Efficacy Study of Pioglitazone Compared to Glimepiride on Coronary Atherosclerotic Disease Progression in Subjects With Type 2 Diabetes Mellitus (PERISCOPE)
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| ClinicalTrials.gov Identifier: NCT00225277 |
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Recruitment Status :
Completed
First Posted : September 23, 2005
Results First Posted : June 10, 2009
Last Update Posted : February 28, 2012
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Diabetes Mellitus | Drug: Pioglitazone Drug: Glimepiride | Phase 3 |
Diabetes is a chronic disease with multiple metabolic defects that result in hyperglycemia arising from inadequate insulin activity. Type 2 diabetes is usually the result of a progression from reduced sensitivity of hepatic and peripheral tissue cells to circulating insulin (ie, insulin resistance) to a progressive inability of the body to produce adequate insulin to overcome insulin resistance (ie, insulin deficiency due to beta-cell insufficiency) resulting in impaired glucose tolerance and ultimately overt diabetes. In the United States, an estimated 21 million people have diabetes, with type 2 diabetes occurring in approximately 90% to 95% of cases. The goal of treating type 2 diabetes is to control blood glucose and thereby prevent long-term complications. Adequate glycemic control is paramount in attempting to avert chronic complications, including blindness; renal dysfunction resulting in dialysis or renal transplantation; neuropathy; non-traumatic amputations; and macrovascular complications, including myocardial ischemia and myocardial infarction, stroke, and peripheral arterial disease. Intensive glucose management in the early stages of diabetes may help forestall such complications.
Therapeutic agents have been developed to address each of the major functional metabolic defects associated with type 2 diabetes: decreased beta-cell function, elevated hepatic glucose output, and insulin resistance. Thiazolidinediones increase glucose utilization, decrease gluconeogenesis, and increase glucose disposal by binding to nuclear receptors known as peroxisome proliferator-activated receptors. Thiazolidinediones reduce insulin resistance by enhancing insulin sensitivity in muscle cells, adipose tissue, and hepatic cells (inhibiting hepatic gluconeogenesis), with no direct impact on insulin secretion. Thus, thiazolidinediones improve glycemic control and result in reduced levels of circulating insulin without predisposing patients to hypoglycemia. Peroxisome proliferator-activated receptors are found in tissues important for insulin action, such as adipose tissue, skeletal muscle, and the liver. The greatest concentration of peroxisome proliferator-activated receptors-gamma receptors is in adipose tissue.
This study was designed to compare the effects of pioglitazone compared to glimepiride on progression of atherosclerotic disease, as measured by intravascular ultrasound.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 547 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | A Double-Blind, Randomized, Comparator-Controlled Study In Subjects With Type 2 Diabetes Mellitus Comparing the Effects of Pioglitazone HCl Versus Glimepiride on the Rate of Progression of Coronary Atherosclerotic Disease as Measured by Intravascular Ultrasound |
| Study Start Date : | July 2003 |
| Actual Primary Completion Date : | October 2007 |
| Actual Study Completion Date : | October 2007 |
| Arm | Intervention/treatment |
|---|---|
| Experimental: Pioglitazone QD |
Drug: Pioglitazone
Up to 45 mg pioglitazone (optimized for glucose control), tablets, orally, once daily for up to 72 weeks.
Other Names:
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| Active Comparator: Glimepiride QD |
Drug: Glimepiride
Up to 4 mg of glimepiride (optimized for glucose control), tablets, orally, once daily for up to 72 weeks. |
- Nominal Change From Baseline in Percent Atheroma Volume [ Time Frame: Baseline and Final Visit (up to 72 weeks) ]The nominal change from baseline in percent atheroma volume for all slices of anatomically comparable segments of the target coronary artery. Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued.
- Nominal Change From Baseline in Normalized Total Atheroma Volume [ Time Frame: Baseline and Final Visit (up to 72 weeks) ]The nominal change in normalized total atheroma volume as measured by the average of plaque areas for all slices of anatomically comparable segments of the target coronary artery multiplied by the mean number of matched slices in the population. Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued.
- Number of Subjects Experiencing Any of the Composite Endpoint A Cardiovascular Events [ Time Frame: Up to 72 weeks ]Due to low event rates, number of subjects experiencing any of the composite endpoint A cardiovascular events is being reported instead of time to first occurrence. Endpoint A conditions listed in Limitations and Caveats section.
- Number of Subjects Experiencing Any of the Composite Endpoint B Cardiovascular Events [ Time Frame: Up to 72 weeks ]Due to low event rates, number of subjects experiencing any of the composite endpoint B cardiovascular events is being reported instead of time to first occurrence. Endpoint B conditions listed in Limitations and Caveats section.
- Number of Subjects Experiencing Any of the Composite Endpoint C Cardiovascular Events [ Time Frame: Up to 72 weeks ]Due to low event rates, number of subjects experiencing any of the composite endpoint C cardiovascular events is being reported instead of time to first occurrence. Endpoint C conditions listed in Limitations and Caveats section.
- Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee [ Time Frame: Up to 72 weeks ]The incidence of cardiovascular events and composite endpoints occurring within 30 days of last dose as adjudicated by the Clinical Endpoint Committee. Abbreviations: PCI: Percutaneous Coronary Intervention; CABG: Coronary Artery Bypass Graft; CHF: Congestive Heart Failure.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 35 Years to 85 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Females of childbearing potential who were sexually active agreed to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.
- Had a diagnosis of type 2 diabetes mellitus
- Have received appropriate counseling on lifestyle modification for type 2 diabetes, including diet and exercise.
- naïve to or was not currently taking antidiabetic therapy, or were currently treated with monotherapy or combination therapy.
- Had a glycosylated hemoglobin level greater than or equal to 6.0% and less than 9% at screening if taking antidiabetic medication or greater than or equal to 6.5% and less than 10% at screening if naive to or not taking antidiabetic medication.
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Angiographic criteria:
- Entire Coronary Circulation: must have angiographic evidence of coronary heart disease as defined by at least 1 lesion in a native coronary artery that has greater than or equal to 20% reduction in lumen diameter by angiographic visual estimation.
- Left Main Coronary Artery: must not have greater than 50% reduction in lumen diameter by visual angiographic estimation.
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Target Coronary Artery:
- The target vessel, which includes the main artery and all of its side branches, had not undergone prior percutaneous coronary intervention or coronary artery bypass graft surgery.
- The target vessel, which includes the main artery and all of its side branches, was not currently a candidate for intervention or a likely candidate for intervention over the next 72 weeks.
- The target vessel was not a bypass graft.
- The target vessel was not infarct related.
- Had previous coronary artery bypass surgery at least six weeks prior to the qualifying intravascular ultrasound are eligible provided they are stable and meet all other entry criteria.
- Had an intravascular ultrasound tape deemed to be of acceptable intravascular ultrasound image quality and demonstrated adherence to the intravascular ultrasound interrogation protocol, as determined by the intravascular ultrasound Core Laboratory™ assessment.
Exclusion Criteria:
- Had type I diabetes mellitus.
- Had participated in another investigational study, or participated in an investigational study 30 days prior to the start of this study, or who were scheduled to participate in an investigational study during the time frame of this study.
- Male subjects who had a serum creatinine level greater than or equal to 2.0 mg/dL (greater than or equal to 177 µmol/L) (greater than or equal to 1.5 mg/dL; [greater than or equal to 133 µmol /L] if taking metformin) and female subjects who have serum creatinine greater than or equal to 1.8 mg/dL [greater than or equal to 159 µmol /L] (greater than or equal to 1.4 mg/dL [greater than or equal to 124 µmol /L] if taking metformin).
- Had unexplained microscopic hematuria greater than +1, confirmed by repeat testing.
- Had a history of drug abuse or a history of alcohol abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per day) within the past 2 years.
- Had clinical cardiac failure as defined by New York Heart Association class III or IV, or known left ventricular dysfunction measured as left ventricular ejection fraction less than 40%, or by current use of diuretics or angiotensin converting enzyme inhibitors for treatment of heart failure.
- Had an alanine transaminase level of greater than 2.5 times the upper limit of normal active liver disease, or jaundice.
- Had a body mass index greater than 48 kg/m2 as calculated by weight (kg)/height (m2) or weight (pounds)/height (inches) 2 x 703.
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Was required to take or intended to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may have interfered with evaluation of the study medication, including:
- Chronically used oral glucocorticoids (eg, prednisone, cortisone, hydrocortisone, dexamethasone)
- Niacin greater than100 mg a day, including niacin-containing products such as Advicor®
- Chronically used steroid-joint injections
- Thiazolidinediones
- Sulfonylureas
- Metformin/sulfonylurea combination
- Other oral antidiabetic medications (eg, nateglinide [Starlix®], acarbose [Precose®]) with the exception of metformin
- Had known or suspected malignancy or recurrence of malignancy within the past 5 years, with the exception of basal cell carcinoma and Stage 1 squamous cell carcinoma of the skin.
- Had any disease where, in the opinion of the investigator (or designee), survival is expected to be less than 72 weeks.
- Clinical status was unstable (ie, requiring vasopressors or intravenous inotropes, intra-aortic balloon pump, hypotension [systolic blood pressure less than 90 mm Hg]).
- Prior to the screening visit, was scheduled for a staged cardiac intervention (percutaneous coronary intervention), peripheral vascular intervention, or coronary artery bypass graft surgery following the screening angiography.
- In the opinion of the investigator (or designee) had clinically significant valvular heart disease likely to require surgical repair/replacement during the course of the study.
- Had persistent, uncontrolled hypertension (ie, sitting systolic blood pressure greater than 160 mm Hg or sitting diastolic blood pressure greater than 100 mm Hg) at randomization.
- Males who had hemoglobin less than 10.5 g/dL (less than 105 g/L) and female subjects who had hemoglobin less than 10.0 g/dL (less than 100 g/L).
- Had a triglyceride level greater than 500 mg/dL (greater than 5.6 mmol/L).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00225277
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| Study Director: | VP Clinical Science | Takeda |
| Responsible Party: | Takeda |
| ClinicalTrials.gov Identifier: | NCT00225277 |
| Other Study ID Numbers: |
01-01-TL-OPI-516 U1111-1114-0400 ( Registry Identifier: WHO ) |
| First Posted: | September 23, 2005 Key Record Dates |
| Results First Posted: | June 10, 2009 |
| Last Update Posted: | February 28, 2012 |
| Last Verified: | February 2012 |
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Glucose Metabolism Disorder Dysmetabolic Syndrome Type II Diabetes Diabetes Mellitus, Lipoatrophic |
Dyslipidemia Drug Therapy Atherosclerosis |
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Diabetes Mellitus Diabetes Mellitus, Type 2 Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases Pioglitazone |
Glimepiride Hypoglycemic Agents Physiological Effects of Drugs Anti-Arrhythmia Agents Immunosuppressive Agents Immunologic Factors |