Effects of Amlodipine and other blood pressure lowering agents on microvascular function in Small Vessel Diseases

Phase 1

• Conditions: Cerebral small vessel disease; Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

• Registration Number: EUCTR2016-002920-10-NL
• Lead Sponsor: Klinikum der Universitaet Muenchen AoeR

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2017-03-01
• Last Update Posted: 23 October 2017

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 105

Inclusion Criteria

•Symptomatic SVD defined as
oHistory of clinical lacunar stroke in the last 5 years with a corresponding recent small subcortical infarct visible on MRI scan or CT scan compatible with the clinical syndrome.
oor cognitive impairment defined as visiting a memory clinic with cognitive complaints, and a clinical dementia rating (CDR) score of =0.5, and capacity to consent, and with confluent deep white matter hyperintensities (WMH) on MRI (defined on the Fazekas scale as deep WMH score = 2)
oor a diagnosis of CADASIL established by molecular genetic testing of the NOTCH3 gene (presence of an archetypical, cysteine-affecting mutation) or the presence of granular osmiophilic material in ultrastructural, electron microscopy analysis of skin biopsy
•Indication for antihypertensive treatment (as defined by meeting one of the following):
oHypertension defined as systolic blood pressure (SBP) =140mmHg or diastolic BP (DBP) =90mmHg without antihypertensive treatment or use of an antihypertensive drug for previously diagnosed hypertension
oPrior history of stroke or transient ischaemic attack (TIA)
•Age 18 years or older
•Written informed consent

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 30
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 75

Exclusion Criteria

•Unwillingness or inability to give written consent
•Pregnant or breastfeeding women, women of childbearing age not taking contraception.
Acceptable contraception in women of childbearing age is a highly effective” contraceptive measure as defined by the Clinical Trials Facilitation Group
•Contraindications to MRI (pacemaker, aneurysm clip, cochlear implant etc.)
•Other major neurological or psychiatric conditions affecting the brain and interfering with the trial design (e.g. multiple sclerosis)
•In case of clinical lacunar stroke syndrome other causes of stroke such as
o=50% luminal stenosis (NASCET) in large arteries supplying the area of ischaemia
omajor-risk cardioembolic source of embolism (permanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumours, mitral stenosis, recent (<4 weeks) myocardial infarction, left ventricular ejection fraction less than 30%, valvular vegetations, or infective endocarditis)
oother specific causes of stroke identified (e.g. arteritis, dissection, migraine/vasospasm, drug misuse)
•Other stroke risk factor requiring immediate intervention that would preclude involvement in the trial
•Renal impairment (eGFR <35ml/min)
•Life expectancy <2 years

•Use of >2 antihypertensive drugs for an appropriate BP control
•Contraindications to the applied antihypertensive drug

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The calcium channel blocker amlodipine has a superior beneficial effect on cerebrovascular reactivity in patients with symptomatic SVDs when compared to either the Angiotensin II type 1 (AT1) receptor blocker losartan or the beta-blocker atenolol.;Secondary Objective: Losartan has a superior beneficial effect on cerebrovascular reactivity when compared to atenolol.;Primary end point(s): Cerebrovascular reactivity (CVR) as determined by BOLD MRI (T2*) brain scan response to hypercapnic challenge.;Timepoint(s) of evaluation of this end point: end of the 2 week run-in phase and after 4 weeks of monotherapy.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): •Mean SBP assessed by daily telemetric monitoring within the last week of the run-in phase and within the last week of each treatment phase<br>•Blood pressure variability (BPv) operationalized as coefficient of variation (100*standard deviation (std)/mean SBP) across multiple measurements and assessed by daily telemetric monitoring within the last week of the run-in phase and within the last week of each treatment phase<br>;Timepoint(s) of evaluation of this end point: see E.5.2