Effects of Amlodipine and Other Blood Pressure Lowering Agents on Microvascular Function

• Status: Recruiting
• Trial end date: 2022-03-31
• Target enrollment: 0
• Participant gender: All

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)

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Ludwig-Maximilians - University of Munich
• Collaborators: Maastricht University Medical Center; UMC Utrecht; University of Edinburgh; University of Oxford
• Treatments: Amlodipine; Atenolol; Losartan

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)