Clinical trial NCT03082014: Effects of Amlodipine and Other Blood Pressure Lowering Agents on Microvascular Function
Official title: EffecTs of Amlodipine and Other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Cerebral Small Vessel Diseases
Keywords: Hypertension
Cerebrovascular Reactivity
Blood Pressure Variability
Lead sponsor: Ludwig-Maximilians - University of Munich
Sponsor class: OTHER
Collaborators: name: University of Edinburgh
name: Maastricht University Medical Center
name: UMC Utrecht
name: University of Oxford
First posted: 2017-03-17
Enrollment: 101
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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).
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Change from Baseline Cerebrovascular Reactivity (CVR) at 4 weeks of Monotherapy
timeFrame: 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:
measure: Change from Baseline Mean Systolic Blood Pressure (SBP) at the last week of each treatment phase
timeFrame: within the last week of the run-in phase and within the last week of each treatment phase
measure: Change from Baseline Blood Pressure Variability (BPv) at the last week of each treatment phase
timeFrame: within the last week of the run-in phase and within the last week of each treatment phase
Other outcomes:
Locations:
city: Munich
country: Germany
facility: Insitute for Stroke and Dementia Research
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Oxford
country: United Kingdom
facility: Nuffield Department of Clinical Neurosciences
state: England
city: Edinburgh
country: United Kingdom
facility: Centre for Clinical Brain Sciences
state: Scotland
Study officials:
affiliation: Institute for Stroke and Dementia Research
name: Martin Dichgans, Prof.
role: STUDY_DIRECTOR
affiliation: Neuroimaging Sciences and Brain Research Imaging Centre
name: Joanna Wardlaw, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Maastricht University Medical Center (UM), Department of Neurology
name: Robert van Oostenbrugge, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: UMC Utrecht Brain Center Robert Magnus (UMCU)
name: Geert Jan Biessels, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Nuffield Department of Clinical Neurosciences, Oxford (UOXF)
name: Peter Rothwell, Prof.
role: PRINCIPAL_INVESTIGATOR
References: