PPAR: Pharmacogenomics of Thiazolidinediones
Study Details
Study Description
Brief Summary
The purpose of this study is to determine predictors of response to pioglitazone, an anti-diabetic medication. The investigators know from randomized clinical trials that some 30% of patients do not respond to this type of medication. There is presently no way to identify this group of patients leading to unnecessary drug exposure and medication costs.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| N/A |
Detailed Description
In phase I, subjects who are eligible based on height and weight and general health information will sign informed consent. In phase II, subjects will be screened to ensure that they fit the inclusion/exclusion criteria, including an oral glucose tolerance test. Other blood tests will be performed to check complete blood count, lipids, liver functions and electrolytes.
Qualifying volunteers will enter phase III, which will consist of outpatient radioimaging and body composition, metabolic testing (intravenous glucose tolerance test), and tissue biopsies. Blood will also be drawn for genetic testing and for microarray studies of leukocytes. Written medication information and instructions for pioglitazone, discharge instructions and satisfaction surveys following the tissue biopsy procedures will be given to subjects during the study. During phase IV, subjects will begin pioglitazone therapy. Every 4 weeks throughout the drug intervention, glycemic control, lipoprotein profile, and weight will be monitored. After 12 weeks of pioglitazone therapy, the X-ray and magnetic resonance (MR) measurements of body composition, the biopsies and the metabolic tests performed during phase III will be repeated (phase V), and blood will be drawn for microarray studies of leukocytes.
Thereafter, subjects will have the option to be enrolled in a 10 week, behavioral weight loss program (phase VI). Following the 10-week weight loss program, a few outcome measurements will be repeated (phase VII).
Throughout the study, Women of Child Bearing Potential (WCBP) will have human human chorionic gonadotrophin (HCG) urine pregnancy tests. Pregnancy tests will only be performed on Women of childbearing potential, meaning women who are pre-menopausal and who have not had surgical sterilization. Women who have not had a hysterectomy or tubal ligation at least six months prior to signing informed consent or have been postmenopausal for at least one year, will be instructed to practice one of the following methods of birth control throughout the study: oral, transdermal, or implantable hormonal contraceptives, intrauterine device, diaphragm plus spermicide, condom plus spermicide, or abstinence. Pioglitazone may reduce the effectiveness of some hormonal types of contraceptives. Women using hormonal methods of birth control will be advised to use a barrier method as well. Female subjects are informed to notify the investigators immediately if they think they might have become pregnant during the study.
Participants who are eligible have 10 visits over an approximate 15-week period. Participants can choose to participate in an optional weight management program for an additional 10 weeks after treatment and before their final visit.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Pioglitazone (Actos) Participants will have metabolism studies to consist of outpatient X-ray and MR measurements of bone density and body composition, metabolic testing (intravenous glucose tolerance test), and muscle and adipose tissue biopsies. Blood will also be drawn for genetic testing and for microarray studies of leukocytes. Upon completion of the above studies, the participant will begin pioglitazone therapy. Every 4 weeks throughout the drug intervention, glycemic control, lipoprotein profile, and weight will be monitored. After 12 weeks of pioglitazone therapy, the X-ray and MR measurements of body composition, the biopsies, microarray studies for leukocytes and the metabolic tests will be repeated. |
Drug: Pioglitazone
30 mg tablet once daily for 4 weeks, then increased to 45 mg once daily for an additional 8 weeks. Total dosage period is 12 weeks.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change in Insulin Resistance [12 weeks]
Change in insulin resistance was calculated as change (end of treatment minus baseline) in HOMA-IR index (glucose (mg/dL) x insulin (μU/mL)/405)
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age 35-64
-
BMI: ≥ 25 and ≤ 40
Exclusion Criteria:
-
Pregnancy as determined by urine pregnancy test Breast-feeding, or planning to become pregnant during the study
-
Physical dimensions exceeding the limits of any equipment used
-
Stage III or greater congestive heart failure
-
Symptomatic peripheral vascular disease
-
Stroke
-
Severe hypertension (>170/100 mmHg)
-
Anemia (Hgb and Hct < normal reference range)
-
Receiving treatment for thyroid, pituitary, kidney or liver disease (except controlled thyroid hormone replacement)
-
History of diabetes (as told by doctor, or taking diabetic medications Fasting glucose value diagnostic for diabetes 2-h oral glucose tolerance test diagnostic for diabetes
-
Rheumatoid arthritis
-
History of wrist, hip or leg fracture after the age of 45
-
History of kidney stones
-
Medications that the investigator judges will make interpretation of the results difficult or increase the risk of participation (e.g. anticoagulants)
-
Any disease or condition that the investigator judges will affect bone metabolism or make interpretation of the results difficult or increase the risk of participation (e.g. anemia, cardiac decompensation, intolerance to pioglitazone, lidocaine, or other agents used)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Maryland School of Medicine | Baltimore | Maryland | United States | 21201 |
Sponsors and Collaborators
- University of Maryland, Baltimore
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
- Principal Investigator: Dawei Gong, MD, PhD, University of Maryland, Baltimore
Study Documents (Full-Text)
More Information
Publications
None provided.- HP-00043497
- R01DK074828
Study Results
Participant Flow
| Recruitment Details | Recruitment was through advertisements in local publications and bulletin boards in the University of Maryland and Baltimore area. Additional recruitment among the Old Order Amish was through the University of Maryland Amish Research Clinic in Lancaster County, Pennsylvania. |
|---|---|
| Pre-assignment Detail | Screening assessments done following informed consent include anthropometry, screening bloodwork, medical history and baseline study assessments. Participants may be excluded prior to start of study drug and/or baseline assessments if they do not meet eligibility criteria. |
| Arm/Group Title | Pioglitazone (Actos) |
|---|---|
| Arm/Group Description | Participants will have metabolism studies to consist of outpatient X-ray and magnetic resonance (MR) measurements of bone density and body composition, metabolic testing (intravenous glucose tolerance test), and muscle and adipose tissue biopsies. Blood will also be drawn for genetic testing and for microarray studies of leukocytes. Upon completion of the above studies, the participant will begin pioglitazone therapy. Every 4 weeks throughout the drug intervention, glycemic control, lipoprotein profile, and weight will be monitored. After 12 weeks of pioglitazone therapy, the X-ray and MR measurements of body composition, the biopsies, microarray studies for leukocytes and the metabolic tests will be repeated. Pioglitazone: 30 mg tablet once daily for 4 weeks, then increased to 45 mg once daily for an additional 8 weeks. Total dosage period is 12 weeks. |
| Period Title: Screening | |
| STARTED | 114 |
| COMPLETED | 81 |
| NOT COMPLETED | 33 |
| Period Title: Screening | |
| STARTED | 81 |
| COMPLETED | 66 |
| NOT COMPLETED | 15 |
| Period Title: Screening | |
| STARTED | 66 |
| COMPLETED | 62 |
| NOT COMPLETED | 4 |
Baseline Characteristics
| Arm/Group Title | Pioglitazone (Actos) |
|---|---|
| Arm/Group Description | Participants will have metabolism studies to consist of outpatient X-ray and MR measurements of bone density and body composition, metabolic testing (intravenous glucose tolerance test), and muscle and adipose tissue biopsies. Blood will also be drawn for genetic testing and for microarray studies of leukocytes. Upon completion of the above studies, the participant will begin pioglitazone therapy. Every 4 weeks throughout the drug intervention, glycemic control, lipoprotein profile, and weight will be monitored. After 12 weeks of pioglitazone therapy, the X-ray and MR measurements of body composition, the biopsies, microarray studies for leukocytes and the metabolic tests will be repeated. Pioglitazone: 30 mg tablet once daily for 4 weeks, then increased to 45 mg once daily for an additional 8 weeks. Total dosage period is 12 weeks. |
| Overall Participants | 114 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
114
100%
|
| >=65 years |
0
0%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
64
56.1%
|
| Male |
50
43.9%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
8
7%
|
| White |
106
93%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
| Insulin resistance (HOMA-IR index is unitless by definition) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [HOMA-IR index is unitless by definition] |
2.74
(1.82)
|
Outcome Measures
| Title | Change in Insulin Resistance |
|---|---|
| Description | Change in insulin resistance was calculated as change (end of treatment minus baseline) in HOMA-IR index (glucose (mg/dL) x insulin (μU/mL)/405) |
| Time Frame | 12 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Included subjects are those who had complete data, including HOMA-IR index at both baseline and after treatment. |
| Arm/Group Title | Pioglitazone (Actos) |
|---|---|
| Arm/Group Description | The study is a one-arm design. All participants will receive Pioglitazone: 30 mg tablet once daily for 4 weeks, then increased to 45 mg once daily for an additional 8 weeks. Total dosage period is 12 weeks. |
| Measure Participants | 59 |
| Mean (Standard Deviation) [HOMA-IR index is unitless by definition] |
-0.83
(1.23)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pioglitazone (Actos) |
|---|---|---|
| Comments | After the change (end-of-treatment minus baseline) in HOMA-IR index had been calculated for each subject, the change (end-of-treatment minus baseline) in expression of each of approximately 45,000 transcripts contained in a human gene array was calculated. A Pearson correlation quotient was calculated for the correlation between change in gene expression and change in HOMA-IR index, with the purpose of identifying the genes whose expression changed in concert with changes in HOMA-IR index. | |
| Type of Statistical Test | Other | |
| Comments | The genes with the 20 lowest P-values were selected for further analysis | |
| Statistical Test of Hypothesis | p-Value | <0.000001 |
| Comments | The genes with the 20 lowest p-values were selected for further analysis | |
| Method | The top 20 genes were selected | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Pearson correlation p-value |
| Estimated Value | 0.000001 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | The genes with the 20 lowest P-values were selected for further analysis | |
Adverse Events
| Time Frame | 12 weeks (treatment phase) + 4 weeks (follow-up) = 16 weeks | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Pioglitazone (Actos) | |
| Arm/Group Description | Participants will have metabolism studies to consist of outpatient X-ray and MR measurements of bone density and body composition, metabolic testing (intravenous glucose tolerance test), and muscle and adipose tissue biopsies. Blood will also be drawn for genetic testing and for microarray studies of leukocytes. Upon completion of the above studies, the participant will begin pioglitazone therapy. Every 4 weeks throughout the drug intervention, glycemic control, lipoprotein profile, and weight will be monitored. After 12 weeks of pioglitazone therapy, the X-ray and MR measurements of body composition, the biopsies, microarray studies for leukocytes and the metabolic tests will be repeated. Pioglitazone: 30 mg tablet once daily for 4 weeks, then increased to 45 mg once daily for an additional 8 weeks. Total dosage period is 12 weeks. | |
All Cause Mortality |
||
| Pioglitazone (Actos) | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/114 (0%) | |
Serious Adverse Events |
||
| Pioglitazone (Actos) | ||
| Affected / at Risk (%) | # Events | |
| Total | 2/114 (1.8%) | |
| Cardiac disorders | ||
| Vasovagal response | 1/114 (0.9%) | 1 |
| Endocrine disorders | ||
| hypoglycemia | 1/114 (0.9%) | 2 |
Other (Not Including Serious) Adverse Events |
||
| Pioglitazone (Actos) | ||
| Affected / at Risk (%) | # Events | |
| Total | 15/114 (13.2%) | |
| Endocrine disorders | ||
| Hypoglycemia during intravenous glucose tolerance test | 8/114 (7%) | 9 |
| Skin and subcutaneous tissue disorders | ||
| Hematoma at abdominal fat biopsy site | 7/114 (6.1%) | 7 |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Soren Snitker, MD, PhD |
|---|---|
| Organization | University of Maryland School of Medicine |
| Phone | 4107061511 |
| ssnitker@som.umaryland.edu |
- HP-00043497
- R01DK074828