Official Title: “A Phase III, 18 Month, Multicenter, Randomized, Double-Blind, Active-Controlled Clinical Trial to Compare Rosiglitazone Versus Glipizide on the Progression of Atherosclerosis in Subjects With Type 2 Diabetes Mellitus and Cardiovascular Disease (APPROACH)”

The purpose of this study is to test the safety and effectiveness of rosiglitazone against a sulfonylurea in reducing or slowing the development of atherosclerosis in the blood vessels of the heart.

Study Type: Interventional

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

Study Primary Completion Date: September 2008

Intervention(s) in this Clinical Trial

• Drug: Glipizide
• Drug: rosiglitazone

Primary Measures

• Progression of atherosclerosis as measured by IVUS (intravascular ultrasound).
  • Time Frame: 18 Months
    

Secondary Measures

• Assessments of other angiographic and IVUS-derived atherosclerotic endpoints.
  • Time Frame: 18 Months
    
• Other IVUS-derived endpoints measured within the same 40 mm segment in non-intervened coronary arteries from baseline to 18-months: The change in percent atheroma area
• The absolute change and percentage change in atheroma area and volume The absolute change and percentage change in lumen area and volume The absolute change and percentage change in vessel area and volume.
• IVUS-derived endpoints measured within a 15mm proximal segment of intervened coronary arteries from baseline to 18-months (IVUS pullback to be performed through a proximal segment of the vessel starting at least 5mm from the proximal edge of the stent):
• The change in percent atheroma area and volume The absolute change and percentage change in atheroma area and volume The absolute change and percentage change in lumen area and volume
• Time to first occurrence of composite adjudicated MACE including all-cause mortality, non-fatal MI, stroke, coronary revascularization and repeat hospitalizations for recurrent myocardial ischemia from baseline to 18-months
• Changes in the glycemic endpoints from baseline to 18-months: glycated hemoglobin (HbA1c), fasting plasma glucose (FPG) Changes in CV markers from baseline to 18-months: high sensitivity C-reactive protein (hsCRP), matrix metalloproteinase-9 (MMP-9)
• Changes in lipids from baseline to 18-months: total cholesterol, triglyceride, free fatty acids (FFA), apoprotein B (apo B), high density lipoprotein-cholesterol (HDL-c) and HDL-c subclasses, low density lipoprotein-cholesterol (LDL-c),
• LDL-c peak particle density measured by LDL relative flotation, total cholesterol/HDL-c ratio, LDL-c/HDL-c ratio
• Assessment of adverse events (AE), hypoglycemic events, vital signs, weight and other physical examinations plus clinical chemistry and hematology. The absolute change and percentage change in vessel area and volume.

Inclusion criteria:

• Male or female between 30 to 80 years of age, inclusive.
• Established diagnosis of T2DM (based on diagnostic criteria of the American Diabetes
• Association (ADA), WHO guidelines or local national guidelines).
•   Subjects who are undergoing coronary angiography for evaluation of suspected or previously diagnosed coronary artery disease or who are undergoing PCI.
• Subjects' prior anti-hyperglycemic diabetic therapy:
• Diet and exercise only (drug naïve), with HbA1c >7.0 and £ 10.0%. HbA1c > 6.5 and £ 8.5%.
•   Left ventricular ejection fraction (EF) ³ 40% as assessed by contrast ventriculography (or previously documented in medical notes within one month prior to index procedure by other methods e.g. echocardiography or nuclear study)
• Female subjects must be postmenopausal (i.e., >6 months without menstrual period), surgically sterile, or using effective contraceptive measures (oral contraceptives, Norplant, Depo-Provera, an intra-uterine device (IUD), a diaphragm with spermicide or a condom with spermicide). Women of childbearing potential must use effective contraceptive measures for at least 1 month prior to visit 1a, and should continue to use the same contraceptive method during the study and for 30 days after discontinuing study medication.
• Willingness and ability to give informed consent prior to entering the study and available to complete the study.

Exclusion Criteria:

• Type 1 diabetes and/or history of diabetic ketoacidosis.
•   Exposure to a TZD or other PPAR-g agonist within the 6 months prior to screening visit.
• Subjects treated with triple OAD therapy or high dose dual combination OAD therapy
• [1].
• Subjects who have required chronic insulin use in the last 6 months (except during pregnancy or acute episodes such as hospitalization, trauma or infection).
• ST segment elevation myocardial infarction in the last 30 days.
•   Subjects who have a history or are scheduled to receive coronary artery bypass graft surgery (CABG), valve repair or replacement, aneurysmectomy or planned major non-cardiac surgery during the study period.
• Subjects who have severe cardiac valvular disease
• Stroke or resuscitated in the past 6 months
• History of congestive heart failure (NYHA class I - IV)
• History of significant hypersensitivity or reaction (e.g., difficulty swallowing, difficulty breathing, tachycardia or skin reaction) to any TZD, SU, biguanide or insulin
• Prior history of severe edema or edema requiring medical treatment.
• Chronic disease requiring chronic or intermittent treatment with oral, intravenous, or injected corticosteroids (use of topical, inhaled, or nasal corticosteroids is permissible).
• Recent history or suspicion of current drug abuse or alcohol abuse within the last 6 months.
• Untreated hypo- or hyperthyroidism
• A diagnosis of cancer (other than superficial squamous, basal cell skin cancer, or adequately treated cervical carcinoma in situ) in the past 3 years or current treatment for the active cancer.
• Any clinically significant abnormality identified at the screening visit, physical examination, laboratory tests, or electrocardiogram which, in the judgement of the Investigator, would preclude safe completion of the study.
• Blood pressure: SBP >170 or DBP > 100 mmHg
• Significant anemia (Hemoglobin < 11 g/dL for males and < 10 g/dL for females).
• Significant renal disease manifested by serum creatinine (> 1.5mg/dL for males or >
• 1.4mg/dL for females), or where the use of metformin is contra-indicated.
• Hepatic disease or biliary tract obstruction, or significant hepatic enzyme elevation (ALT or AST > 2.5 times upper limit of normal (ULN) or bilirubin >2x ULN).
• History of myopathy or history of elevated creatine kinase (CK) > 3 times upper normal limit.
• Use of an investigational drug within 30 days or 5 half-lives (whichever is the longer).
• Women who are lactating, pregnant or planning to become pregnant during the course of the study.
• Unwillingness or inability to comply with the procedures described in this protocol.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 30 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: GlaxoSmithKline

Overall Clinical Trial Officials and Contacts

GSK Clinical Trials, MD Study Director GlaxoSmithKline  

Information obtained from ClinicalTrials.gov on August 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00116831

Study ID Number: AVD100521

ClinicalTrials.gov Identifier: NCT00116831

Health Authority: United States: Food and Drug Administration