To estimate the effect of rosiglitazone compared to placebo on ischemia-reperfusion injury as assessed by annexin A5 scintigraphy in the human forearm in subjects with the metabolic syndrome.
ID
Source
Brief title
Condition
- Myocardial disorders
- Diabetic complications
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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
The effect of rosiglitazone as compared to placebo on the HOMA-index.
Background 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. 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-injuryby
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 objective
To estimate the effect of rosiglitazone compared to placebo on
ischemia-reperfusion injury as assessed by annexin A5 scintigraphy in the human
forearm in subjects with the metabolic syndrome.
Study design
This is a single-center randomized, double blind, placebo-controlled crossover
study comparing 8 weeks of treatment with rosiglitazone 4mg bd and placebo bd.
In between the treatment periods there is a washout period of 6 weeks.
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.
Study burden and risks
Drug intervention: Rosiglitazone 4 mg bd and placebo bd both during 8 weeks.
Ambulant clinic visits: During at maximum 30 weeks, 5 visits (screening visit
1.5 hour, other visits 45 minutes). During all these visits anamnesis, physical
examination, blood measurements (fasting at screening and two other visits).
Ischemic exercise protocol: In week 8 and 22. The subject has to come to the
hospital after an overnight fast and refrain of using caffeine for the last 24
hours. During this day one venous catheter will be inserted. Then ischemia will
be applied to the non-dominant forearm of the subject for 10 minutes, while the
subject is asked to do hand gripping with half maximum strength. Directly
following this ischemic exercise, the Annexin will be injected. After having
made a scintigraphic picture 4 hours later the subject may go home. Blood
drawing: During the whole study protocol 131 ml of blood will be drawn.
Risks: Rosiglitazone has been used worldwide for several years already and does
not seem to induce severe adverse events in a high frequency, especially not
when used in subjects without diabetes and exogenous use of insulin. Adverse
events most frequently reported are weight increase and fluid retention.
Theoretically, Annexin could induce an allergic reaction, but this was not
described before. The amount of radioactivity is within the range that is
allowed for use in volunteers.
Geert groote plein Noord 21
6525 EZ
Nederland
Geert groote plein Noord 21
6525 EZ
Nederland
Listed location countries
Age
Inclusion criteria
1). At least 3 features of the metabolic syndrome (AHA/NHLBI) (10)
2). Willing and able to provide a signed and dated written informed consent.
3). Male and postmenopausal female subjects aged between 20 and 70 years
Exclusion criteria
1). 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.
2). Exposure to a PPAR-g agonist during the last 4 months or a documented significant hypersensitivity to a PPAR-g agonist.
3). Participant in another study.
4). Angina or heart failure (NYHA I-IV).
5). Clinically significant liver disease (3 times the upper normal limit of ALAT, ASAT, AF, γGT or LDH)
6). Clinically significant anaemia (male Hb < 6,9 mmol/L, female < 6,25 mmol/L)
7). Creatinin clearance < 40 mL/min
8). Alcohol or drug abuse.
9). Any physical inability to perform the exercise protocol.
10). Administration of any radiotracer for research purposes during the previous 5 years.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2006-006208-13-NL |
| ClinicalTrials.gov | NCT00405015 |
| CCMO | NL15030.091.06 |