Effects of Pioglitazone on Insulin and Glucose Metabolism in Women With Polycystic Ovary Syndrome (PCOS)

• Sponsor: Virginia Commonwealth University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00868140
• Collaborator: (none)
• Enrollment: 51
• Locations: 2
• Arms: 2
• Duration (Months): 29.9
• Patients Per Site: 25.5
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

Our hypothesis is that hyperinsulinemia increases the renal clearance of D-chiro-inositol (DCI) in women with polycystic ovary syndrome (PCOS) and that this leads to a reduction in circulating insulin-stimulated D-chiro-inositol-containing inositol phosphoglycan (DCI-IPG) release. To assess the effects of a chronic reduction in circulating insulin on DCI metabolism, we propose to reduce circulating insulin in obese women with PCOS by improving insulin sensitivity with the drug pioglitazone. Pioglitazone is a thiazolidinedione that improves peripheral insulin sensitivity, presumably by activation of the peroxisome proliferator-activated receptor gamma (PPARγ) receptor. Administration of pioglitazone to women with PCOS has been shown to improve insulin sensitivity, reduce insulin secretion, and decrease both fasting and post-prandial serum insulin concentrations.

Condition or Disease	Intervention/Treatment	Phase
Polycystic Ovary Syndrome	Drug: pioglitazone; Drug: Placebo	N/A

Detailed Description

This protocol focuses on the hypothesis that a deficiency in a putative inositolphosphoglycan (IPG) mediator of insulin action, namely a D-chiro-inositol-containing IPG (DCI-IPG), contributes to the insulin resistance of some women with PCOS. Our interest in this area stems directly from our previous studies, which demonstrated that administration of the precursor, D-chiro-inositol (DCI), to both obese and lean women with PCOS improved glucose intolerance while reducing circulating insulin, and simultaneously improved ovulatory function and decreased serum androgens. These findings were recently confirmed in a large-scale study by an independent group. The findings of these three studies suggested that administration of DCI improved insulin sensitivity in PCOS, which then resulted in an improved hormonal and metabolic milieu.

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Health Services Research
• Official Title: Determination if Indirectly Reducing Circulating Insulin by Improving Insulin Sensitivity With Pioglitazone Reduces Renal Clearance of D-chiro-inositol (DCI) Increases the Circulating Concentration of DCI and Enhances Insulin-stimulated Release of the D-chiro-inositol-containing Inositolphosphoglycan (DCI-IPG) Mediator in Obese Women With PCOS
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1/Pioglitazone Pioglitazone in pill form at 45mg twice per day for 6 months	Drug: pioglitazone; pioglitazone 45 mg
Placebo Comparator: 2/Placebo Placebo control to arm 1 in pill form identical to treatment form also twice per day for 6 months	Drug: Placebo; placebo daily

Outcome Measures

Primary Outcome Measures

1. AUC DCI-IPG (%/Min) [Baseline]

   Change in the Area Under the Curve DCI-IPG measurements in blood samples taken at 15 minute intervals during the 2 hour OGTT before treatment with pioglitazone or placebo. Values reported as a percentage of bioactivity measured at time 0. Negative values indicate a decrease relative to the time 0 measurement.

2. AUC DCI-IPG (%/Min) [6 months]

   Change in the Area Under the Curve DCI-IPG measurements in blood samples taken at 15 minute intervals during the 2 hour OGTT following 6 months of treatment with pioglitazone or placebo. Values reported as a percentage of bioactivity measured at time 0. Negative values indicate a decrease relative to the time 0 measurement.

3. Fasting Serum Insulin [baseline]

   Fasting serum insulin (uIU.min/ml) measured at 0, 60 and 120 minutes of a 2 hour OGTT before treatment with either pioglitazone or placebo

4. Fasting Serum Insulin (uIU/ml) [6 months]

   Fasting serum insulin (uIU.min/ml) measured at 0, 60 and 120 minutes of a 2 hour OGTT following 6 months treatment with either pioglitazone or placebo

Secondary Outcome Measures

1. Matsuda Index [Baseline]

   Whole body insulin sensitivity as determined by the Matsuda Index as calculated using the following formula: 10,000 divided by the square root of (FPI* FPG) * (xGPC* xIPC) Where FPI is fasting plasma insulin expressed as uU/ml, FPG is fasting plasma glucose expressed as mg/dL, xGPC is mean plasma glucose concentration after the load and xIPC is the mean insulin concentration after the load. Values calculated on samples taken at 0, 30, 60, 90 and 120 minutes of a 2 hour OGTT. Values typically range from 0 to 12 units with higher scores indicating better insulin sensitivity. A value of 2.5 or less is indicative of insulin resistance.

2. Matsuda Index [6 months]

   Whole body insulin sensitivity as determined by the Matsuda Index

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Obese (Body Mass Index or BMI greater than or equal to 30 kg/m2) women with PCOS between 18-40 years of age:

• oligomenorrhea (less than 8 menstrual periods annually)

• biochemical hyperandrogenemia (elevated total or free testosterone)

• normal thyroid function tests and serum prolactin; AND

• exclusion of 21a-hydroxylase deficiency by a fasting 17a-hydroxyprogesterone less than 200 ng/dl.51,

1. acceptable health on the basis of interview, medical history, physical examination, and laboratory tests (Complete Blood Chemistry or CBC, Comprehensive Metabolic Panel denoted SMA20, urinalysis, negative pregnancy test).

2. Signed, witnessed informed consent.

3. Ability to comply with study requirements.

Exclusion Criteria:

1. Diabetes mellitus by fasting glucose or oral glucose tolerance test (OGTT), or clinically significant pulmonary, cardiac, renal, hepatic, neurologic, psychiatric, infectious, neoplastic and malignant disease (other than non-melanoma skin cancer).

2. Current use of oral contraceptives.

3. Documented or suspected recent (within one year) history of drug abuse or alcoholism.

4. Ingestion of any investigational drug within two months prior to study onset.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Virginia Commonwealth University General Clinical Research Center	Richmond	Virginia	United States	23298
2	Hospital de Clinical Caracas	Caracas		Venezuela	1071

Sponsors and Collaborators

• Virginia Commonwealth University

Investigators

• Principal Investigator: John E. Nestler, M.D., Virginia Commonwealth University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT00868140
• Other Study ID Numbers: VCUIRB4480; GCRC0824
• First Posted: Mar 24, 2009
• Last Update Posted: Jun 10, 2016
• Last Verified: May 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Polycystic Ovary Syndrome; Syndrome; Pioglitazone

Study Results

Participant Flow

Arm/Group Title	1/Pioglitazaone Treated	2/Placebo
Arm/Group Description	Pioglitazone treated subjects pioglitazone: pioglitazone 45 mg	Placebo control to arm 1 Placebo: placebo daily
Period Title: Overall Study
STARTED	26	25
COMPLETED	26	25
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	1/Pioglitazaone Treated	2/Placebo	Total
Arm/Group Description	Pioglitazone treated subjects pioglitazone: pioglitazone 45 mg	Placebo control to arm 1 Placebo: placebo daily	Total of all reporting groups
Overall Participants	16	16	32
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	16 100%	16 100%	32 100%
>=65 years	0 0%	0 0%	0 0%
Sex/Gender, Customized (participants) [Number]
Females	16 100%	16 100%	32 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 62.5%	9 56.3%	19 59.4%
Not Hispanic or Latino	6 37.5%	7 43.8%	13 40.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 6.3%	1 6.3%	2 6.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 6.3%	1 6.3%	2 6.3%
White	14 87.5%	14 87.5%	28 87.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Venezuela	16 100%	16 100%	32 100%

Outcome Measures

1. Primary Outcome

Title	AUC DCI-IPG (%/Min)
Description	Change in the Area Under the Curve DCI-IPG measurements in blood samples taken at 15 minute intervals during the 2 hour OGTT before treatment with pioglitazone or placebo. Values reported as a percentage of bioactivity measured at time 0. Negative values indicate a decrease relative to the time 0 measurement.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1/Pioglitazaone Treated	2/Placebo
Arm/Group Description	Pioglitazone pioglitazone: pioglitazone 45 mg	control to arm 1 Placebo: placebo daily
Measure Participants	16	16
Mean (Standard Error) [% bioactivity at time 0 of OGTT]	13162.06 (1240.6)	14054.17 (1373.1)

2. Secondary Outcome

Title	Matsuda Index
Description	Whole body insulin sensitivity as determined by the Matsuda Index as calculated using the following formula: 10,000 divided by the square root of (FPI* FPG) * (xGPC* xIPC) Where FPI is fasting plasma insulin expressed as uU/ml, FPG is fasting plasma glucose expressed as mg/dL, xGPC is mean plasma glucose concentration after the load and xIPC is the mean insulin concentration after the load. Values calculated on samples taken at 0, 30, 60, 90 and 120 minutes of a 2 hour OGTT. Values typically range from 0 to 12 units with higher scores indicating better insulin sensitivity. A value of 2.5 or less is indicative of insulin resistance.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1/Pioglitazaone Treated	2/Placebo
Arm/Group Description	Pioglitazone pioglitazone: pioglitazone 45 mg	control to arm 1 Placebo: placebo daily
Measure Participants	16	16
Mean (Standard Error) [units on a scale]	3.36 (0.18)	3.05 (0.15)

3. Primary Outcome

Title	AUC DCI-IPG (%/Min)
Description	Change in the Area Under the Curve DCI-IPG measurements in blood samples taken at 15 minute intervals during the 2 hour OGTT following 6 months of treatment with pioglitazone or placebo. Values reported as a percentage of bioactivity measured at time 0. Negative values indicate a decrease relative to the time 0 measurement.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1/Pioglitazaone Treated	2/Placebo
Arm/Group Description	Pioglitazone pioglitazone: pioglitazone 45 mg	control to arm 1 Placebo: placebo daily
Measure Participants	16	16
Mean (Standard Error) [% bioactivity at time 0 of OGTT]	-412.22 (1295.7)	-699.45 (1890.71)

4. Primary Outcome

Title	Fasting Serum Insulin
Description	Fasting serum insulin (uIU.min/ml) measured at 0, 60 and 120 minutes of a 2 hour OGTT before treatment with either pioglitazone or placebo
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1/Pioglitazaone Treated	2/Placebo
Arm/Group Description	Pioglitazone pioglitazone: pioglitazone 45 mg	control to arm 1 Placebo: placebo daily
Measure Participants	16	16
Mean (Standard Error) [uIU.min/ml]	15.04 (1.23)	15.91 (1.32)

5. Primary Outcome

Title	Fasting Serum Insulin (uIU/ml)
Description	Fasting serum insulin (uIU.min/ml) measured at 0, 60 and 120 minutes of a 2 hour OGTT following 6 months treatment with either pioglitazone or placebo
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1/Pioglitazaone Treated	2/Placebo
Arm/Group Description	Pioglitazone treated subjects pioglitazone: pioglitazone 45 mg	Placebo control to arm 1 Placebo: placebo daily
Measure Participants	16	16
Mean (Standard Error) [uIU.min/ml]	-8.69 (1.23)	-0.24 (1.50)

6. Secondary Outcome

Title	Matsuda Index
Description	Whole body insulin sensitivity as determined by the Matsuda Index
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1/Pioglitazaone Treated	2/Placebo
Arm/Group Description	Pioglitazone pioglitazone: pioglitazone 45 mg	control to arm 1 Placebo: placebo daily
Measure Participants	16	16
Mean (Standard Error) [units on a scale]	4.29 (0.36)	0.29 (0.17)

Adverse Events

Time Frame	6 months
Arm/Group Title	1/Pioglitazone		2/Placebo
Arm/Group Description	Pioglitazone in pill form at 45mg twice per day for 6 months pioglitazone: pioglitazone 45 mg		Placebo control to arm 1 in pill form identical to treatment form also twice per day for 6 months Placebo: placebo daily
All Cause Mortality
	1/Pioglitazone		2/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	1/Pioglitazone		2/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	1/Pioglitazone		2/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/26 (11.5%)		0/25 (0%)
General disorders
Edema	3/26 (11.5%)	3	0/25 (0%)	0

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.