TREAT-SVDs: Effects of Amlodipine and Other Blood Pressure Lowering Agents on Microvascular Function
Study Details
Study Description
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)
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Arm A Amlodipine for 4 weeks, Losartan for 4 weeks, Atenolol for 4 weeks. |
Drug: Amlodipine
blood pressure lowering agent - dihydropyridine Ca2+-channel blocker
Drug: Losartan
blood pressure lowering agent - angiotensin-receptor blockers
Drug: Atenolol
blood pressure lowering agent - beta-blocker
|
| Active Comparator: Arm B Atenolol for 4 weeks, Amlodipine for 4 weeks, Losartan for 4 weeks. |
Drug: Amlodipine
blood pressure lowering agent - dihydropyridine Ca2+-channel blocker
Drug: Losartan
blood pressure lowering agent - angiotensin-receptor blockers
Drug: Atenolol
blood pressure lowering agent - beta-blocker
|
| Active Comparator: Arm C Losartan for 4 weeks, Atenolol for 4 weeks, Amlodipine for 4 weeks. |
Drug: Amlodipine
blood pressure lowering agent - dihydropyridine Ca2+-channel blocker
Drug: Losartan
blood pressure lowering agent - angiotensin-receptor blockers
Drug: Atenolol
blood pressure lowering agent - beta-blocker
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
Eligibility Criteria
Criteria
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)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Insitute for Stroke and Dementia Research | Munich | Germany | 81377 | |
| 2 | Maastricht University Medical Center | Maastricht | Netherlands | 6202 AZ | |
| 3 | University Medical Center Utrecht | Utrecht | Netherlands | 3584 CX | |
| 4 | Nuffield Department of Clinical Neurosciences | Oxford | England | United Kingdom | OX1 2JD |
| 5 | Centre for Clinical Brain Sciences | Edinburgh | Scotland | United Kingdom | EH16 4SB |
Sponsors and Collaborators
- Ludwig-Maximilians - University of Munich
- University of Edinburgh
- Maastricht University Medical Center
- UMC Utrecht
- University of Oxford
Investigators
- Study Director: Martin Dichgans, Prof., Institute for Stroke and Dementia Research
- Principal Investigator: Joanna Wardlaw, Prof., Neuroimaging Sciences and Brain Research Imaging Centre
- Principal Investigator: Robert van Oostenbrugge, Prof., Maastricht University Medical Center (UM), Department of Neurology
- Principal Investigator: Geert Jan Biessels, Prof., UMC Utrecht Brain Center Robert Magnus (UMCU)
- Principal Investigator: Peter Rothwell, Prof., Nuffield Department of Clinical Neurosciences, Oxford (UOXF)
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TRE-1486--0105-I