EffecTs of Amlodipine and Other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases
| Registry | NCT03082014, acronym TREAT-SVDs |
|---|---|
| Status | Terminated - completed for the primary study group of sporadic SVD patients, halted prematurely for the additional study group due to slow recruitment at 26 of 30 CADASIL patients in December 2022 |
| Phase | Phase 3 |
| Study type | Interventional; randomized, crossover, masking: single, treatment |
| Enrollment | 101 (Actual) |
| Sponsor | Ludwig-Maximilians - University of Munich (Other); collaborators: University of Edinburgh, Maastricht University Medical Center, UMC Utrecht, University of Oxford |
| Conditions | Cerebral Small Vessel Diseases |
| Interventions | Amlodipine, Losartan, Atenolol (Drug) |
| Dates | start 2018-02-22, primary completion 2022-07-28, completion 2022-07-28, first posted 2017-03-17, last updated 2023-03-09 |
| Locations | 5 sites in Germany, Netherlands, United Kingdom |
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All trials for Cerebral Small Vessel Diseases All trials of Amlodipine All trials of Losartan
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)
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.
| Arm | Type | Interventions | Description |
|---|---|---|---|
| Arm A | Active comparator | Drug: Amlodipine; Drug: Losartan; Drug: Atenolol | Amlodipine for 4 weeks, Losartan for 4 weeks, Atenolol for 4 weeks. |
| Arm B | Active comparator | Drug: Amlodipine; Drug: Losartan; Drug: Atenolol | Atenolol for 4 weeks, Amlodipine for 4 weeks, Losartan for 4 weeks. |
| Arm C | Active comparator | Drug: Amlodipine; Drug: Losartan; Drug: Atenolol | Losartan for 4 weeks, Atenolol for 4 weeks, Amlodipine for 4 weeks. |
Sex: All, ages: 18 Years to any
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)| Facility | City | Country | Status |
|---|---|---|---|
| Insitute for Stroke and Dementia Research | Munich | Germany | |
| Maastricht University Medical Center | Maastricht | Netherlands | |
| University Medical Center Utrecht | Utrecht | Netherlands | |
| Nuffield Department of Clinical Neurosciences | Oxford, England | United Kingdom | |
| Centre for Clinical Brain Sciences | Edinburgh, Scotland | United Kingdom |