E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cerebral small vessel disease |
Cerebrale Mikroangiopathie |
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E.1.1.1 | Medical condition in easily understood language |
Cerebral small vessel disease. |
Krankhafte Veränderung der kleinen Gefaesse im Gehirn. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The calcium channel blocker amlodipine has a superior beneficial effect on cerebrovascular reactivity in patients with symptomatic SVDs when compared to either the Angiotensin II type 1 (AT1) receptor blocker losartan or the beta-blocker atenolol. |
Der Effekt des Calcium-Kanalblockers Amlodipin auf die cerebrovaskuläre Reaktivität (CVR) bei Patienten mit symptomatischer cerebraler Mikroangiopathie ist dem des AT1-Blockers Losartan oder des Betablockers Atenolol überlegen. |
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E.2.2 | Secondary objectives of the trial |
Losartan has a superior beneficial effect on cerebrovascular reactivity when compared to atenolol. |
Der Effekt von Losartan auf die CVR ist dem von Atenolol überlegen. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Symptomatic SVD defined as
o History of clinical lacunar stroke in the last 5 years with a corresponding recent small subcortical infarct visible on MRI scan or CT scan compatible with the clinical syndrome. On MRI, recent infarct is defined as a 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.
o 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))
o 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):
o Hypertension defined as systolic blood pressure (SBP) ≥140mmHg or diastolic BP (DBP) ≥90mmHg without antihypertensive treatment or use of an antihypertensive drug for previously diagnosed hypertension
o Prior history of stroke or transient ischaemic attack (TIA)
• Age 18 years or older
• Written informed consent
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E.4 | Principal exclusion criteria |
•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
• 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
o ≥50% luminal stenosis (NASCET) in large arteries supplying the area of ischaemia
o 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)
o 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 drug
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E.5 End points |
E.5.1 | Primary end point(s) |
Cerebrovascular reactivity (CVR) as determined by BOLD MRI (T2*) brain scan response to hypercapnic challenge. |
Die CVR die als Veränderung auf eine hyperkapnische Stimulation gemessen wird. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
end of the 2 week run-in phase and after 4 weeks of monotherapy. |
Gemessen am Ende der zweiwöchigen Run-In Phase und jeweils am Ende der 4 Wochen Monotherapie. |
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E.5.2 | Secondary end point(s) |
• 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
• Blood pressure variability (BPv) operationalized as coefficient of variation (100*standard deviation (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
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• Der mittlere SBD, der durch tägliche telemetrische Blutdruckmessungen in der letzten Woche der Run-in Phase und jeweils in der letzten Woche der einzelnen Behandlungsphasen erhoben wurde.
• Die Blutdruckvariabilität errechnet als Variationskoeffizient (100*Standardabweichung/mittlerer SBD) über mehrere Messungen hinweg; erhoben durch tägliche telemetrische Blutdruckmessungen in der letzten Woche der Run-in Phase und jeweils in der letzten Woche der einzelnen Behandlungsphasen.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 7 |