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

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ClinicalTrials.gov Identifier: NCT03082014
Recruitment Status : Recruiting
First Posted : March 17, 2017
Last Update Posted : August 14, 2019
Sponsor:
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

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.


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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

Resource links provided by the National Library of Medicine


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




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



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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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03082014


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

Locations
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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
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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)

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Responsible Party: Martin Dichgans, Prof. Dr. Martin Dichgans, Ludwig-Maximilians - University of Munich
ClinicalTrials.gov Identifier: NCT03082014     History of Changes
Other Study ID Numbers: TRE-1486--0105-I
First Posted: March 17, 2017    Key Record Dates
Last Update Posted: August 14, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Cerebral Small Vessel Diseases
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Losartan
Atenolol
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