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

Primary Purpose

Cerebral Small Vessel Diseases

Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Amlodipine
Losartan
Atenolol
Sponsored by
Ludwig-Maximilians - University of Munich
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cerebral Small Vessel Diseases focused on measuring Hypertension, Cerebrovascular Reactivity, Blood Pressure Variability

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Insitute for Stroke and Dementia Research
  • Maastricht University Medical Center
  • University Medical Center Utrecht
  • Nuffield Department of Clinical Neurosciences
  • Centre for Clinical Brain Sciences

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

Arm A

Arm B

Arm C

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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
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

Full Information

First Posted
March 8, 2017
Last Updated
March 7, 2023
Sponsor
Ludwig-Maximilians - University of Munich
Collaborators
University of Edinburgh, Maastricht University Medical Center, UMC Utrecht, University of Oxford
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1. Study Identification

Unique Protocol Identification Number
NCT03082014
Brief Title
Effects of Amlodipine and Other Blood Pressure Lowering Agents on Microvascular Function
Acronym
TREAT-SVDs
Official Title
EffecTs of Amlodipine and Other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Terminated
Why Stopped
completed for the primary study group of sporadic SVD patients, halted prematurely for the additional study group due to slow recruitment at 26 of 30 CADASIL patients in December 2022
Study Start Date
February 22, 2018 (Actual)
Primary Completion Date
July 28, 2022 (Actual)
Study Completion Date
July 28, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ludwig-Maximilians - University of Munich
Collaborators
University of Edinburgh, Maastricht University Medical Center, UMC Utrecht, University of Oxford

4. Oversight

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
Data Monitoring Committee
No

5. 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)
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cerebral Small Vessel Diseases
Keywords
Hypertension, Cerebrovascular Reactivity, Blood Pressure Variability

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
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
Outcomes Assessor
Masking Description
Cerebrovascular reactivity measures will be assessed centrally by a blinded rater.
Allocation
Randomized
Enrollment
101 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A
Arm Type
Active Comparator
Arm Description
Amlodipine for 4 weeks, Losartan for 4 weeks, Atenolol for 4 weeks.
Arm Title
Arm B
Arm Type
Active Comparator
Arm Description
Atenolol for 4 weeks, Amlodipine for 4 weeks, Losartan for 4 weeks.
Arm Title
Arm C
Arm Type
Active Comparator
Arm Description
Losartan for 4 weeks, Atenolol for 4 weeks, Amlodipine for 4 weeks.
Intervention Type
Drug
Intervention Name(s)
Amlodipine
Intervention Description
blood pressure lowering agent - dihydropyridine Ca2+-channel blocker
Intervention Type
Drug
Intervention Name(s)
Losartan
Intervention Description
blood pressure lowering agent - angiotensin-receptor blockers
Intervention Type
Drug
Intervention Name(s)
Atenolol
Intervention Description
blood pressure lowering agent - beta-blocker
Primary Outcome Measure Information:
Title
Change from Baseline Cerebrovascular Reactivity (CVR) at 4 weeks of Monotherapy
Description
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.
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)
Secondary Outcome Measure Information:
Title
Change from Baseline Mean Systolic Blood Pressure (SBP) at the last week of each treatment phase
Description
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
Time Frame
within the last week of the run-in phase and within the last week of each treatment phase
Title
Change from Baseline Blood Pressure Variability (BPv) at the last week of each treatment phase
Description
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
Time Frame
within the last week of the run-in phase and within the last week of each treatment phase

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Martin Dichgans, Prof.
Organizational Affiliation
Institute for Stroke and Dementia Research
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Joanna Wardlaw, Prof.
Organizational Affiliation
Neuroimaging Sciences and Brain Research Imaging Centre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Robert van Oostenbrugge, Prof.
Organizational Affiliation
Maastricht University Medical Center (UM), Department of Neurology
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Geert Jan Biessels, Prof.
Organizational Affiliation
UMC Utrecht Brain Center Robert Magnus (UMCU)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Peter Rothwell, Prof.
Organizational Affiliation
Nuffield Department of Clinical Neurosciences, Oxford (UOXF)
Official's Role
Principal Investigator
Facility Information:
Facility Name
Insitute for Stroke and Dementia Research
City
Munich
ZIP/Postal Code
81377
Country
Germany
Facility Name
Maastricht University Medical Center
City
Maastricht
ZIP/Postal Code
6202 AZ
Country
Netherlands
Facility Name
University Medical Center Utrecht
City
Utrecht
ZIP/Postal Code
3584 CX
Country
Netherlands
Facility Name
Nuffield Department of Clinical Neurosciences
City
Oxford
State/Province
England
ZIP/Postal Code
OX1 2JD
Country
United Kingdom
Facility Name
Centre for Clinical Brain Sciences
City
Edinburgh
State/Province
Scotland
ZIP/Postal Code
EH16 4SB
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No

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

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