Cerebral Small Vessel DiseasesPhase 3TREAT-SVDsNCT03082014

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

A Phase 3 study testing Amlodipine, Losartan and Atenolol in people with Cerebral Small Vessel Diseases, run by Ludwig-Maximilians - University of Munich at 5 sites in 3 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

Search all trials

Trial 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… Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Cerebral Small Vessel Diseases
What is being tested?: Amlodipine, Losartan and Atenolol
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 101 participants
Where: 5 sitesin 3 countries
Study dates: 22 Feb 2018to 28 Jul 2022
Phase: Phase 3
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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)

Show all 39Show fewer

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)

Who cannot join

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

Trial locations and contacts

5 sites in 3 countries.

Country

City, postcode or hospital

5 sites in 3 countries

Netherlands2 sites

Maastricht University Medical Center
Maastricht, 6202 AZ
University Medical Center Utrecht
Utrecht, 3584 CX

Other trials in Netherlands

United Kingdom2 sites

Centre for Clinical Brain Sciences
Edinburgh, Scotland, EH16 4SB
Nuffield Department of Clinical Neurosciences
Oxford, England, OX1 2JD

Other trials in United Kingdom

Germany1 site

Insitute for Stroke and Dementia Research
Munich, 81377

Other trials in Germany

About this study

Official title: 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)

Read the 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
Being tested: Amlodipine, Losartan, Atenolol
Keywords: Hypertension, Cerebrovascular Reactivity, Blood Pressure Variability
Medical subject headings: Cerebral Small Vessel Diseases, Hypertension

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

AmlodipineDrug
blood pressure lowering agent - dihydropyridine Ca2+-channel blocker
LosartanDrug
blood pressure lowering agent - angiotensin-receptor blockers
AtenololDrug
blood pressure lowering agent - beta-blocker

Study groups in NCT03082014
Study group	Role	What they receive
Arm A	Active comparator	Amlodipine for 4 weeks, Losartan for 4 weeks, Atenolol for 4 weeks. Receives: Drug: Amlodipine; Drug: Losartan; Drug: Atenolol
Arm B	Active comparator	Atenolol for 4 weeks, Amlodipine for 4 weeks, Losartan for 4 weeks. Receives: Drug: Amlodipine; Drug: Losartan; Drug: Atenolol
Arm C	Active comparator	Losartan for 4 weeks, Atenolol for 4 weeks, Amlodipine for 4 weeks. Receives: Drug: Amlodipine; Drug: Losartan; Drug: Atenolol

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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 outcomes (2)

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
Measured: 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
Measured: within the last week of the run-in phase and within the last week of each treatment phase

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

22 Feb 201828 Jul 2022

First posted17 Mar 2017
Study start22 Feb 2018
Primary completion28 Jul 2022
Study completion28 Jul 2022

Why it 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

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Cerebral Small Vessel DiseasesStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
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 blind
Who is masked: Outcomes assessor
Enrolment: 101 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03082014
Sponsor's protocol ID: TRE-1486--0105-I
Acronym: TREAT-SVDs
Status last verified: Mar 2023
First submitted: 8 Mar 2017
Last updated: 9 Mar 2023
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No

Publications

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.
PubMed 37863608
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.
PubMed 37021189

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Cerebral Small Vessel Diseases trials

Study at a glance

From the registry record, last updated by the sponsor on 9 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: EffecTs of Amlodipine and Other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases
ClinicalTrials.gov ID: NCT03082014
Acronym / sponsor ID: TREAT-SVDs / TRE-1486--0105-I
Conditions: Cerebral Small Vessel Diseases
Keywords: Hypertension, Cerebrovascular Reactivity, Blood Pressure Variability
Phase: Phase 3
Study type: Interventional
Recruitment status: TerminatedReason 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
Enrolment: 101 participants (actual)
Lead sponsor: Ludwig-Maximilians - University of MunichUniversity, hospital or other
Collaborators: University of Edinburgh, Maastricht University Medical Center, UMC Utrecht, University of Oxford
Study start: 22 Feb 2018 (actual)
Primary completion: 28 Jul 2022 (actual)
Study completion: 28 Jul 2022 (actual)
First posted: 17 Mar 2017 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

Arm A: Amlodipine > Losartan > Atenolol

Arm B: Atenolol > Amlodipine > Losartan

Arm C: Losartan > Atenolol > Amlodipine.

Patients will be monitored telemetrically with a dedicated BP device during the whole trial period of 14 weeks.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Single blind (outcomes assessor)
Number of arms: 3
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).

Arm	Type	Receives
Arm A	Active comparator	Drug: Amlodipine, Drug: Losartan, Drug: AtenololAmlodipine for 4 weeks, Losartan for 4 weeks, Atenolol for 4 weeks.
Arm B	Active comparator	Drug: Amlodipine, Drug: Losartan, Drug: AtenololAtenolol for 4 weeks, Amlodipine for 4 weeks, Losartan for 4 weeks.
Arm C	Active comparator	Drug: Amlodipine, Drug: Losartan, Drug: AtenololLosartan for 4 weeks, Atenolol for 4 weeks, Amlodipine for 4 weeks.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (39 listed)

Symptomatic SVD defined as
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.
concluded by the treating physician based on a validated cognitive measurement tool (for example but not limited to MoCA or CAMCOG)
Indication for antihypertensive treatment (as defined by meeting one of the following):
Age 18 years or older

Key exclusion criteria (1 listed)

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Amlodipineblood pressure lowering agent - dihydropyridine Ca2+-channel blocker	Drug	Arm A, Arm B, Arm C
Losartanblood pressure lowering agent - angiotensin-receptor blockers	Drug	Arm A, Arm B, Arm C
Atenololblood pressure lowering agent - beta-blocker	Drug	Arm A, Arm B, Arm C

Primary outcome

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.

2 secondary outcomes

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
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

Results and safety

The study was stopped early (reason given: 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). Results are not available in the source record.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 9 Mar 2023.
Derived from this study: PubMed 37863608Kopczak 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.
Derived from this study: PubMed 37021189Kopczak 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.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Martin Dichgans, Prof. study director

Institute for Stroke and Dementia Research

Joanna Wardlaw, Prof. principal investigator

Neuroimaging Sciences and Brain Research Imaging Centre

Robert van Oostenbrugge, Prof. principal investigator

Maastricht University Medical Center (UM), Department of Neurology

5 sites in 3 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Amlodipine, Losartan and Atenolol in people with Cerebral Small Vessel Diseases, run by Ludwig-Maximilians - University of Munich at 5 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 39 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 9 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Netherlands, United Kingdom, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03082014, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Mar 2023.