Primary objective:To test the hypothesis that 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…
ID
Source
Brief title
Condition
- Central nervous system vascular disorders
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• The primary outcome measure is the cerebrovascular reactivity (CVR) as
determined by BOLD MRI (T2*) brain scan response to hypercapnic challenge at
the end of the 2 week run-in phase and after 4 weeks of monotherapy while still
on medication.
Secondary outcome measures:
• Mean systolic blood pressure (SBP) assessed by daily telemetric monitoring
within the last week of the run-in phase and within the last week of each
treatment phase
• 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
Secondary outcome
• Mean systolic blood pressure (SBP) assessed by daily telemetric monitoring
within the last week of the run-in phase and within the last week of each
treatment phase
• 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
Background summary
Stroke and dementia rank among the most pressing health issues in Europe.
Cerebral small vessel diseases (SVDs) have emerged as a central link between
these two major co-morbidities. SVDs account for more than 30% of strokes and
at least 40% of dementia. Despite this profound impact on human health, there
are no treatments with proven efficacy against SVDs. Treat-SVDs is part of a
coordinated programme to elucidate key mechanisms common to different SVDs, and
determine how these mechanisms contribute to individual SVDs (SVDs@Target
Project, funded by the European Horizon 2020 Scheme).
Recently, it has been proposed that endothelial dysfunction of microvessels
plays a key role in the development of SVDs. Endothelial dysfunction in the
brain can be measured by assessing blood flow response to a stimulus. This
measure is termed cerebrovascular reactivity (CVR). CVR is known to be impaired
after stroke as a marker for endothelium dysfunction.
Studying the effects of different antihypertensive drug classes on
microvascular function, assessed by CVR and BPv, holds great promise for
improving our mechanistic understanding of SVDs, stroke, and dementia.
Currently there are no specific treatments to prevent the clinical or
radiological progression of SVDs. Proving the feasibility of multi-centre,
multinational trials using CVR and telemetric BP monitoring will be vital for
proceeding to future, larger trials of new SVDs therapies
Study objective
Primary objective:
To test the hypothesis that 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:
To test the hypothesis that losartan has a superior beneficial effect on
cerebrovascular reactivity when compared to atenolol
Study design
Treat-SVDs has a multicentre, multinational, prospective randomised,
open-label, 3 sequence crossover study design with blinded endpoint assessment
(PROBE)
Intervention
There are three different antihypertensive medicinal products used in this
study:
• amlodipine 2.5 to 10 mg orally administered once daily
• losartan 25 to 100 mg orally administered once daily
• atenolol 25 to 100 mg orally administered once daily
Every patient will take three different antihypertensive medicinal products
from three separate drug classes for four weeks, each with a different
mechanism that affects the cerebrovascular reactivity.
Patients meeting eligibility criteria will be randomly allocated to one of
three sequences of antihypertensive treatment:
Group 1: amlodipine > losartan > atenolol
Group 2: atenolol > amlodipine > losartan
Group 3: losartan > atenolol > amlodipine.
Study burden and risks
Participants will attend for 5 visits over a period of 14 weeks.
After enrolment participant have to stop taking their antihypertensive
medication for the two weeks run-in period. During this run-in period there
will be an increased risk for cardiovascular events and for hypertensive crisis.
To counteract this, we
a) exclude patients taking more than two antihypertensive drugs
b) measure blood pressure regularly during the whole trial period
c) administer rescue medication as needed (and)
d) withdraw subjects in case of persisting hypertension despite
antihypertensive treatment according to the trial protocol.
During the first visit (the screening), patients proceed to have a full medical
history, physical examination will be performed, cognitive testing will be
performed and blood samples will be taken for analysis. Participants receive a
BP machine to perform home BP monitoring with the device 2-3 times daily for
the next 14 weeks.
The visits next 4 visits take place from week two with an interval of 4 weeks.
During the visits the patients undergo MRI with a CVR measurement. No contrast
agent is used during the MRI scans. Total MRI time the first visit is 60
minutes divided in two sessions. The MRI during the next three visits takes 40
minutes. During every visit a physical examination is performed and blood
samples will be taken for analysis.
The patients included in the trial are in need of an antihypertensive treatment
due to hypertension or the secondary prevention of stroke. In both cases, the
application of antihypertensive drugs is generally recommended and in line with
clinical standards.
Every participating patient will take antihypertensive drugs belonging to three
different drug classes with different impact on BPv. For the purpose of a
personalised medicine, each patient participating in this trial will be
informed which medication does have the highest benefit for lowering blood
pressure. Trial participants will receive an individualised feedback on the
development of his/her BP and on pulse wave analysis depending on the three
different drugs.
The results of this trial will reveal new insights on the influence of
different antihypertensive drugs in SVDs and will lead to a better
understanding of SVDs. Based on the results of our trial, we aim to optimise
treatment in patients with SVDs.
Marchioninistraße 15
München D-81377
DE
Marchioninistraße 15
München D-81377
DE
Listed location countries
Age
Inclusion criteria
• Symptomatic SVD defined as
- a history compatible with clinical lacunar stroke syndrome in the last 5
years with a small subcortical infarct visible on MRI scan or CT scan
compatible with the clinical syndrome
- or cognitive impairment defined as visiting a memory clinic with cognitive
complains*, and capacity to and capacity to consent with confluent deep WMH on
MRI (defined on the Fazekas scale as deep WMH score >= 2).
*concluded by the treating physician based on a validated cognitive measurement
tool (for example but not limited to MoCA or CAMCOG)
-or a diagnosis of CADASIL (NOTCH 3 mutation carriers)
• Indication for antihypertensive treatment (as defined by meeting one of the
following):
o Hypertension defined as SBP >=140mmHg or diastolic BP (DBP) >=90mmHg without
antihypertensive treatment or use of an antihypertensive drug for previously
diagnosed hypertension
o Prior history of stroke or transient ischaemic attack (TIA),
• Age 18 years or older, written informed consent
Exclusion criteria
• Inclusion criteria are not met,
• Unwillingness or inability to give written consent,
• Pregnant or breastfeeding women, women of childbearing age not taking
contraception. ,
• Contraindications to MRI (pacemaker, aneurysm clip, cochlear implant etc.) ,
• Other major neurological or psychiatric conditions affecting the brain and
interfering with the study design (e.g. multiple sclerosis), In case of
clinical lacunar stroke other causes of stroke such as
o >=50% luminal stenosis (NASCET) in large arteries supplying the infarct area
o major-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)
o other specific causes of stroke (e.g. arteritis, dissection, migraine/
vasospasm, drug misuse) ,
• Other stroke risk factor requiring immediate intervention that would preclude
involvement in the study,
• Renal impairment (eGFR <35 ml/min),
• Panic disorder,
• Life expectancy <2 years,
• Use of >2 antihypertensive drugs at maximum dose or equivalent (one drug at
the maximum dose and two drugs at half of the maximum dose) for an appropriate
BP control,
• Contraindications to the applied antihypertensive drugs as known
o Severe aortic stenosis
o Bilateral renal artery stenosis
o Severe arterial circulatory disorders
o Atrioventricular block II° or III° or sick sinus syndrome
o Heart failure (NYHA III or IV)
o Bradycardia, resting heart rate <50/min
o Bronchospastic diseases such as severe bronchial asthma
o Severe hepatic dysfunction such as liver cirrhosis
o Use of monoamine oxidase (MAO)-A-blockers
o Use of simvastatin >20mg/d
o Metabolic acidosis
o Disturbed electrolyte homeostasis such as hypercalcaemia, hypokalaemia, and
hyponatraemia
o Symptomatic hyperuricaemia (gout)
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 | EUCTR2016-002920-10-NL |
| ClinicalTrials.gov | NCT03082014 |
| CCMO | NL59984.068.17 |