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

Ludwig Maximilian University of Munich

Status and phase: Terminated; Phase 3

Conditions: Cerebral Small Vessel Diseases

Treatments: Drug: Losartan; Drug: Atenolol; Drug: Amlodipine

Study type: Interventional

Funder types: Other

Identifiers

NCT03082014

TRE-1486--0105-I

Details and patient eligibility

About

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)

Full 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.

Enrollment: 101 patients

Sex: All

Ages: 18+ years old

Volunteers: No 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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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101 participants in 3 patient groups

Arm A

Active Comparator group

Description:

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

Treatment:

Drug: Atenolol

Drug: Amlodipine

Drug: Losartan

Arm B

Active Comparator group

Description:

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

Treatment:

Drug: Atenolol

Drug: Amlodipine

Drug: Losartan

Arm C

Active Comparator group

Description:

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

Treatment:

Drug: Atenolol

Drug: Amlodipine

Drug: Losartan