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

• ClinicalTrials.gov Identifier: NCT03082014
• Recruitment Status: Recruiting
• First Posted: March 17, 2017
• Last Update Posted: August 14, 2019
• Sponsor: Ludwig-Maximilians - University of Munich
• Collaborators: University of Edinburgh; Maastricht University Medical Center; UMC Utrecht; University of Oxford
• Information provided by (Responsible Party): Martin Dichgans, Ludwig-Maximilians - University of Munich

Study Description

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)

Condition or disease	Intervention/treatment	Phase
Cerebral Small Vessel Diseases	Drug: Amlodipine; Drug: Losartan; Drug: Atenolol	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 105 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: TREAT-SVDs is a multi-centre, multinational phase III b clinical trial with a three sequence crossover design. It will be carried out as a rater blinded trial which is also known as PROBE-design (prospective, randomised, open-label trial with blinded endpoint assessment).
• Masking: Single (Outcomes Assessor)
• Masking Description: Cerebrovascular reactivity measures will be assessed centrally by a blinded rater.
• Primary Purpose: Treatment
• Official Title: EffecTs of Amlodipine and Other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases
• Actual Study Start Date: February 22, 2018
• Estimated Primary Completion Date: March 31, 2020
• Estimated Study Completion Date: September 30, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Change from Baseline Cerebrovascular Reactivity (CVR) at 4 weeks of Monotherapy [ Time Frame: 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 :

1. Change from Baseline Mean Systolic Blood Pressure (SBP) at the last week of each treatment phase [ Time Frame: 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
2. Change from Baseline Blood Pressure Variability (BPv) at the last week of each treatment phase [ Time Frame: 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

Eligibility Criteria

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

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)

Contacts and Locations

Contacts

Contact: Anna Kopczak, Dr.; +49 (0)89 4400 ext 46125; anna.kopczak@med.uni-muenchen.de

Locations

Germany

Insitute for Stroke and Dementia Research; Recruiting

Munich, Germany, 81377

Contact: Martin Dichgans, Prof. +49 89 4400 ext 46019

Contact: Anna Kopczak, MD +49 89 4400 ext 46125

Netherlands

Maastricht University Medical Center; Recruiting

Maastricht, Netherlands, 6202 AZ

Contact: Robert van Oostenbrugge, Prof.

Contact: Julie Staals, MD, PhD

Sub-Investigator: Danielle Kerkhofs

University Medical Center Utrecht; Recruiting

Utrecht, Netherlands, 3584 CX

Contact: Geert Jan Biessels, Prof.

Contact: Laurien Onkenhout, MD

United Kingdom

Nuffield Department of Clinical Neurosciences; Recruiting

Oxford, England, United Kingdom, OX1 2JD

Contact: Peter Rothwell, Prof.

Contact: Alastair Webb, MD, PhD

Centre for Clinical Brain Sciences; Recruiting

Edinburgh, Scotland, United Kingdom, EH16 4SB

Contact: Joanna Wardlaw, Prof.

Contact: Fergus Doubal, MD, PhD

Sponsors and Collaborators

Ludwig-Maximilians - University of Munich

University of Edinburgh

Maastricht University Medical Center

UMC Utrecht

University of Oxford

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)

More Information

• Responsible Party: Martin Dichgans, Prof. Dr. Martin Dichgans, Ludwig-Maximilians - University of Munich
• ClinicalTrials.gov Identifier: NCT03082014
• Other Study ID Numbers: TRE-1486--0105-I
• First Posted: March 17, 2017
• Last Update Posted: August 14, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Martin Dichgans, Ludwig-Maximilians - University of Munich:

Hypertension; Cerebrovascular Reactivity; Blood Pressure Variability

Additional relevant MeSH terms:

Atenolol; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Losartan; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Vasodilator Agents; Anti-Arrhythmia Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Sympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents