The Effect of Rosiglitazone on Ischemia-reperfusion-injury Using Annexin A5 Scintigraphy.

Study Overview
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Brief Summary
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Cardiovascular disease is the leading cause of death in diabetic patients due to both a high event rate and a worse outcome. A pharmacological intervention that reduces ischemia-reperfusion-injury would improve the outcome of diabetic patients after a cardiovascular event. In the present study, we will use annexinA5 scintigraphy to address the following hypothesis: Rosiglitazone reduces ischemia-reperfusion-injury in humans with insulin resistance.

Detailed Description
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Rationale: Cardiovascular disease is the leading cause of death in diabetic patients due to both a high event rate and a worse outcome. A pharmacological intervention that reduces ischemia-reperfusion-injury would improve the outcome of diabetic patients after a cardiovascular event. The thiazolidinedione derivatives are peroxisome proliferator-activated receptor-γ (PPARγ) ligands that are approved for the treatment of hyperglycemia in type 2 diabetes mellitus. Animal data suggest that PPARγ ligands can protect against ischemia-reperfusion-injury by improving insulin responsiveness. However, no human data on these beneficial effects are available. Recently, our group developed a human in vivo model to quantify ischemia-reperfusion-injury. In this model annexin A5 scintigraphy is used to visualize early and reversible cellular membrane changes that occur in the forearm skeletal muscle vascular bed after ischemic exercise. In the present study, we will use this approach to address the following hypothesis: Rosiglitazone reduces ischemia-reperfusion-injury in humans with insulin resistance, selected by using the criteria for the metabolic syndrome. Study design: This is a single-center randomized, double blind, placebo-controlled crossover study with a washout period of 6 weeks. Study population: Men and postmenopausal women, age 20-70 years with the metabolic syndrome. Intervention: Every subject uses during 8 weeks rosiglitazone 4 mg bd and placebo bd. Week 8 and 22: assessment of ischemic-reperfusion injury with Technetium Annexin A5 Scintigraphy. Ischemic intervention: 10 minutes ischemia of the non-dominant arm with at the same time rhythmic contractions of the forearm and hand muscles. Main study parameters/endpoints: Annexin targeting in the thenar muscle after ischemic exercise. The primary analysis is the difference in annexin targeting following 8 weeks of treatment with rosiglitazone 4 mg bd or placebo.

Official Title
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The Effect of Rosiglitazone on Ischemia-reperfusion-injury Using Annexin A5 Scintigraphy. A Double Blind Placebo- Controlled Cross-over Study in Subjects With the Metabolic Syndrome

Conditions
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Ischemia-Reperfusion Injury, The Metabolic Syndrome

Intervention / Treatment
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* Drug: rosiglitazone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 3 features of the metabolic syndrome (AHA/NHLBI). Willing and able to provide a signed and dated written informed consent. Men or postmenopausal women aged between 20 and 70 years. Exclusion Criteria: Fasting glucose > 7,0 mmol/L or the use of hypoglycaemic agents. If fasting plasma glucose is between 6.1 and 7,0 mmol/L, an oral 75 g glucose test will be performed to exclude diabetes mellitus. Exposure to a PPAR-g agonist during the last 4 months or a documented significant hypersensitivity to a PPAR-g agonist. Participant in another study. Angina or heart failure (NYHA I-IV). Clinically significant liver disease (3 times the upper normal limit of ALAT, ASAT, AF, γGT or LDH) Clinically significant anemia (male Hb < 6,9 mmol/L, female < 6,25 mmol/L) Creatinin clearance < 40 mL/min Alcohol or drug abuse. Any physical inability to perform the exercise protocol. Administration of any radio pharmacon for research purposes in the previous 5 years.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 70 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Placebo first | Drug: rosiglitazone<br>* Rosiglitazone 4 mg bidaily for 8 weeks<br>|
| Experimental: 2<br>Rosiglitazone first | Drug: rosiglitazone<br>* Rosiglitazone 4 mg bidaily for 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annexin targeting in the thenar muscle after ischemic exercise. The primary analysis is the difference in annexin targeting following 8 weeks of treatment with rosiglitazone 4 mg bd or placebo. |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of rosiglitazone as compared to placebo on the HOMA-index. |  |  | 
| Changes in vital signs, body weight, clinical laboratory parameters and adverse events monitoring during the study. |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rosiglitazone, ischemia-reperfusion injury, human, Annexin A5 scintigraphy, metabolic syndrome