Clinical trial NCT00405015: The Effect of Rosiglitazone on Ischemia-reperfusion-injury Using Annexin A5 Scintigraphy.
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ischemia-Reperfusion Injury
The Metabolic Syndrome
Keywords: rosiglitazone
ischemia-reperfusion injury
human
Annexin A5 scintigraphy
metabolic syndrome
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2006-11-29
Enrollment: 13
Sex: ALL
Minimum age (years): 20
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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 outcomes:
measure: The effect of rosiglitazone as compared to placebo on the HOMA-index.
measure: Changes in vital signs, body weight, clinical laboratory parameters and adverse events monitoring during the study.
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Clinical research Center Nijmegen
Study officials:
affiliation: Radboud University Nijmegen Medical Center, department pharmacology-Toxicology
name: Gerard A Rongen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Nijmegen Medical Center, department of pharmacology-Toxicology
name: Alexander JM Rennings, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Nijmegen Medical Center, head of department of Parmacology-Toxicology
name: Paul Smits, MD, PhD
role: STUDY_DIRECTOR
References:
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. doi: 10.1161/01.cir.100.10.1134. No abstract available.
citation: 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. doi: 10.7326/0003-4819-126-4-199702150-00006.
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. doi: 10.2337/diabetes.54.2.554.
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. doi: 10.1161/01.CIR.0000151612.02223.F2. Epub 2004 Dec 27.