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

Phase 3

Completed

Conditions: Atherosclerosis

Interventions: Drug: rosiglitazone maleate
Drug: Glipizide

Registration Number: NCT00116831

Lead Sponsor: GlaxoSmithKline

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 672

Inclusion Criteria

Not provided

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
rosiglitazone maleate	rosiglitazone maleate	oral anti-diabetic medication
Glipizide	Glipizide	oral anti-diabetic medication

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Percent Atheroma Volume (PAV) to Month 18	Baseline 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.
Model Adjusted Change From Baseline in Percent Atheroma Volume (PAV) to Month 18	Baseline to Month 18	Model Adjusted Change (MAC) = Baseline + Region + Sex + Treatment + Cardiac Procedure + Prior Oral Anti-Hyperglycemic Diabetic Medications(s) (OAD).

Secondary Outcome Measures

Name	Time	Method
Model Adjusted Change From Baseline in Vessel Volume to Month 18	Baseline 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.
Change From Baseline in Atheroma, Vessel, and Lumen Volume to Month 18	Baseline to Month 18	IVUS-derived endpoints measured within the same segment (in non-intervened coronary arteries) from Baseline to Month 18
Model Adjusted Change From Baseline in Lumen Volume to Month 18	Baseline 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.
Change From Baseline in Atheroma, Vessel, and Lumen Area to Month 18	Baseline to Month 18	IVUS-derived endpoints measured within the same segment (in non-intervened coronary arteries) from Baseline to Month 18
Percent Change in Brain Natriuretic Peptide (BNP) From Baseline to Month 18	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.
Model Adjusted Change in Atheroma Area Within the 10 mm of the Non-intervened Vessel Segment With the Greatest Atheroma Volume at Baseline	Baseline to Month 18	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.
Model Adjusted Change in Fasting Plasma Glucose (FPG) From Baseline to Month 18	Baseline to Month 18	From repeated measures analysis model: Change = Baseline + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit.
Percent Change From Baseline to Month 18 in HDL-3	Baseline to Month 18	Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit.
Percent Change From Baseline to Month 18 in Low Density Lipoprotein Cholesterol (LDL-c)	Baseline to Month 18	Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit.
Percent Change From Baseline to Month 18 in Triglycerides (TG)	Baseline to Month 18	Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit.
Change From Baseline to Month 18 in LDL-c Peak Particle Density Measured by LDL Relative Flotation	Baseline to Month 18	From repeated measures analysis model: Change = baseline + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit.
Model Adjusted Change From Baseline in Atheroma Volume to Month 18	Baseline 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.
Repeated Measures Analysis of Percent Change in hsCRP From Baseline to Month 18	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.
Repeated Measures Analysis of Percent Change in MMP 9 From Baseline to Month 18	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.
Percent Change From Baseline to Month 18 in Total Cholesterol (TC)	Baseline to Month 18	Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit.
Percent Change From Baseline to Month 18 in High Density Lipoprotein Cholesterol (HDL-c)	Baseline to Month 18	Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit.
Percent Change From Baseline to Month 18 in Free Fatty Acids (FFA)	Baseline to Month 18	Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit.
Model Adjusted Change From Baseline in Atheroma Area to Month 18	Baseline 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.
Model Adjusted Change From Baseline in Vessel Area to Month 18	Baseline 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.
Change From Baseline in Normalized Atheroma Volume	Baseline to Month 18	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 From Baseline in Normalized Atheroma Volume	Baseline to Month 18	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.
Change in Atheroma Area Within the 10 mm of the Non-intervened Vessel Segment With the Greatest Atheroma Volume at Baseline	Baseline to Month 18	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 Percent Change in Brain Natriuretic Peptide (BNP) From Baseline to Month 18	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.
Percent Change From Baseline to Month 18 in HDL-2	Baseline to Month 18	Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit.
Change From Baseline to Month 18 in Total Cholesterol/HDL-c Ratio	Baseline to Month 18	From repeated measures analysis model: Change = baseline + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit.
Model Adjusted Change From Baseline in Lumen Area to Month 18	Baseline 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.
Change in Atheroma Volume Within the 10 mm of the Non-intervened Vessel Segment With the Greatest Atheroma Volume at Baseline	Baseline to Month 18	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 in Atheroma Volume Within the 10 mm of the Non-intervened Vessel Segment With the Greatest Atheroma Volume at Baseline	Baseline to Month 18	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.
Model Adjusted Change in Glycated Hemoglobin (HbA1c) From Baseline to Month 18	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.
Percent Change From Baseline to Month 18 in Apoprotein B (apoB)	Baseline to Month 18	Repeated measures analysis model: Log(value) - log (Baseline) = log(Baseline) + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit.
Change From Baseline to Month 18 in LDL-c/HDL-c Ratio	Baseline to Month 18	From repeated measures analysis model: Change = baseline + visit + sex + region + treatment + prior OAD + cardiac procedure + treatment x visit.
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)	Baseline to Month 21	This was 1 of 2 MACE composite endpoints and was a secondary efficacy endpoint.
Number of Other Cardiovascular Events	Baseline to Month 21	This was one of the secondary endpoints of the study.
Number of Participants With the Indicated Treatment Emergent Major Cardiovascular Events (MACE) for Cardiovascular Death, Nonfatal MI, or Nonfatal Stroke (MACE Composite 2)	Baseline to Month 21	This was 1 of 2 MACE composite endpoints and was a secondary efficacy endpoint.