Effects of Amlodipine and Other Blood Pressure Lowering Agents on Microvascular Function (TREAT-SVDs)

EffecTs of Amlodipine and Other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases

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)

Study Overview

• Status: Terminated
• Conditions: Cerebral Small Vessel Diseases
• Intervention / Treatment: Drug: Amlodipine; Drug: Losartan; Drug: Atenolol

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 Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anna Kopczak, Dr.; Phone Number: 46125 +49 (0)89 4400; Email: anna.kopczak@med.uni-muenchen.de

Study Locations

• Germany
  • Munich, Germany, 81377
    • Insitute for Stroke and Dementia Research
• Netherlands
  • Maastricht, Netherlands, 6202 AZ
    • Maastricht University Medical Center
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht
• United Kingdom
  • England
    • Oxford, England, United Kingdom, OX1 2JD
      • Nuffield Department of Clinical Neurosciences
  • Scotland
    • Edinburgh, Scotland, United Kingdom, EH16 4SB
      • Centre for Clinical Brain Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline Cerebrovascular Reactivity (CVR) at 4 weeks of Monotherapy	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.	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline Mean Systolic Blood Pressure (SBP) at 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	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	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	within the last week of the run-in phase and within the last week of each treatment phase

Collaborators and Investigators

• Sponsor: Ludwig-Maximilians - University of Munich
• Collaborators: Maastricht University Medical Center; UMC Utrecht; University of Oxford; University of Edinburgh
• 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 record dates

Study Major Dates

• Study Start (Actual): February 22, 2018
• Primary Completion (Actual): July 28, 2022
• Study Completion (Actual): July 28, 2022

Study Registration Dates

• First Submitted: March 8, 2017
• First Submitted That Met QC Criteria: March 16, 2017
• First Posted (Actual): March 17, 2017

Study Record Updates

• Last Update Posted (Estimate): March 9, 2023
• Last Update Submitted That Met QC Criteria: March 7, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Hypertension; Cerebrovascular Reactivity; Blood Pressure Variability
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Amlodipine; Losartan; Atenolol
• Other Study ID Numbers: TRE-1486--0105-I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No