Rosiglitazone and Metformin: Outcomes Trial in Nondiabetic Patients With Stable Coronary Syndromes (Romance) Pilot Study

This study has been terminated.
(FDA concerns regarding Avandamet)
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by:
Intermountain Health Care, Inc.
ClinicalTrials.gov Identifier:
NCT00343395
First received: June 21, 2006
Last updated: March 15, 2011
Last verified: March 2011
  Purpose

Nearly half of all Americans will die from cardiovascular disease caused by the build up of atherosclerotic plaque within coronary arteries. Most deaths in these patients arise from the development of acute coronary syndromes (ACS) such as myocardial infarction, unstable angina, or sudden death. ACS is characterized by coronary plaque erosion or rupture, which is triggered by endothelial changes, including inflammation, and thrombosis. Diabetes, with insulin resistance as a major component, has been shown to engender adverse metabolic events within the endothelial cell [1], including impaired endothelial function, augmented vasoconstriction, increased inflammation and thrombosis. Activation of the transcription factors nuclear factor KB (NF-KB) and activator protein 1 (AP-1) induces inflammatory gene expression, with liberation of leukocyte-attracting chemokines, increased production of inflammatory cytokines, and augmented expression of cellular adhesion molecules. These metabolic processes may therefore play a significant role in the development of ACS.The hypothesis is that rosiglitazone and metformin, or the combination of both may provide positive anti-atherogenic effect, even among patients without diabetes. This pilot study proposes to evaluate the effect of placebo vs. combined rosiglitazone/metformin (Avandamet®) on surrogate blood markers of atherosclerosis activity among non-diabetic and pre-diabetic patients with known stable coronary syndromes. This will provide further evidence justifying a large definitive outcomes-based clinical trial.


Condition Intervention Phase
Coronary Artery Disease
Drug: AVANDAMET
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Single-Center, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Combined Rosiglitazone/Metformin (Avandamet®) vs. Placebo on Serological Outcomes in Non-Diabetic Patients With Stable Coronary Syndromes

Resource links provided by NLM:


Further study details as provided by Intermountain Health Care, Inc.:

Primary Outcome Measures:
  • To demonstrate the effect (change from baseline) of each study intervention on hs-C-reactive protein. [ Time Frame: Study completion ] [ Designated as safety issue: No ]
  • To demonstrate the safety of the interventions on clinical outcomes (death, MI, cardiovascular hospitalizations) and serious drug-related adverse events. [ Time Frame: Study completion ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To demonstrate the effect (change from baseline) of each study intervention on lipid levels [ Time Frame: Study completion ] [ Designated as safety issue: No ]
  • To demonstrate the effect (change from baseline) of each study intervention on inflammatory marker levels other than hs-CRP [ Time Frame: Study completion ] [ Designated as safety issue: No ]
  • To demonstrate the effect (change from baseline) of each study intervention on HgbA1C [ Time Frame: Study completion ] [ Designated as safety issue: No ]
  • To demonstrate the effect (change from baseline) of each study intervention on fasting blood glucose [ Time Frame: Study completion ] [ Designated as safety issue: No ]
  • Safety: Differences in adverse events between the two arms [ Time Frame: Interim; completion of study ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 200
Study Start Date: June 2006
Study Completion Date: January 2008
Primary Completion Date: November 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Avandamet
AVANDAMET 2/500 mg
Drug: AVANDAMET
2/500 mg
Placebo Comparator: Placebo Drug: AVANDAMET
2/500 mg

Detailed Description:

This is a single-center, randomized, double-blind trial comparing combined rosiglitazone/metformin (Avandametä) to placebo in subjects with normal or intermediate fasting glucose (IFG) and stable coronary artery disease.Subjects meeting entry criteria will be randomized in a 1:1 ratio to receive either placebo or combined rosiglitazone/metformin (Avandametä) 4/1000 mg. Laboratory specimens including high sensitivity C-reactive protein (hs-CRP), glucose, HgbA1C, complete lipid profile, will be obtained after a 10 hour fast as specified by study visits. Subjects will return for repeat study visits at 2, 4, 6 and 8 months for repeat laboratory evaluations, including safety labs consisting of serum creatinine, liver enzymes, and a CBC. Additionally, subjects will have IL-6 and TNF-a measured for research purposes at baseline and subsequent follow-up visits. All subjects will be followed for a minimum of 8 months. This pilot study proposes to evaluate the effect of placebo, or combined rosiglitazone/metformin onsurrogate blood markers of atherosclerosis activity among non-diabetic and pre-diabetic patients with known stable coronary syndromes.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The patient (male or non-pregnant female) must be > 18 years of age.
  • The patient or legally authorized representative must sign a written informed consent, prior to the procedure, using a form that is approved by the local Institutional Review Board.
  • Angiographically documented coronary artery disease defined as the presence of at least one 50% or greater stenosis of a major coronary artery.
  • Stabilized post any prior ACS event (i.e., without ongoing ischemic rest pain, congestive heart failure, or malignant arrhythmias) for at least 3 months
  • Fasting blood glucose 87-125 mg/dL

Exclusion Criteria:

  • Age <18 years
  • Known hypersensitivity to metformin or rosiglitazone
  • Renal insufficiency defined as calculated creatinine clearance (CrCl) <40 mL/min using the following formula:

Men: CrCL (mL/min) = Weight (kg) x (140-age) 72 x serum creatinine (mg/dL) Women: 0.85 x the value calculated for men

  • Pregnant and/or lactating women, and women of child bearing potential are excluded from this trial
  • Co-morbidity such that the patient is not expected to survive >2 years
  • Current therapy with rosiglitazone or metformin
  • PCI within the previous six months (other than for the qualifying event)
  • Prior CABG within the previous two months, scheduled CABG, or a decision to perform CABG made prior to enrollment
  • Overt diabetes mellitus (FBG>126 or antidiabetic therapy)
  • Any diagnosis of congestive heart failure
  • Obstructive hepatobiliary disease or other significant hepatic disease (defined as the presence of at least one of the following: AST, ALT, GGT, total bilirubin, or alkaline phosphatase >3x upper limit normal, not related to MI
  • Participation in any other clinical trials involving investigational or marketed products within 30 days prior to entry in the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00343395

Locations
United States, Utah
Intermountain Medical Center
Murray, Utah, United States, 84157
Sponsors and Collaborators
Intermountain Health Care, Inc.
GlaxoSmithKline
Investigators
Principal Investigator: Joseph B Muhlestein, MD Intermountain Healthcare, LDS Hospital
  More Information

No publications provided

Responsible Party: J. Brent Muhlestein, MD, Intermountain Healthcare
ClinicalTrials.gov Identifier: NCT00343395     History of Changes
Other Study ID Numbers: 128-013
Study First Received: June 21, 2006
Last Updated: March 15, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Intermountain Health Care, Inc.:
rosiglitazone
metformin
hs-CRP
inflammation

Additional relevant MeSH terms:
Coronary Artery Disease
Coronary Disease
Myocardial Ischemia
Arterial Occlusive Diseases
Arteriosclerosis
Cardiovascular Diseases
Heart Diseases
Vascular Diseases
Metformin
Rosiglitazone
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 23, 2014