Title:
Azithromycin for the prevention of the progression of ischemic cerebral lesions in patients surviving a non-cardioembolic cerebral infarct, The ACSI-trial
Rationale:
Chlamydia pneumoniae (CP) infection has been linked to the initiation and progression of atherosclerosis, with serological markers of CP infection being more prevalent in stroke and ischemic heart disease patients than healthy controls. The risk to develop recurrent stroke, myocardial infarction or vascular death after a first stroke is about 15% in two years, despite regular secondary prophylactic therapy. Moreover, 40-60% of ischemic stroke patients showed and increase in white matter lesions and/or brain infarcts (mostly silent) on follow-up CT scan at three years. Main objective of this study is to explore whether azithromycin reduces the progression of ischemic cerebral lesions on MRI in stroke patients surviving a non-cardioembolic cerebral infarct
Design:
Patients eligible for the study who gave written informed consent, are randomized three months after ischemic stroke. Follow-ups are at 3, 6, 12, 18 and 24 months after randomisation.
Sample size:
To detect a 50% reduction in patients with progression of ischemic brain lesions (from 40% to 20%), using a significance level of 5% (one-sided) and a power of 80%, 63 seropositive patients are needed in each treatment group. Patients were included regardless of seropositivity for CP. Seroprevalence is estimated at 75%, so that 170 patients should be included.
Population studied:
Ischemic stroke patients admitted to the neurological wards, or visiting the neurologic outpatient clinic of the University Hospital Maastricht or the Maasland Hospital in Sittard, The Netherlands.
Only patients with atherosclerosis as cause of the stroke are included, exclusion criteria include cardial embolism, hematologic disorders, or other rare causes of stroke. Patients scheduled for carotid endarterectomy are also excluded.
Intervention:
Azithromycin or placebo: 500 mg/day for 3 days, followed by 500mg / week for 12 weeks.
Outcome measure:
Primary:
The increase in number of lacunar infarcts and severity of diffuse cerebral ischemic damage (leukoaraiosis) on T2 weighted MRI images of the brain.
Secondary:
Cerebro- or cardiovascular events, and vascular death; Change in the degree of cognitive score measured by CAMCOG; Functional decline measured by Rankin scale and Barthel index; Increase in IMT of common carotid artery; Serum parameters: antibodies against CP, hsCRP; Presence of CP in peripheral blood monocytes (PBMC)
Statistical analysis
The difference in risk of developing an increase in ischemic cerebral disease between the placebo and treatment group is tested with a Chi-square test, and by a multivariate logistic regression model. The logistic regression model will also be used to asses the influence of the treatment on the presence of serum antibodies against CP, and presence of CP in PBMC's. Difference in hsCRP between the two treatment groups will be tested using a Student’s T test.
Trial status:
Start date: june 2000, Number of patients enrolled: 169, inclusion ended in september 2003. Follow up will end in september 2005.
Principal ivestigators:
Manuela Voorend, M. D.
Andre van der Ven, M. D., PhD
Jan Lodder, M. D., PhD
Cathrien Bruggeman, PhD
Trial methodologist, Fons Kessels, M. D., MSc
Sponsor:
Netherlands Heart Foundation
Contact information:
Correspondence to : Manuela Voorend
e-mail : m.voorend@neurologie.azm.nl