Clinical trial
EffecTs of Amlodipine and Other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases
Name
TRE-1486--0105-I
Description
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)
Trial arms
Trial start
2018-02-22
Estimated PCD
2022-07-28
Trial end
2022-07-28
Status
Terminated
Phase
Early phase I
Treatment
Amlodipine
blood pressure lowering agent - dihydropyridine Ca2+-channel blocker
Arms:
Arm A, Arm B, Arm C
Losartan
blood pressure lowering agent - angiotensin-receptor blockers
Arms:
Arm A, Arm B, Arm C
Atenolol
blood pressure lowering agent - beta-blocker
Arms:
Arm A, Arm B, Arm C
Size
101
Primary endpoint
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)
Eligibility 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)
Protocol
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Updated at
2023-03-09
1 organization
1 product
2 drugs
1 indication
Organization
Ludwig-Maximilians University of MunichDrug
AmlodipineIndication
Cerebral Small Vessel DiseasesDrug
LosartanProduct
Atenolol