Official Title: “A Randomized, Double-Blind, Comparator-Controlled Study of Pioglitazone HCl vs Glyburide in the Treatment of Subjects With Type 2 (Non-Insulin Dependent) Diabetes Mellitus and Mild to Moderate Congestive Heart Failure”

The primary objective of this study was to evaluate the progression of congestive heart failure (CHF) in subjects with type 2 diabetes mellitus and mild to moderate CHF defined as New York Heart Association (NYHA) Class II or early Class III after 6 months of treatment with 30 to 45 mg of pioglitazone or 10 to 15 mg of glyburide with or without insulin.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Active Control, Parallel Assignment, Safety/Efficacy Study

Following Screening, eligible subjects were assigned to a treatment group according to a randomized treatment.group. The initial pioglitazone dose was 30 mg QD (administered as two 15 mg tablets), and the initial glyburide dose was 10 mg QD (administered as two 5 mg capsules).

During the Treatment Period, scheduled assessments included recording of vital signs and weight, NYHA classification, FPG, self-monitoring blood glucose level, treatment compliance, prior/concomitant medication use, and adverse events; A1c, serum pregnancy, chest x-ray, 12-lead ECG, hematocrit, hemoglobin, ALT, and lipid panel were also assessed periodically.

Changes to study drug dosing were made in response to either hyperglycemia (defined as an FPG greater than 140 mg/dL) or hypoglycemia (based on symptomology and/or FPG).

At Visit 10 (week 24) or at the Final Visit for subjects who did not complete the study, a complete physical examination (including recording of vital signs, weight, NYHA class, and BMI) was conducted; blood and urine samples were collected for clinical chemistry, hematology, and urine analysis; and an echocardiogram (read by a central facility), 6-minute walking distance test, Minnesota Living with Heart Failure Questionnaire, physician and subject CHF global assessment, study drug compliance, and prior/concomitant medication use and adverse events assessments were completed

Intervention(s) in this Clinical Trial

• Drug: Pioglitazone HCl, glyburide

Primary Measures

• Time to the composite endpoint of CHF progression (defined as the first occurrence of death due to cardiovascular causes, overnight hospitalization for worsening CHF, or emergency room visit for CHF).
  • Time Frame: Time to event
    

Secondary Measures

• Changes from Baseline in A1c, FPG, triglycerides, cholesterol, blood pressure, heart rate, body weight, left ventricular mass, cardiac index, fractional shortening, left ventricular ejection
  • Time Frame: Study visits and end of study
    

Inclusion Criteria:

• Male or female subjects who were at least 18 years of age.
• Diagnosis of type 2 diabetes mellitus
• Clinical diagnosis of CHF, NYHA Class II, or early Class III (the NYHA Functional
• Capacity Scale and left ventricular ejection fraction of less than 40 percent at
• Screening based on an echocardiogram).
• Subjects who demonstrated the need for oral hypoglycemic agents and had participated in dietary counseling.
• Subjects with A1c values greater than or equal to 7.0 percent at Screening.
• Subjects on optimal therapy for CHF. Medication doses were stable for at least 2 weeks prior to randomization, including any combination of a diuretic, an angiotensin-converting enzyme inhibitor (ACE I), or if an ACE I was not tolerated, then therapeutic intervention according to local clinical practice. Stable doses of digitalis and β-blockers could also have been used; however, initiation of beta-blockers was discouraged

Exclusion Criteria:

• Subjects who were naïve to antidiabetic therapy.
• Subjects who, within the 3 months before enrollment, were treated with rosiglitazone, pioglitazone, or troglitazone or those previously treated with rosiglitazone, pioglitazone, or troglitazone but discontinued from therapy because of lack of efficacy or clinical or laboratory signs of intolerance.
• Subjects with type 1 (insulin-dependent) diabetes mellitus or a history of ketoacidosis.
• Female subjects who are pregnant or lactating.
• Subjects who had any of the following within 3 months prior to Visit 1: myocardial infarction, coronary angioplasty or bypass graft, unstable angina pectoris, transient ischemic attacks, or documented cerebrovascular accident that in the investigator's opinion would warrant exclusion from the study.
• Subjects who had abdominal, thoracic, or vascular surgery during the 3 months prior to Visit 1 that in the investigator's opinion would warrant exclusion from the study.
• Subjects with a BMI greater than 48 kg/m2 as calculated by [weight (kg)/height (m)2].
• Subjects with anemia defined as having a hemoglobin value less than 10.5 g/dL for male subjects and less than 10 g/dL for female subjects.
• Subjects with a thyroid-stimulating hormone (TSH) value greater than or equal to 3.5 mU/L or less than 0.3 mU/L. The TSH could have been repeated at 2 months. The subject was eligible if the Screening TSH was elevated, and the repeat value at 2 months was less than 3.5 mU/L. The primary physician could have initiated treatment for subjects with subclinical or clinical hypothyroidism during and continuing after the 2-month interim if they felt it was clinically indicated.
• Subjects with a triglyceride level greater than 500 mg/dL.
• Subjects with clinical evidence of active liver disease or alanine aminotransaminase (ALT) levels greater than 1.5 times the upper limit of normal (ULN).
• Male subjects with serum creatinine greater than 2.0 mg/dL or female subjects with serum creatinine greater than 1.8 mg/dL or urinalysis protein (albumin) excretion greater than 2+ on Combistix or equivalent (if elevated, the subject could have been rescreened after 1 month).
• Subjects with a systolic blood pressure greater than 150 mm Hg or diastolic blood pressure greater than 100 mm Hg.
• Subjects with symptomatic orthostatic hypotension or systolic blood pressure less than 90 mmHg.
• Subjects with severe, advanced peripheral vascular disease (limb threatening ischemia) or claudication that resulted in the inability to walk greater than 1 block or to climb 10 stairs without interruption.
• Subjects with lower extremity amputation.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Takeda Global Research & Development Center, Inc.

Overall Clinical Trial Officials and Contacts

Alfonso Perez Study Director Takeda Global Research and Developmnet Center Inc  

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00521820

Study ID Number: 01-00-TL-OPI-504

ClinicalTrials.gov Identifier: NCT00521820

Health Authority: United States: Food and Drug Administration