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

Phase 3

Terminated

• Conditions: Cerebral Small Vessel Diseases
• Interventions: Drug: Amlodipine; Drug: Losartan; Drug: Atenolol

• Registration Number: NCT03082014
• Lead Sponsor: Ludwig-Maximilians - University of Munich

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.

Study Timeline

• Study First Submitted: 2017-03-08
• Study First Submitted QC: 2017-03-16
• Study First Posted: 2017-03-17
• Study Start: 2018-02-22
• Primary Completion: 2022-07-28
• Study Completion: 2022-07-28
• Status Verified: 2023-03
• Last Update Submitted: 2023-03-07
• Last Update Posted: 2023-03-09

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 101

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Arm A	Amlodipine	Amlodipine for 4 weeks, Losartan for 4 weeks, Atenolol for 4 weeks.
Arm C	Amlodipine	Losartan for 4 weeks, Atenolol for 4 weeks, Amlodipine for 4 weeks.
Arm A	Losartan	Amlodipine for 4 weeks, Losartan for 4 weeks, Atenolol for 4 weeks.
Arm A	Atenolol	Amlodipine for 4 weeks, Losartan for 4 weeks, Atenolol for 4 weeks.
Arm B	Amlodipine	Atenolol for 4 weeks, Amlodipine for 4 weeks, Losartan for 4 weeks.
Arm B	Losartan	Atenolol for 4 weeks, Amlodipine for 4 weeks, Losartan for 4 weeks.
Arm C	Losartan	Losartan for 4 weeks, Atenolol for 4 weeks, Amlodipine for 4 weeks.
Arm B	Atenolol	Atenolol for 4 weeks, Amlodipine for 4 weeks, Losartan for 4 weeks.
Arm C	Atenolol	Losartan for 4 weeks, Atenolol for 4 weeks, Amlodipine for 4 weeks.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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

Trial Locations

Locations (5)

Insitute for Stroke and Dementia Research; 🇩🇪 Munich, Germany

Maastricht University Medical Center; 🇳🇱 Maastricht, Netherlands

Centre for Clinical Brain Sciences; 🇬🇧 Edinburgh, Scotland, United Kingdom

Nuffield Department of Clinical Neurosciences; 🇬🇧 Oxford, England, United Kingdom

University Medical Center Utrecht; 🇳🇱 Utrecht, Netherlands