Official Title: “A Randomized, Comparator Controlled, Double-Blind Study of the Liver Safety of Pioglitazone HCl vs Glyburide With Metformin and Insulin as Part of Step Therapy in Subjects With Type 2 (Non-Insulin Dependent) Diabetes”

This was a long-term study comparing the liver safety of pioglitazone and the sulfonylurea glyburide when taken with metformin and/or insulin.

Study Type: Interventional

Study Design: Treatment, Randomized, Double-Blind, Active Control, Parallel Assignment, Safety Study

This was a double-blind, randomized, active-comparator study involving subjects with type 2 diabetes. The study consisted of a 6-month treatment period. The primary objective was to compare pioglitazone with the sulfonylurea glyburide with respect to the incidence of abnormal hepatic function laboratory tests. At study entry, patients began taking pioglitazone and glyburide, which were titrated to a maximum dose of 45 and 15 mg, respectively. Patients who were taking a sulphonylurea at study entry stopped this therapy, but metformin use was allowed to continue as needed. During the study, metformin and then insulin could be added to attain and maintain glycemic targets. Subjects were evaluated periodically during the study, and glycemic control and hepatic function were monitored during the evaluations.

Intervention(s) in this Clinical Trial

• Drug: pioglitazone HCl, glyburide

Primary Measures

• Hepatic inflammation or injury, as monitored by serum alanine aminotranaminase (ALT) elevation (greater than 3 times the upper limit of normal) confirmed by an immediate repeat test.
  • Time Frame: 6 months
    

Secondary Measures

• ALT >8X ULN;4 consecutive ALTs between 3X and 8X ULN;ALT >3X ULN and total bilirubin >2X ULN; ALT, AST, total/direct bilirubin, alkaline phosphatasetase, or GGT >1.5X ULN or Baseline; all causes mortality
  • Time Frame: 6 months
    

Inclusion Criteria:

• The subject was a man or woman aged 18 to 80 years.
• Women of childbearing potential (including perimenopausal women who had had a menstrual period within 1 year) had to be surgically sterile or using appropriate birth control methods.
• The subject had a diagnosis of type 2 (non-insulin dependent) diabetes mellitus and was currently taking glyburide, glipizide, glimepiride, or metformin alone, or glyburide, glipizide, or glimepiride in combination with metformin.
• The subject had an HbA1c level greater than or equal to 7.0 percent
• The subject had a fasting C-peptide level greater than or equal to 0.7 ng/mL

Exclusion Criteria:

• The subject had type 1 (insulin-dependent) diabetes mellitus.
• The subject had prior exposure to a thiazolidinedione, except subjects who discontinued use of troglitazone in March or April of 2000, provided they were not experiencing adverse effects and were not then taking thiazolidinediones.
• The subject had a history of ketoacidosis.
• The subject had significant diabetic nephropathy.
• The subject had anemia with a hemoglobin level less than 12 g/dL for men and less than 10 g/dL for women.
• The subject had a diastolic blood pressure greater than 100 mm Hg or a systolic blood pressure greater than 180 mm Hg.
• The subject had evidence of ongoing cardiac rhythm disturbance, delayed QT waves, or second-degree atrioventricular heart block (PR greater than 0.26, QRS greater than 0.20, or QTc greater than 0.45 or greater than 30 percent of normal rate calculated interval). Uncomplicated first-degree atrioventricular bock was allowed.
• The subject had significant cardiovascular disease including, but not limited to, New
• York Heart Association Functional (Cardiac) Classification III or IV, or the subject had a history of myocardial infarction, acute cardiovascular event, or cerebrovascular accident within the preceding 6 months.
• The subject had a body mass index less than 20 or greater than 48 (calculated as weight [kg]/height [m2]).
• The subject had an ALT level greater than or equal to 2.5 times the upper limit of normal or a history of liver disease, jaundice, hepatitis, or biliary tract disease (except for uncomplicated and treated gall stones by either lithotomy or cholecystectomy).
• The subject had evidence of acute or unstable chronic pulmonary disease or, if a chest x-ray was available, had unexplained pulmonary lesions.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 80 Years

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 & Development Center, Inc.  

Information obtained from ClinicalTrials.gov on November 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00494312

Study ID Number: 01-00-TL-OPI-506

ClinicalTrials.gov Identifier: NCT00494312

Health Authority: United States: Food and Drug Administration