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

  • STATUS
    Recruiting
  • days left to enroll
    33
  • participants needed
    105
  • sponsor
    Ludwig-Maximilians - University of Munich
Updated on 4 October 2022

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)

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.

Details
Condition Cerebral Small Vessel Diseases
Treatment losartan, Amlodipine, Atenolol
Clinical Study IdentifierNCT03082014
SponsorLudwig-Maximilians - University of Munich
Last Modified on4 October 2022

Eligibility

Yes No Not Sure

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
Renal impairment (eGFR < 35ml/min)
weeks) myocardial infarction, left ventricular ejection fraction less than 30%
Life expectancy < 2 years
valvular vegetations, or infective endocarditis)
other specific causes of stroke identified (e.g. arteritis, dissection
Contraindications to the applied antihypertensive drugs as known
Severe aortic stenosis
migraine/vasospasm, drug misuse)
Other stroke risk factor requiring immediate intervention that would preclude
Bilateral renal artery stenosis
involvement in the trial
Severe arterial circulatory disorders
Heart failure (NYHA III or IV)
Bradycardia, resting heart rate < 50/min
Use of > 2 antihypertensive drugs at maximum dose or equivalent (one drug at the
Bronchospastic diseases such as severe bronchial asthma
maximum dose and two drugs at half of the maximum dose) for an appropriate BP control
Severe hepatic dysfunction such as liver cirrhosis
Use of monoamine oxidase (MAO)-A-blockers
Use of simvastatin > 20mg/d
Metabolic acidosis
Atrioventricular block II° or III° or sick sinus syndrome
Symptomatic hyperuricaemia (gout)
Disturbed electrolyte homeostasis such as hypercalcaemia, hypokalaemia, and
hyponatraemia
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