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

Ischemia-Reperfusion Injury Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00405015
• Other study ID #: AR49653-4
• Secondary ID: EudraCT number 2
• Status: Completed
• Phase: Phase 2
• First received: November 28, 2006
• Last updated: August 23, 2010
• Start date: April 2007
• Est. completion date: October 2008

Study information

• Verified date: October 2008
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 13
• Est. completion date: October 2008
• Est. primary completion date: July 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years to 70 Years

Eligibility

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, ?GT 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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Ischemia
• Ischemia-Reperfusion Injury
• Metabolic Syndrome X
• Reperfusion Injury
• The Metabolic Syndrome

Intervention

Drug:
• rosiglitazone
Rosiglitazone 4 mg bidaily for 8 weeks

Locations

Country	Name	City	State
Netherlands	Clinical research Center Nijmegen	Nijmegen

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University	GlaxoSmithKline

Country where clinical trial is conducted

Netherlands, 

References & Publications (4)

Aronson D, Rayfield EJ, Chesebro JH. Mechanisms determining course and outcome of diabetic patients who have had acute myocardial infarction. Ann Intern Med. 1997 Feb 15;126(4):296-306. Review. — View Citation

Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, Mitch W, Smith SC Jr, Sowers JR. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 1999 Sep 7;100(10):1134-46. Review. Erratum in: Circulation 2000 Apr 4;101(13):1629-31. — View Citation

Rongen GA, Oyen WJ, Ramakers BP, Riksen NP, Boerman OC, Steinmetz N, Smits P. Annexin A5 scintigraphy of forearm as a novel in vivo model of skeletal muscle preconditioning in humans. Circulation. 2005 Jan 18;111(2):173-8. Epub 2004 Dec 27. — View Citation

Yue TL, Bao W, Gu JL, Cui J, Tao L, Ma XL, Ohlstein EH, Jucker BM. Rosiglitazone treatment in Zucker diabetic Fatty rats is associated with ameliorated cardiac insulin resistance and protection from ischemia/reperfusion-induced myocardial injury. Diabetes. 2005 Feb;54(2):554-62. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	The effect of rosiglitazone as compared to placebo on the HOMA-index.
Secondary	Changes in vital signs, body weight, clinical laboratory parameters and adverse events monitoring during the study.