194116
• Other Study ID Numbers: UHHS 08-03-07
• First Posted: Sep 19, 2005
• Last Update Posted: Jul 17, 2019
• Last Verified: May 1, 2019

• Additional relevant MeSH terms: Bipolar Disorder; Valproic Acid

Study Results

Participant Flow

Arm/Group Title	Divalproex Sodium ER	Placebo
Arm/Group Description	Divalproex Sodium ER: Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.	Placebo: . Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.
Period Title: Overall Study
STARTED	26	28
COMPLETED	13	13
NOT COMPLETED	13	15

Baseline Characteristics

Arm/Group Title	Divalproex Sodium ER	Placebo	Total
Arm/Group Description	Divalproex Sodium ER: Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.	Placebo: . Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.	Total of all reporting groups
Overall Participants	26	28	54
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.7 (10.3)	38.8 (14.4)	39.2 (12.5)
Sex: Female, Male (Count of Participants)
Female	15 57.7%	16 57.1%	31 57.4%
Male	11 42.3%	12 42.9%	23 42.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 7.7%	0 0%	2 3.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 11.5%	6 21.4%	9 16.7%
White	20 76.9%	22 78.6%	42 77.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 3.8%	0 0%	1 1.9%
DSM-IV Diagnosis (Count of Participants)
Bipolar I Disorder	10 38.5%	10 35.7%	20 37%
Bipolar II Disorder	16 61.5%	18 64.3%	34 63%

Outcome Measures

1. Primary Outcome

Title	Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
Description	MADRS total scores range from 0-60, where higher scores are indicative of more depression.
Time Frame	Acute phase (week0-week6)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Divalproex Sodium ER	Placebo
Arm/Group Description	Divalproex Sodium ER: Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.	Placebo: . Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.
Measure Participants	26	28
Least Squares Mean (Standard Error) [units on a scale]	-9.64 (1.49)	-5.32 (1.40)

2. Secondary Outcome

Title	Change in Young Mania Rating Scale (YMRS) Total Score
Description	YMRS Scores range from 0 to 60 where higher scores are indicative of more mania.
Time Frame	Acute phase (week0-week6)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Divalproex Sodium ER	Placebo
Arm/Group Description	Divalproex Sodium ER: Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.	Placebo: . Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.
Measure Participants	26	28
Mean (Standard Deviation) [units on a scale]	-0.54 (5.04)	-0.46 (3.28)

3. Secondary Outcome

Title	Change in General Behavior Inventory (GBI) Depression Scale Score
Description	GBI Depression Scale Scores range from 46-184, where higher scores are indicative of more depression.
Time Frame	Acute phase (week0-week6)

Outcome Measure Data

Analysis Population Description

Not all subjects completed the GBI at study end point

Arm/Group Title	Divalproex Sodium ER	Placebo
Arm/Group Description	Divalproex Sodium ER: Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.	Placebo: . Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.
Measure Participants	9	8
Mean (Standard Deviation) [units on a scale]	-11.56 (14.0)	0.9 (18.4)

4. Secondary Outcome

Title	Change in General Behavior Inventory (GBI) Hypomanic/Biphasic Scale Score
Description	GBI Hypomanic/Biphasic Scale scores range from 28-112, where higher scores are indicative of more hypomanic/manic symptoms.
Time Frame	Acute phase (week0-week6)

Outcome Measure Data

Analysis Population Description

Not all subjects completed the GBI at study end point

Arm/Group Title	Divalproex Sodium ER	Placebo
Arm/Group Description	Divalproex Sodium ER: Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.	Placebo: . Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.
Measure Participants	9	8
Mean (Standard Deviation) [units on a scale]	-7.2 (8.3)	-6.8 (7.3)

5. Secondary Outcome

Title	Change in Short Form Health Survey (SF-36) Physical Component Summary Score
Description	SF-36 Physical Component Summary scores range from 0-100, with a higher score indicating better physical health.
Time Frame	Acute phase (week0-week6)

Outcome Measure Data

Analysis Population Description

Not all subjects completed the SF-36 at study end point

Arm/Group Title	Divalproex Sodium ER	Placebo
Arm/Group Description	Divalproex Sodium ER: Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.	Placebo: . Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.
Measure Participants	18	14
Mean (Standard Deviation) [units on a scale]	-3.4 (15.7)	-4.2 (9.2)

6. Secondary Outcome

Title	Change in Short Form Health Survey (SF-36) Mental Component Summary Score
Description	SF-36 Mental Component Summary scores range from 0-100, with a higher score indicating better mental health.
Time Frame	Acute phase (week0-week6)

Outcome Measure Data

Analysis Population Description

Not all subjects completed the SF-36 at study end point

Arm/Group Title	Divalproex Sodium ER	Placebo
Arm/Group Description	Divalproex Sodium ER: Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.	Placebo: . Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.
Measure Participants	18	14
Mean (Standard Deviation) [units on a scale]	17.9 (18.4)	13.5 (15.7)

7. Secondary Outcome

Title	Change in Hamilton Anxiety Rating Scale (HAMA) Total Score
Description	HAMA Scores range from 0 to 56 where higher scores are indicative of more anxiety.
Time Frame	Acute phase (week0-week6)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Divalproex Sodium ER	Placebo
Arm/Group Description	Divalproex Sodium ER: Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.	Placebo: . Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.
Measure Participants	26	28
Mean (Standard Deviation) [units on a scale]	-4.6 (4.6)	-3.5 (7.0)

Adverse Events

Arm/Group Title	Divalproex Sodium ER		Placebo
Arm/Group Description	Divalproex Sodium ER: Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.		Placebo: . Tablets will be available in 250mg and 500mg strengths. Divalproex will be titrated to a minimum blood level of 50 mg/L. However, the investigators will titrate divalproex to the maximum tolerable dose with an expected average dose of 2000mg per day. By dosing in this manner, all subjects will have a minimum blood level of 50 mg/L, but the mean level is likely to be considerably higher.
All Cause Mortality
	Divalproex Sodium ER		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/28 (0%)
Serious Adverse Events
	Divalproex Sodium ER		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	Divalproex Sodium ER		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/26 (50%)		5/28 (17.9%)
Gastrointestinal disorders
Nausea	9/26 (34.6%)	26	4/28 (14.3%)	28
Diarrhea	3/26 (11.5%)	3	2/28 (7.1%)	2
Stomach Cramps	3/26 (11.5%)	3	0/28 (0%)	0
General disorders
Increased Appetite	4/26 (15.4%)	4	2/28 (7.1%)	2
Fatigue	3/26 (11.5%)	3	3/28 (10.7%)	3
Dry Mouth	3/26 (11.5%)	3	1/28 (3.6%)	1

Limitations/Caveats

[Not Specified]

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.