Effectiveness of Aripiprazole for Improving Side Effects of Clozapine in the Treatment of People With Schizophrenia

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00345033
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 38
• Location: 1
• Arms: 2
• Duration (Months): 67
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This study will evaluate the effects of combination treatment with aripiprazole and clozapine on insulin resistance, blood fat levels, and weight gain in people diagnosed with schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Insulin Resistance	Drug: Aripiprazole; Drug: Placebo	Phase 4

Detailed Description

Schizophrenia is a severely disabling brain disorder. People with schizophrenia often experience hallucinations and delusions, as well as overall difficulty with everyday functioning. Although the medications available to treat the disorder are generally effective, many cause undesirable side effects. Clozapine, for example, is a strong tranquilizer that functions like an antipsychotic medication. It has been shown to be effective in reducing the symptoms of schizophrenia, but can bring about serious side effects, including heart failure, weight gain, and diabetes. Aripiprazole, an atypical antipsychotic medication, has been shown to have fewer side effects than older antipsychotic drugs. The addition of aripiprazole to a clozapine treatment regimen may reduce the negative side effects of clozapine. This study will evaluate the effects of combination treatment with aripiprazole and clozapine on insulin resistance, blood fat levels, and weight gain in people with schizophrenia.

Individuals interested in participating in this 8-week, double-blind study will first attend a screening session at the study site. Medical and psychiatric evaluations will be completed, blood samples will be taken, and an EKG will be performed. Eligible participants will undergo baseline assessments and then be randomly assigned to receive either aripiprazole or placebo in addition to their prescribed dose of clozapine. Participants will take one 15-mg capsule of their assigned medication once a day for 8 weeks. Study visits will occur biweekly for the first 8 weeks, followed by one final follow-up visit at Week 12. At each study visit, medication will be distributed, and the following criteria will be assessed: vital signs; weight; complete blood count; medication side effects; and extrapyramidal symptoms (EPS), which are potential neurological side effects of antipsychotic medications and may include involuntary movements, tremors, and rigidity. The Week 8 visit will include an EKG, and assessments of the following criteria: vital signs; medication side effects; treatment efficacy; blood counts; weight and height; and waist and hip circumference. At baseline and Week 8, participants will also undergo a frequently sampled intravenous glucose tolerance test (FSIVGTT). This involves intravenous infusion of glucose followed by frequent blood sampling to measure insulin and glucose concentrations. During the 4 days prior to each FSIVGTT, participants will record their food intake and wear an activity monitor.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Aripiprazole for Clozapine Associated Medical Morbidity
• Study Start Date: Mar 1, 2005
• Actual Primary Completion Date: Oct 1, 2009
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Participants will take aripiprazole 15mg/day for 8 weeks.	Drug: Aripiprazole; 15-mg dose once a day for 8 weeks
Placebo Comparator: 2 Participants will take placebo for 8 weeks.	Drug: Placebo; 1 tablet placebo dose once a day for 8 weeks

Outcome Measures

Primary Outcome Measures

1. Change in Total Cholesterol [Measured at Baseline and Week 8]

   A comparison of aripiprazole group and placebo group in change in total cholesterol measured at Baseline and Week 8.

2. Change in Weight [Measured at Baseline and Week 8]

   A comparison between aripiprazole group and placebo group in change in weight measured at Baseline and Week 8.

3. Change in Body Mass Index (BMI) [Measured at Baseline and Week 8]

   A comparison between aripiprazole group and placebo group of change in Body Mass Index (BMI) measured at Baseline and Week 8.

4. Change in Glucose Metabolism [Measured at Baseline and Week 8]

   A comparison between the aripiprazole group and placebo group in change in glucose metabolism measured at Baseline and Week 8.

5. Change in Triglycerides [Measured at Baseline and Week 8]

6. Change in Insulin Resistance [Measured at Baseline and Week 8]

   A comparison between aripiprazole group and placebo group of change in insulin resistance measured at Baseline and Week 8.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of schizophrenia (any subtype) or schizoaffective disorder (any subtype)

• Treatment with clozapine for at least 1 year

• Stable dose of clozapine for at least 1 month

• Well established compliance with outpatient medications

• Female participants of non-childbearing potential or of childbearing potential and willing to practice appropriate birth control methods (complete abstinence from sexual intercourse, female sterilization, sterilization of male partner, implants of levonorgestrel, injectable progestogen, oral contraceptives, intrauterine devices, or double barrier methods of contraception using spermicide with either a condom or diaphragm) during the study

Exclusion Criteria:

• Current substance abuse

• Psychiatrically unstable

• Significant medical illness, including severe cardiovascular, hepatic, or renal disease

• History of immunosuppression

• Current or recent radiation or chemotherapy treatment for cancer

• Chronic use of steroids

• Pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital Schizophrenia Program	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: David C. Henderson, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

• Casey DE, Carson WH, Saha AR, Liebeskind A, Ali MW, Jody D, Ingenito GG; Aripiprazole Study Group. Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study. Psychopharmacology (Berl). 2003 Apr;166(4):391-9. Epub 2003 Feb 28.
• Goldstein LE, Sporn J, Brown S, Kim H, Finkelstein J, Gaffey GK, Sachs G, Stern TA. New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment. Psychosomatics. 1999 Sep-Oct;40(5):438-43.
• Hadigan C, Miller K, Corcoran C, Anderson E, Basgoz N, Grinspoon S. Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus-infected women. J Clin Endocrinol Metab. 1999 Jun;84(6):1932-7.
• Henderson DC, Cagliero E, Gray C, Nasrallah RA, Hayden DL, Schoenfeld DA, Goff DC. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry. 2000 Jun;157(6):975-81.
• Marder SR, McQuade RD, Stock E, Kaplita S, Marcus R, Safferman AZ, Saha A, Ali M, Iwamoto T. Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophr Res. 2003 Jun 1;61(2-3):123-36.
• Visser M, Fuerst T, Lang T, Salamone L, Harris TB. Validity of fan-beam dual-energy X-ray absorptiometry for measuring fat-free mass and leg muscle mass. Health, Aging, and Body Composition Study--Dual-Energy X-ray Absorptiometry and Body Composition Working Group. J Appl Physiol (1985). 1999 Oct;87(4):1513-20.
• Wirshing DA, Boyd JA, Meng LR, Ballon JS, Marder SR, Wirshing WC. The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry. 2002 Oct;63(10):856-65.

• Responsible Party: David C. Henderson, Associate Professor of Psychiatry, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00345033
• Other Study ID Numbers: R01MH072635; R01MH072635; DSIR 83-ATAP
• First Posted: Jun 27, 2006
• Last Update Posted: Jun 23, 2014
• Last Verified: Jun 1, 2014

• Keywords provided by David C. Henderson, Associate Professor of Psychiatry, Massachusetts General Hospital: Glucose Metabolism
• Additional relevant MeSH terms: Insulin Resistance; Schizophrenia; Aripiprazole

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from the Freedom Trail Clinic at the Erich Lindemann Mental Health Center and were studied at the General Clinical Research Center (GCRC) at the Massachusetts General Hospital (MGH), Boston and the Freedom Trail Clinic.
Pre-assignment Detail	After providing written informed consent, subjects underwent a diagnostic evaluation by a research psychiatrist using the Structured Clinical Interview for DSM-IV (SCID). All subjects were screened and enrolled based on eligibility criteria. Baseline study assessments were completed prior to intervention.

Arm/Group Title	Aripiprazole	Placebo
Arm/Group Description	Participants will take aripiprazole for 8 weeks.	Participants will take placebo for 8 weeks.
Period Title: Overall Study
STARTED	20	18
COMPLETED	16	14
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Aripiprazole	Placebo	Total
Arm/Group Description	Participants will take aripiprazole for 8 weeks.	Participants will take placebo for 8 weeks.	Total of all reporting groups
Overall Participants	20	18	38
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	20 100%	18 100%	38 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.3 (8.2)	44.2 (8.9)	44.25 (8.6)
Sex: Female, Male (Count of Participants)
Female	4 20%	8 44.4%	12 31.6%
Male	16 80%	10 55.6%	26 68.4%
Region of Enrollment (participants) [Number]
United States	20 100%	18 100%	38 100%

Outcome Measures

1. Primary Outcome

Title	Change in Total Cholesterol
Description	A comparison of aripiprazole group and placebo group in change in total cholesterol measured at Baseline and Week 8.
Time Frame	Measured at Baseline and Week 8

Outcome Measure Data

Analysis Population Description

The number of participants for analysis (intent to treat) were those that completed the study (N = 30).

Arm/Group Title	Aripiprazole	Placebo
Arm/Group Description	Participants will take aripiprazole for 8 weeks.	Participants will take placebo for 8 weeks.
Measure Participants	16	14
Mean (Standard Deviation) [mg/dL]	-15.3 (33.3)	5.6 (34.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole, Placebo
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A priori power calculation determined the power to detect a change in total cholesterol is over 99%.
Statistical Test of Hypothesis	p-Value	0.125
	Comments
	Method	ANCOVA
	Comments

2. Primary Outcome

Title	Change in Weight
Description	A comparison between aripiprazole group and placebo group in change in weight measured at Baseline and Week 8.
Time Frame	Measured at Baseline and Week 8

Outcome Measure Data

Analysis Population Description

The number of participants for analysis (intent to treat) were those that completed the study (N=30).

Arm/Group Title	Aripiprazole	Placebo
Arm/Group Description	Participants will take aripiprazole for 8 weeks.	Participants will take placebo for 8 weeks.
Measure Participants	16	14
Mean (Standard Deviation) [kg]	-1.5 (2.3)	0.3 (2.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole, Placebo
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A priori power calculation determined the power to detect a change in weight will be over 99%.
Statistical Test of Hypothesis	p-Value	0.109
	Comments
	Method	ANCOVA
	Comments

3. Primary Outcome

Title	Change in Body Mass Index (BMI)
Description	A comparison between aripiprazole group and placebo group of change in Body Mass Index (BMI) measured at Baseline and Week 8.
Time Frame	Measured at Baseline and Week 8

Outcome Measure Data

Analysis Population Description

The number of participants for analysis (intent to treat) were those that completed the study (N=30).

Arm/Group Title	Aripiprazole	Placebo
Arm/Group Description	Participants will take aripiprazole for 8 weeks.	Participants will take placebo for 8 weeks.
Measure Participants	16	14
Mean (Standard Deviation) [kg/m^2]	-0.52 (0.79)	0.03 (0.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole, Placebo
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A priori power calculation determined the power to detect a change in Body Mass Index (BMI) will be over 99%.
Statistical Test of Hypothesis	p-Value	0.229
	Comments
	Method	ANCOVA
	Comments

4. Primary Outcome

Title	Change in Glucose Metabolism
Description	A comparison between the aripiprazole group and placebo group in change in glucose metabolism measured at Baseline and Week 8.
Time Frame	Measured at Baseline and Week 8

Outcome Measure Data

Analysis Population Description

The number of participants for analysis (intent to treat) were those that completed the study (N=30).

Arm/Group Title	Aripiprazole	Placebo
Arm/Group Description	Participants will take aripiprazole for 8 weeks.	Participants will take placebo for 8 weeks.
Measure Participants	16	14
Mean (Standard Deviation) [min^-1]	0.003 (0.006)	-0.005 (0.007)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole, Placebo
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A priori power calculation determined the power to detect a change in glucose metabolism to be 90%.
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	ANCOVA
	Comments

5. Primary Outcome

Title	Change in Triglycerides
Time Frame	Measured at Baseline and Week 8

Outcome Measure Data

Analysis Population Description

The number of participants for analysis (intent to treat) were those that completed the study (N=30)

Arm/Group Title	Aripiprazole	Placebo
Arm/Group Description	Participants will take aripiprazole for 8 weeks.	Participants will take placebo for 8 weeks.
Measure Participants	16	14
Mean (Standard Deviation) [mg/dL]	-5.9 (75.1)	-7.3 (100.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole, Placebo
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A priori power calculation determined the power to detect a change in triglycerides will be 81%.
Statistical Test of Hypothesis	p-Value	0.982
	Comments
	Method	ANCOVA
	Comments

6. Primary Outcome

Title	Change in Insulin Resistance
Description	A comparison between aripiprazole group and placebo group of change in insulin resistance measured at Baseline and Week 8.
Time Frame	Measured at Baseline and Week 8

Outcome Measure Data

Analysis Population Description

The number of participants for analysis (intent to treat) were those that completed the study (N=30)

Arm/Group Title	Aripiprazole	Placebo
Arm/Group Description	Participants will take aripiprazole for 8 weeks.	Participants will take placebo for 8 weeks.
Measure Participants	16	14
Mean (Standard Deviation) [HOMA score]	0.6 (3.8)	0.65 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole, Placebo
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A priori power calculation determined the power to detect a change in Insulin Resistance will be 90%.
Statistical Test of Hypothesis	p-Value	0.082
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Arm/Group Title	Aripiprazole		Placebo
Arm/Group Description	Participants will take aripiprazole for 8 weeks.		Participants will take placebo for 8 weeks.
All Cause Mortality
	Aripiprazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Aripiprazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Aripiprazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/16 (25%)		3/14 (21.4%)
Eye disorders
eye irritation/swelling	1/16 (6.3%)	1	0/14 (0%)	0
Gastrointestinal disorders
stomach pain	0/16 (0%)	0	1/14 (7.1%)	1
General disorders
dizziness during IVGTT procedure	0/16 (0%)	0	1/14 (7.1%)	1
Psychiatric disorders
psychiatric decompensation	1/16 (6.3%)	1	0/14 (0%)	0
psychiatric decompensation	1/16 (6.3%)	1	0/14 (0%)	0
psychiatric decompensation	1/16 (6.3%)	1	0/14 (0%)	0
Respiratory, thoracic and mediastinal disorders
asthma	0/16 (0%)	0	1/14 (7.1%)	1

Limitations/Caveats

The limitations of this study include the relatively small sample size, short intervention period (8 weeks) and the lack of generalizability of our findings to patients with schizophrenia treated by antipsychotic agents other than clozapine.

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.