Rosiglitazone Versus a Sulfonylurea On Progression Of Atherosclerosis In Patients With Heart Disease And Type 2 Diabetes

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Atherosclerosis

Intervention / Treatment
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* Drug: Glipizide
* Drug: rosiglitazone maleate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Glipizide<br>oral anti-diabetic medication | Drug: Glipizide<br>* oral anti-diabetic medication<br>|
| Experimental: rosiglitazone maleate<br>oral anti-diabetic medication | Drug: rosiglitazone maleate<br>* oral antidiabetic medication<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Percent Atheroma Volume (PAV) to Month 18 | The primary efficacy endpoint was change in PAV (defined as total atheroma volume divided by total vessel volume x 100) within a 40 mm segment in non-intervened coronary arteries from Baseline to Month 18, based upon Intravascular Ultrasound (IVUS) assessment. | Baseline to Month 18 | 
| Model Adjusted Change From Baseline in Percent Atheroma Volume (PAV) to Month 18 | Model Adjusted Change (MAC) = Baseline + Region + Sex + Treatment + Cardiac Procedure + Prior Oral Anti-Hyperglycemic Diabetic Medications(s) (OAD). | Baseline to Month 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Atheroma, Vessel, and Lumen Volume to Month 18 | IVUS-derived endpoints measured within the same segment (in non-intervened coronary arteries) from Baseline to Month 18 | Baseline to Month 18 | 
| Model Adjusted Change From Baseline in Atheroma Volume to Month 18 | IVUS-derived endpoints measured within the same segment (in non-intervened coronary arteries) from Baseline to Month 18. Model Adjusted Change (MAC) = Baseline + Region + Sex + Treatment + Cardiac Procedure + Prior OAD Medication. | Baseline to Month 18 | 
| Model Adjusted Change From Baseline in Lumen Volume to Month 18 | IVUS-derived endpoints measured within the same segment (in non-intervened coronary arteries) from Baseline to Month 18. Model Adjusted Change (MAC) = Baseline + Region + Sex + Treatment + Cardiac Procedure + Prior OAD Medication. | Baseline to Month 18 | 
| Model Adjusted Change From Baseline in Vessel Volume to Month 18 | IVUS-derived endpoints measured within the same segment (in non-intervened coronary arteries) from Baseline to Month 18. Model Adjusted Change (MAC) = Baseline + Region + Sex + Treatment + Cardiac Procedure + Prior OAD Medication. | Baseline to Month 18 | 
| Change From Baseline in Atheroma, Vessel, and Lumen Area to Month 18 | IVUS-derived endpoints measured within the same segment (in non-intervened coronary arteries) from Baseline to Month 18 | Baseline to Month 18 | 
| Model Adjusted Change From Baseline in Atheroma Area to Month 18 | IVUS-derived endpoints measured within the same segment (in non-intervened coronary arteries) from Baseline to Month 18. Model Adjusted Change (MAC) = Baseline + Region + Sex + Treatment + Cardiac Procedure + Prior OAD Medication. | Baseline to Month 18 | 
| Model Adjusted Change From Baseline in Lumen Area to Month 18 | IVUS-derived endpoints measured within the same segment (in non-intervened coronary arteries) from Baseline to Month 18. Model Adjusted Change (MAC) = Baseline + Region + Sex + Treatment + Cardiac Procedure + Prior OAD Medication. | Baseline to Month 18 | 
| Model Adjusted Change From Baseline in Vessel Area to Month 18 | IVUS-derived endpoints measured within the same segment (in non-intervened coronary arteries) from Baseline to Month 18. Model Adjusted Change (MAC) = Baseline + Region + Sex + Treatment + Cardiac Procedure + Prior OAD Medication. | Baseline to Month 18 | 
| Change From Baseline in Normalized Atheroma Volume | IVUS-derived endpoints measured within the same segment (in non-intervened coronary arteries) from Baseline to Month 18. Normalized atheroma volume is defined as mean atheroma area x median segment length in cohort. | Baseline to Month 18 | 
| Model Adjusted Change From Baseline in Normalized Atheroma Volume | IVUS-derived endpoints measured within the same segment (in non-intervened coronary arteries) from Baseline to Month 18. Normalized atheroma volume is defined as mean atheroma area x median segment length in cohort. Model Adjusted Change = Baseline + Region + Sex + Treatment + Cardiac Procedure + Prior OAD Medication. | Baseline to Month 18 | 
| Change in Atheroma Volume Within the 10 mm of the Non-intervened Vessel Segment With the Greatest Atheroma Volume at Baseline | IVUS-derived endpoints measured within the same 10 mm segment of non-intervened coronary arteries with the greatest degree of atheroma volume at Baseline, from Baseline to Month 18, including the nominal change in atheroma volume and atheroma area | Baseline to Month 18 | 
| Model Adjusted Change in Atheroma Volume Within the 10 mm of the Non-intervened Vessel Segment With the Greatest Atheroma Volume at Baseline | IVUS-derived endpoints measured within the same 10 mm segment of non-intervened coronary arteries with the greatest degree of atheroma volume at Baseline, from Baseline to Month 18, including the nominal change in atheroma volume and atheroma area. Model Adjusted Change = Baseline + Region + Sex + Treatment + Cardiac Procedure + Prior OAD Medication. | Baseline to Month 18 | 
| Change in Atheroma Area Within the 10 mm of the Non-intervened Vessel Segment With the Greatest Atheroma Volume at Baseline | IVUS-derived endpoints measured within the same 10 mm segment of non-intervened coronary arteries with the greatest degree of atheroma volume at Baseline, from Baseline to Month 18, including the nominal change in atheroma volume and atheroma area | Baseline to Month 18 | 
| Model Adjusted Change in Atheroma Area Within the 10 mm of the Non-intervened Vessel Segment With the Greatest Atheroma Volume at Baseline | IVUS-derived endpoints measured within the same 10 mm segment of non-intervened coronary arteries with the greatest degree of atheroma volume at Baseline, from Baseline to Month 18, including the nominal change in atheroma volume and atheroma area. Model Adjusted Change = Baseline + Region + Sex + Treatment + Cardiac Procedure + Prior OAD Medication. | Baseline to Month 18 | 
| Model Adjusted Change in Glycated Hemoglobin (HbA1c) From Baseline to Month 18 | From repeated measures analysis model: Change = Baseline + visit + sex + region + treatment + prior Oral Anti-Hyperglycemic Diabetic Medications(s) (OAD) + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Model Adjusted Change in Fasting Plasma Glucose (FPG) From Baseline to Month 18 | From repeated measures analysis model: Change = Baseline + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Repeated Measures Analysis of Percent Change in hsCRP From Baseline to Month 18 | Changes in cardiovascular biomarkers from Baseline to Month 18, such as high sensitivity C-reactive protein (hsCRP) . Repeated measures analysis model: Log(value) - log(baseline) = log(baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Repeated Measures Analysis of Percent Change in MMP 9 From Baseline to Month 18 | Changes in cardiovascular biomarkers from Baseline to Month 18, such as matrix metalloproteinase-9 (MMP-9). Repeated measures analysis model: Log(value) - log(baseline) = log(baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Percent Change in Brain Natriuretic Peptide (BNP) From Baseline to Month 18 | It was measured as ratio to baseline as percentage change based on log-transformed data : 100 x (exp(Mean change on log scale) - 1)It was measured as ratio to baseline as percentage change based on log-transformed data : 100 x (exp(Mean change on log scale) - 1). Ratio to baseline as %change mean (%) was used as the estimation parameter for both groups. | Baseline to Month 18 | 
| Model Adjusted Percent Change in Brain Natriuretic Peptide (BNP) From Baseline to Month 18 | It was measured as ratio to baseline as percentage change based on log-transformed data : 100 x (exp(Mean change on log scale) - 1). Model Adjusted change based on ANCOVA: Log(value) - log(Baseline) = log(Baseline) + sex + region + treatment + prior OAD + cardiac procedure. | Baseline to Month 18 | 
| Percent Change From Baseline to Month 18 in Total Cholesterol (TC) | Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Percent Change From Baseline to Month 18 in High Density Lipoprotein Cholesterol (HDL-c) | Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Percent Change From Baseline to Month 18 in HDL-2 | Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Percent Change From Baseline to Month 18 in HDL-3 | Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Percent Change From Baseline to Month 18 in Low Density Lipoprotein Cholesterol (LDL-c) | Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Percent Change From Baseline to Month 18 in Triglycerides (TG) | Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Percent Change From Baseline to Month 18 in Free Fatty Acids (FFA) | Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Percent Change From Baseline to Month 18 in Apoprotein B (apoB) | Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Change From Baseline to Month 18 in LDL-c Peak Particle Density Measured by LDL Relative Flotation | From repeated measures analysis model: Change = baseline + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Change From Baseline to Month 18 in Total Cholesterol/HDL-c Ratio | From repeated measures analysis model: Change = baseline + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Change From Baseline to Month 18 in LDL-c/HDL-c Ratio | From repeated measures analysis model: Change = baseline + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit. | Baseline to Month 18 | 
| Number of Participants With the Indicated Treatment Emergent Major Cardiovascular Events (MACE) for All-cause Death, Non-fatal MI, Non-fatal Stroke, Coronary Revascularization, or Hospitalization for Recurrent Myocardial Ischemia (MACE Composite 1) | This was 1 of 2 MACE composite endpoints and was a secondary efficacy endpoint. | Baseline to Month 21 | 
| Number of Participants With the Indicated Treatment Emergent Major Cardiovascular Events (MACE) for Cardiovascular Death, Nonfatal MI, or Nonfatal Stroke (MACE Composite 2) | This was 1 of 2 MACE composite endpoints and was a secondary efficacy endpoint. | Baseline to Month 21 | 
| Number of Other Cardiovascular Events | This was one of the secondary endpoints of the study. | Baseline to Month 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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atheroma, IVUS, Intravascular ultrasound, atherosclerosis