Cerebral Small Vessel Diseases
Conditions
Keywords
Hypertension, Cerebrovascular Reactivity, Blood Pressure Variability
Brief summary
Multicentre, multinational, prospective randomised, open-label, 3 sequence crossover phase III b clinical trial with blinded endpoint assessment (PROBE-design) * in 75 patients with sporadic small vessel diseases (SVDs) and * in 30 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
Detailed description
TREAT-SVDs will be carried out as a multicentre open label trial at five trial sites across 3 European countries: Germany, the Netherlands, and the United Kingdom. Patients meeting eligibility criteria will be randomly allocated to one of three sequences of antihypertensive treatment which are given as open-label oral medications in standard dose in the following order Arm A: Amlodipine \> Losartan \> Atenolol Arm B: Atenolol \> Amlodipine \> Losartan Arm C: Losartan \> Atenolol \> Amlodipine. The study starts with a two week run-in phase. During these first two weeks, patients are not allowed to take antihypertensive drugs except for the rescue medication. After the run-in period,every patient will take subsequently three different antihypertensive drugs (each drug from a separate drug class) according to the randomly assigned arm. Each study drug will be administered for four weeks. Patients will be monitored telemetrically with a dedicated BP device during the whole trial period of 14 weeks.
Interventions
DRUGAmlodipine
blood pressure lowering agent - dihydropyridine Ca2+-channel blocker
DRUGLosartan
blood pressure lowering agent - angiotensin-receptor blockers
DRUGAtenolol
blood pressure lowering agent - beta-blocker
Sponsors
University of Edinburgh
Maastricht University Medical Center
UMC Utrecht
University of Oxford
Ludwig-Maximilians - University of Munich
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Cerebrovascular reactivity measures will be assessed centrally by a blinded rater.
Intervention model description
TREAT-SVDs is a multi-centre, multinational phase III b clinical trial with a three sequence crossover design. It will be carried out as a rater blinded trial which is also known as PROBE-design (prospective, randomised, open-label trial with blinded endpoint assessment).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients may be enrolled in the trial if all of the following criteria have been met: * Symptomatic SVD defined as * History of clinical lacunar stroke in the last 5 years with a corresponding small subcortical infarct visible on MRI scan or CT scan\* compatible with the clinical syndrome. \*On MRI, recent infarct is defined as a diffusion-weighted imaging (DWI) lesion on the acute MRI scan. On CT, recent infarct is defined as a novel infarct on CT within 3 weeks after the event that was not visible on the admission CT. Patients admitted to the hospital with an obvious lacunar syndrome and an admission CT/CT perfusion compatible with a lacunar infarct but without an MRI in the (sub)acute stage and no repeat CT performed in the context of clinical care can be recruited for TREAT-SVDs. After providing informed consent they will be invited for the screening visit including a 3T MRI. The 3T MRI will be used to verify the presence of a new lesion, relative to the admission CT, compatible with a lacunar infarct and compatible with the lacunar syndrome. If such a lesion is present the patient will undergo the further TREAT-SVDs workup. If no such lesion is observed the patient will be excluded from the study and considered as a screening failure. * or cognitive impairment defined as visiting a memory clinic with cognitive complaints, objective cognitive impairment\*, and capacity to consent, and with confluent deep white matter hyperintensities (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 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): * Hypertension defined as SBP ≥ 140 mmHg or diastolic BP (DBP) ≥ 90 mmHg without antihypertensive treatment or use of an antihypertensive drug for previously diagnosed hypertension * Prior history of stroke or transient ischaemic attack (TIA) * Age 18 years or older * Written informed consent
Exclusion criteria
Patients will be excluded from the trial for any of the following reasons: * Inclusion criteria are not met * 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 and includes combined (oestrogen and progesterone containing) or progesterone-only contraception associated with inhibition of ovulation, or intrauterine device, or bilateral tubal occlusion. * 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 * ≥ 50% luminal stenosis (NASCET) in large arteries supplying the area of ischaemia * 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) * other 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 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 * Severe aortic stenosis * Bilateral renal artery stenosis * Severe arterial circulatory disorders * Atrioventricular block II° or III° or sick sinus syndrome * Heart failure (NYHA III or IV) * Bradycardia, resting heart rate \< 50/min * Bronchospastic diseases such as severe bronchial asthma * Severe hepatic dysfunction such as liver cirrhosis * Use of monoamine oxidase (MAO)-A-blockers * Use of simvastatin \> 20mg/d * Metabolic acidosis * Disturbed electrolyte homeostasis such as hypercalcaemia, hypokalaemia, and hyponatraemia * Symptomatic hyperuricaemia (gout)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline Cerebrovascular Reactivity (CVR) at 4 weeks of Monotherapy | baseline measure at the end of the run-in phase (week 2); after 4 weeks of each monotherapy (week 6, week 10, and week 14) | The primary outcome variable is CVR as determined by blood oxygen level-dependent (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
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline Mean Systolic Blood Pressure (SBP) at the last week of each treatment phase | within the last week of the run-in phase and within the last week of each treatment phase | 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 |
| Change from Baseline Blood Pressure Variability (BPv) at the last week of each treatment phase | within the last week of the run-in phase and within the last week of each treatment phase | BPv operationalized as coefficient of variation (100\*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 |
Countries
Germany, Netherlands, United Kingdom
Outcome results
None listed