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

NCT ID: NCT03082014

Last Updated: 2023-03-09

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 101 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-02-22
• Study Completion Date: 2022-07-28

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.

Conditions

Cerebral Small Vessel Diseases

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Arm A

Amlodipine for 4 weeks, Losartan for 4 weeks, Atenolol for 4 weeks.

Group Type: ACTIVE_COMPARATOR

Amlodipine

Intervention Type: DRUG

blood pressure lowering agent - dihydropyridine Ca2+-channel blocker

Losartan

Intervention Type: DRUG

blood pressure lowering agent - angiotensin-receptor blockers

Atenolol

Intervention Type: DRUG

blood pressure lowering agent - beta-blocker

Arm B

Atenolol for 4 weeks, Amlodipine for 4 weeks, Losartan for 4 weeks.

Group Type: ACTIVE_COMPARATOR

Amlodipine

Intervention Type: DRUG

blood pressure lowering agent - dihydropyridine Ca2+-channel blocker

Losartan

Intervention Type: DRUG

blood pressure lowering agent - angiotensin-receptor blockers

Atenolol

Intervention Type: DRUG

blood pressure lowering agent - beta-blocker

Arm C

Losartan for 4 weeks, Atenolol for 4 weeks, Amlodipine for 4 weeks.

Group Type: ACTIVE_COMPARATOR

Amlodipine

Intervention Type: DRUG

blood pressure lowering agent - dihydropyridine Ca2+-channel blocker

Losartan

Intervention Type: DRUG

blood pressure lowering agent - angiotensin-receptor blockers

Atenolol

Intervention Type: DRUG

blood pressure lowering agent - beta-blocker

Interventions

Amlodipine

blood pressure lowering agent - dihydropyridine Ca2+-channel blocker

Intervention Type: DRUG

Losartan

blood pressure lowering agent - angiotensin-receptor blockers

Intervention Type: DRUG

Atenolol

blood pressure lowering agent - beta-blocker

Intervention Type: DRUG

Eligibility 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

• 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)

Exclusion Criteria

Patients will be excluded from the trial for any of the following reasons:

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Edinburgh

OTHER

Sponsor Role: collaborator

Maastricht University Medical Center

OTHER

Sponsor Role: collaborator

UMC Utrecht

OTHER

Sponsor Role: collaborator

University of Oxford

OTHER

Sponsor Role: collaborator

Ludwig-Maximilians - University of Munich

OTHER

Sponsor Role: lead

Responsible Party

Martin Dichgans

Prof. Dr. Martin Dichgans

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Martin Dichgans, Prof.

Role: STUDY_DIRECTOR

Institute for Stroke and Dementia Research

Joanna Wardlaw, Prof.

Role: PRINCIPAL_INVESTIGATOR

Neuroimaging Sciences and Brain Research Imaging Centre

Robert van Oostenbrugge, Prof.

Role: PRINCIPAL_INVESTIGATOR

Maastricht University Medical Center (UM), Department of Neurology

Geert Jan Biessels, Prof.

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht Brain Center Robert Magnus (UMCU)

Peter Rothwell, Prof.

Role: PRINCIPAL_INVESTIGATOR

Nuffield Department of Clinical Neurosciences, Oxford (UOXF)

Locations

Insitute for Stroke and Dementia Research

Munich, , Germany

Maastricht University Medical Center

Maastricht, , Netherlands

University Medical Center Utrecht

Utrecht, , Netherlands

Nuffield Department of Clinical Neurosciences

Oxford, England, United Kingdom

Centre for Clinical Brain Sciences

Edinburgh, Scotland, United Kingdom

Countries

Germany; Netherlands; United Kingdom

References

Kopczak A, Stringer MS, van den Brink H, Kerkhofs D, Blair GW, van Dinther M, Reyes CA, Garcia DJ, Onkenhout L, Wartolowska KA, Thrippleton MJ, Kampaite A, Duering M, Staals J, Lesnik-Oberstein S, Muir KW, Middeke M, Norrving B, Bousser MG, Mansmann U, Rothwell PM, Doubal FN, van Oostenbrugge R, Biessels GJ, Webb AJS, Wardlaw JM, Dichgans M; TREAT-SVDs collaborators. Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial. Lancet Neurol. 2023 Nov;22(11):991-1004. doi: 10.1016/S1474-4422(23)00293-4.

Reference Type: DERIVED

PMID: 37863608 (View on PubMed)

Kopczak A, S Stringer M, van den Brink H, Kerkhofs D, W Blair G, van Dinther M, Onkenhout L, A Wartolowska K, Thrippleton MJ, Duering M, Staals J, Middeke M, Andre E, Norrving B, Bousser MG, Mansmann U, Rothwell PM, N Doubal F, van Oostenbrugge R, Biessels GJ, Webb AJ, Wardlaw JM, Dichgans M. The EffecTs of Amlodipine and other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases (TREAT-SVDs) trial: Study protocol for a randomised crossover trial. Eur Stroke J. 2023 Mar;8(1):387-397. doi: 10.1177/23969873221143570. Epub 2022 Dec 16.

Reference Type: DERIVED

PMID: 37021189 (View on PubMed)

Other Identifiers

TRE-1486--0105-I

Identifier Type: -

Identifier Source: org_study_id