Pioglitazone as a Treatment for Lipid and Glucose Abnormalities In Patients With Schizophrenia

• Sponsor: Nathan Kline Institute for Psychiatric Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT00231894
• Collaborator: (none)
• Enrollment: 56
• Location: 1
• Arms: 2
• Duration (Months): 56
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This is a study with an approved drug for treating type 2 diabetes, for its effects on treating glucose and lipid abnormalities in patients being treated with first or second-generation antipsychotics, and comparison of effects of this drug with another treatment lifestyle modification. Patients who meet inclusion criteria will be treated with pioglitazone for 12 weeks. They will be evaluated for fasting glucose and lipids, glucose-tolerance tests, and neurocognitive battery and tests of verbal memory at baseline and during treatment with pioglitazone.

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Schizophrenia; Insulin Resistance; Cognitive Impairment	Drug: Pioglitazone; Behavioral: Life style diet group; Other: Placebo	Phase 4

Detailed Description

The aim of this study is to investigate the effects of pioglitazone added to weight-lifestyle intervention vs. placebo plus lifestyle intervention on reversing or reducing impaired or abnormal triglycerides, HDL and glucose metabolism in schizophrenics treated with first or second-generation antipsychotics.. Another aim is to examine the effects of impaired glucose metabolism on verbal memory and other cognitive function in schizophrenic patients treated with these medications and the relationship to improvements in impaired glucose metabolism to impairments in cognitive function. Clozapine and olanzapine, and some other first or second-generation antipsychotics effective for treating schizophrenia and bipolar disorders, have been reported to be associated with increased incidence of diabetic type metabolic abnormalities, decreases in insulin sensitivity, and abnormal glucose tolerance tests. This can lead to the development of type 2 diabetes and also abnormal lipid metabolic levels which can lead to atherosclerotic changes and increased risk of cardiovascular disease and other diabetes related complications. Drug treatments which could reduce or correct these diabetic metabolic changes would permit many patients to continue to receive the benefits of these antipsychotic medications with reduced drug-induced comorbidity. Previous research using non-psychotic subjects has shown that diabetes and impaired glucose tolerance are associated with cognitive impairments, especially in verbal memory, and provides a rationale for testing whether corrections of impaired glucose metabolism are associated with cognitive improvements in schizophrenic patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Pioglitazone as a Treatment for Lipid and Glucose Abnormalities In Patients With Schizophrenia Treated With Antipsychotic Medication And Potential Effects on Cognitive Function
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Pioglitazone and life-style group Pioglitazone (30-45 mg/daily) plus life-style diet group	Drug: Pioglitazone; pioglitazone 30-45 mg/day; Other Names: Actos ; Behavioral: Life style diet group; life style diet education group 1x/week
Placebo Comparator: Placebo and life style group Placebo capsules daily plus life-style diet group	Behavioral: Life style diet group; life style diet education group 1x/week; Other: Placebo; placebo comparator capsules

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Serum Triglycerides at 3 Months ( 3 Months-baseline) US Sample [pre-treatment and during 3 months of treatment]

2. Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) US Sample [pre-treatment and during 3 months of treatment]

   serum high density lipoprotein (HDL)

3. Change From Baseline in Serum Glucose at 3 Months (3 Months-baseline) US Sample [pretreatment and during 3 months of drug treatment]

4. 2 Hour Glucose From Glucose Tolerance Test US Sample [between baseline and 3 months of study drug treatment]

   difference between 2 hr glucose for GTT test at baseline vs after 3 months of drug treatment

Secondary Outcome Measures

1. Change in RBANS List Recognition Scores at 3 Months (3 Months-baseline) US Sample [pre-treatment and 3 months of treatment]

   The scale is Repeatable Battery for the Assessment to Neuropsychological Status (RBANS). This scale measure cognitive function in patients with schizophrenia. Range for list learning sub-score is 0 to 20 . Higher values indicate better performance. For change score (3 months -baseline) positive values indicate improved performance for this cognitive function and negative values indicate poorer performance on this cognitive function.

2. Change From Baseline in Serum Glucose at 3 Months ( 3 Months -Baseline) China Sample [pretreatment and during 3 months of drug treatment]

3. Change From Baseline in Serum Triglycerides at 3 Months (3 Months-baseline) China Sample [pretreatment and during 3 months of drug treatment]

4. 2 Hour Glucose From Glucose Tolerance Test China Sample [between baseline and 3 months of study drug treatment]

   difference between 2 hr glucose for GTT test at baseline vs after 3 months of drug treatment

5. Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) China Site [pretreatment and during 3 months of drug treatment]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients will be males or females, 18-70 yrs of age, with a diagnosis of schizophrenia or schizoaffective disorder, and currently being treated with olanzapine or clozapine.

2. Patients will have evidence of:

3. glucose levels indicating at least impaired fasting glucose: fasting glucose 100 mg/dL or 2 hr glucose tolerance test 140 mg/dL, or current treatment with oral antidiabetic drugs with history of hyperglycemia;

4. Triglyceride levels > 120 mg/dL and/or HDL levels < 40 mg/dL

Exclusion Criteria:

1. Diabetes mellitus, type 1

2. Recent diabetic ketoacidosis;

3. Patients not currently treated with oral antidiabetic drugs but fasting is glucose 140 mg/dL [WHO criteria] on repeat testing in last three months, or random blood glucose

200 mg/dL plus 2 hr glucose on GTT >200 mg/dL; (these patients may need more immediate treatment with antidiabetic drugs and it is less certain if weight-lifestyle treatment would be effective in treating such high glucose levels);

1. Patients with active liver disease with clinical abnormalities which need current treatment, or liver enzymes (Alt) 3 times upper limit for normal values in chart records in last year, or patients who are recorded as positive for hepatitis C;

2. Congestive heart failure (Class III or IV cardiac status) or history of MI in medical record (because pioglitazone can increase blood volume slightly);

3. Hematocrit greater than 10% below normal (hematocrit may be decreased 2 to 4% due to increased plasma volume);

4. Female patients on current oral contraceptives (because pioglitazone may interfere with effects of some oral contraceptives);

5. Patients taking ketoconazole,

6. Patients who have started on atorvastatin or gemfibrozil in the past 2 months or have had a dose increase in atorvastatin in the last month (since these drugs can also lower triglycerides and raise HDL, recent start of therapy with these drugs could be a confound).

7. Patients are not concomitantly treated with aripiprazole or ziprasidone.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nathan Kline Institute for Psychiatric Research	New York	New York	United States	10035

Sponsors and Collaborators

• Nathan Kline Institute for Psychiatric Research

Investigators

• Principal Investigator: Robert C Smith, MD PhD, NYU School of Medicine & Nathan Kline Institute for Psychiatric Research

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Robert C. Smith MD PhD, Research Psychiatrist, Nathan Kline Institute for Psychiatric Research
• ClinicalTrials.gov Identifier: NCT00231894
• Other Study ID Numbers: 04T-584 Stanley Foundation; 04T-584
• First Posted: Oct 4, 2005
• Last Update Posted: Dec 11, 2017
• Last Verified: Nov 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Robert C. Smith MD PhD, Research Psychiatrist, Nathan Kline Institute for Psychiatric Research: atypical antipsychotics; hyperglycemia; triglycerides; HDL; cholesterol; insulin resistance; schizophrenia; verbal memory
• Additional relevant MeSH terms: Insulin Resistance; Schizophrenia; Pioglitazone

Study Results

Participant Flow

Recruitment Details	Recruitment at 6 U.S. sites and one site in Shanghai, China

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Pioglitazone (30-45 mg/daily) plus life-style diet education group	Placebo capsules daily plus life-style diet education group
Period Title: Overall Study
STARTED	31	25
COMPLETED	30	24
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Pioglitazone	Placebo	Total
Arm/Group Description	pioglitazone	placebo	Total of all reporting groups
Overall Participants	30	24	54
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.2 (9.06)	48.5 (10.17)	47.7 (9.8)
Sex: Female, Male (Count of Participants)
Female	3 10%	3 12.5%	6 11.1%
Male	27 90%	21 87.5%	48 88.9%
Region of Enrollment (participants) [Number]
United States	25 83.3%	19 79.2%	44 81.5%
China	5 16.7%	5 20.8%	10 18.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Serum Triglycerides at 3 Months ( 3 Months-baseline) US Sample
Time Frame	pre-treatment and during 3 months of treatment

Outcome Measure Data

Analysis Population Description

Data is from participants at U.S. sites N=44, Pioglitazone =25, Placebo =19, who had values of triglycerides at baseline and three months followup. See table 2 of published paper given in reference for further details.

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	pioglitazone and life-style diet group	placebo and life-style diet group
Measure Participants	25	19
Least Squares Mean (Standard Error) [mg/dL]	-49.65 (24.01)	30.99 (26.82)

2. Primary Outcome

Title	Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) US Sample
Description	serum high density lipoprotein (HDL)
Time Frame	pre-treatment and during 3 months of treatment

Outcome Measure Data

Analysis Population Description

Data is from participants at U.S. sites N=44, Pioglitazone =25, Placebo =19, who had values of HDL at baseline and three months followup. See table 2 of published paper and its supplementary data paper cited in reference for further details.

Arm/Group Title	Piogltiazone	Placebo
Arm/Group Description	pioglitazone and life-style diet group Pioglitazone: pioglitazone 15-45 mg/day Life style diet group: life style diet education group 1x/week	placebo and life-style diet group Life style diet group: life style diet education group 1x/week placebo: placebo comparator
Measure Participants	25	19
Least Squares Mean (Standard Error) [mg/dL]	4.62 (1.77)	-2.59 (2.11)

3. Primary Outcome

Title	Change From Baseline in Serum Glucose at 3 Months (3 Months-baseline) US Sample
Time Frame	pretreatment and during 3 months of drug treatment

Outcome Measure Data

Analysis Population Description

Data is from participants at U.S. sites N=44, Pioglitazone =25, Placebo =19, who had values of serum glucose at baseline and three months follow-up. See table 2 of published paper and its supplementary data paper cited in reference for further details.

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	pioglitazone	placebo
Measure Participants	25	19
Least Squares Mean (Standard Error) [mg/dL]	0.02 (8.14)	24.20 (8.63)

4. Primary Outcome

Title	2 Hour Glucose From Glucose Tolerance Test US Sample
Description	difference between 2 hr glucose for GTT test at baseline vs after 3 months of drug treatment
Time Frame	between baseline and 3 months of study drug treatment

Outcome Measure Data

Analysis Population Description

Data is from participants at U.S. sites N=44, Pioglitazone =25, Placebo =19, who had values of serum glucose at 2-hour point in glucose tolerance test at baseline and three months follow-up. See table 2 of published paper and its supplementary data paper cited in reference for further details.

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	pioglitazone and life-style diet group	placebo and life-style diet group
Measure Participants	25	19
Least Squares Mean (Standard Error) [mg/dL]	-24.19 (17.03)	15.19 (17.75)

5. Secondary Outcome

Title	Change in RBANS List Recognition Scores at 3 Months (3 Months-baseline) US Sample
Description	The scale is Repeatable Battery for the Assessment to Neuropsychological Status (RBANS). This scale measure cognitive function in patients with schizophrenia. Range for list learning sub-score is 0 to 20 . Higher values indicate better performance. For change score (3 months -baseline) positive values indicate improved performance for this cognitive function and negative values indicate poorer performance on this cognitive function.
Time Frame	pre-treatment and 3 months of treatment

Outcome Measure Data

Analysis Population Description

Data is from participants at U.S. sites N=43, Pioglitazone =25, Placebo =18, who had scores of RBANS List learning at 2-hour point at baseline and three months follow-up. See table 2 of published paper and its supplementary data paper cited in reference for further details.

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	pioglitazone	placebo
Measure Participants	25	19
Least Squares Mean (Standard Error) [Units on RBANS scale]	0.27 (0.41)	-1.11 (0.44)

6. Secondary Outcome

Title	Change From Baseline in Serum Glucose at 3 Months ( 3 Months -Baseline) China Sample
Time Frame	pretreatment and during 3 months of drug treatment

Outcome Measure Data

Analysis Population Description

Data is from participants at China site N=10, Pioglitazone =5, Placebo =5, who had values of fasting glucose at baseline and three months follow-up. See published paper and its supplementary data paper cited in reference for further details.

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Pioglitazone (30-45 mg/daily) plus life-style diet education group	Placebo capsules daily plus life-style diet education group
Measure Participants	5	5
Least Squares Mean (Standard Error) [mg/dL]	-13.33 (11.08)	-11.5 (3.44)

7. Secondary Outcome

Title	Change From Baseline in Serum Triglycerides at 3 Months (3 Months-baseline) China Sample
Time Frame	pretreatment and during 3 months of drug treatment

Outcome Measure Data

Analysis Population Description

Data is from participants at China site N=10, Pioglitazone =5, Placebo =5, who had values of triglycerides at baseline and three months followup. See published paper and its supplementary data paper cited in reference for further details.

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Pioglitazone (30-45 mg/daily) plus life-style diet education group	Placebo capsules daily plus life-style diet education group
Measure Participants	5	5
Least Squares Mean (Standard Error) [mg/dL]	32.56 (24.76)	-79.12 (40.72)

8. Secondary Outcome

Title	2 Hour Glucose From Glucose Tolerance Test China Sample
Description	difference between 2 hr glucose for GTT test at baseline vs after 3 months of drug treatment
Time Frame	between baseline and 3 months of study drug treatment

Outcome Measure Data

Analysis Population Description

Data is from participants at china site N=10, Pioglitazone =5, Placebo =5, who had values of serum glucose at 2-hour point in glucose tolerance test at baseline and three months follow-up. See published paper and its supplementary data paper cited in reference for further details.

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Pioglitazone (30-45 mg/daily) plus life-style diet education group	Placebo capsules daily plus life-style diet education group
Measure Participants	5	5
Least Squares Mean (Standard Error) [mg/dL]	-6.82 (21.28)	-40.72 (21.28)

9. Secondary Outcome

Title	Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) China Site
Time Frame	pretreatment and during 3 months of drug treatment

Outcome Measure Data

Analysis Population Description

Data is from participants at china. site N=10, Pioglitazone =5, Placebo =5, who had values of HDL at baseline and three months followup. See of published paper and its supplementary data paper cited in reference for further details

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Pioglitazone (30-45 mg/daily) plus life-style diet education group	Placebo capsules daily plus life-style diet education group
Measure Participants	5	5
Least Squares Mean (Standard Error) [mg/dL]	6.52 (1.14)	7.72 (3.37)

Adverse Events

Arm/Group Title	Pioglitazone		Placebo
Arm/Group Description	pioglitazone		placebo
All Cause Mortality
	Pioglitazone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pioglitazone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Pioglitazone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/31 (3.2%)		2/25 (8%)
Endocrine disorders
glucose increase	0/31 (0%)	0	1/25 (4%)	1
glucose increase	0/31 (0%)	0	1/25 (4%)	1
Musculoskeletal and connective tissue disorders
high CPK	1/31 (3.2%)	1	0/25 (0%)	0

Limitations/Caveats

Sufficient RBANS data at baseline and 3 months followup for China sample was not available for analysis. Subjects failed to complete scales or complete scales with sufficient data.

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.