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    Summary
    EudraCT Number:2016-002920-10
    Sponsor's Protocol Code Number:TRE-1486--0105-I
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-08-04
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2016-002920-10
    A.3Full title of the trial
    TREAT-SVDs:
    EffecTs of Amlodipine and other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases
    Effekte von Amlodipin und anderen blutdrucksenkenden Mitteln auf die mikrovaskuläre Funktion bei zerebralen Mikroangiopathien
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effects of Amlodipine and other blood pressure lowering agents on microvascular function in Small Vessel Diseases
    Effekte von Amlodipin und anderen blutdrucksenkenden Mitteln auf die mikrovaskuläre Funktion bei zerebralen Mikroangiopathien
    A.3.2Name or abbreviated title of the trial where available
    TREAT-SVDs
    A.4.1Sponsor's protocol code numberTRE-1486--0105-I
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorKlinikum der Universitaet Muenchen AoeR
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportInstitut für Schlaganfall- und Demenzforschung, Klinikum der Universität München
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportHorizon2020
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInstitut fuer Schlaganfall- und Demenzforschung
    B.5.2Functional name of contact pointDr. Anna Kopczak
    B.5.3 Address:
    B.5.3.1Street AddressFeodor-Lynen-Strasse 17
    B.5.3.2Town/ cityMuenchen
    B.5.3.3Post code81377
    B.5.3.4CountryGermany
    B.5.4Telephone number004989440046125
    B.5.5Fax number00498941406322
    B.5.6E-mailanna.kopczak@med.uni-muenchen.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAMLODIPINE
    D.3.9.1CAS number 88150-42-9
    D.3.9.4EV Substance CodeSUB05467MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLOSARTAN
    D.3.9.1CAS number 114798-26-4
    D.3.9.4EV Substance CodeSUB08593MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAtenolol
    D.3.9.3Other descriptive nameATENOLOL
    D.3.9.4EV Substance CodeSUB05590MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Cerebral small vessel disease
    Cerebrale Mikroangiopathie
    E.1.1.1Medical condition in easily understood language
    Cerebral small vessel disease.
    Krankhafte Veränderung der kleinen Gefaesse im Gehirn.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    E.4Principal 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
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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
    • 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    see E.5.2
    see E.5.2
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 75
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 105
    F.4.2.2In the whole clinical trial 105
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Continued Treatment by General Practitioner.
    Weiterbehandlung beim Hausarzt.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-09-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-08-03
    P. End of Trial
    P.End of Trial StatusOngoing
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