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    Summary
    EudraCT Number:2016-002920-10
    Sponsor's Protocol Code Number:TRE-1486--0105-I
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-05-15
    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 ConcernedUK - MHRA
    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
    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 responsiveness of small brain blood vessels in chronic vascular brain disease.
    A.3.2Name or abbreviated title of the trial where available
    SVDs@target: TREAT-SVDs
    A.4.1Sponsor's protocol code numberTRE-1486--0105-I
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03082014
    A.5.4Other Identifiers
    Name:Oxford Research Ethics Committee BNumber:17/SC/0338
    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 supportInstitute for Stroke and Dementia Research
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportEuropean Union-Horizon 2020 Programme
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInstitute for Stroke and Dementia Research
    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/ cityMunich
    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 AuthorisationUnited Kingdom
    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.3.1Product nameAmlodipine
    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 CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number2.5 to 10
    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 AuthorisationUnited Kingdom
    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.3.1Product nameLosartan
    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 CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25 to 100
    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 AuthorisationUnited Kingdom
    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.3.1Product nameAtenolol
    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.3.9.1CAS number 29122-68-7
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25 to 100
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    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
    E.1.1.1Medical condition in easily understood language
    Chronic changes in small vessels in the brain, presumed to be due to chronic vascular disease, particularly hypertension.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10051765
    E.1.2Term Leukoaraiosis
    E.1.2System Organ Class 100000004852
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10070557
    E.1.2Term White matter hyperintensities
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Studying the effects of different antihypertensive drug classes on microvascular function, assessed by CVR and BPv, holds great promise for improving our mechanistic understanding of small vessel disease, stroke, and dementia. Currently there are no specific treatments to prevent the clinical or radiological progression of SVDs. Proving the feasibility of multi-centre, multinational trials using CVR and telemetric BP monitoring will be vital for proceeding to future, larger trials of new SVDs therapies.

    Primary objective
    To test the hypothesis that 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.
    E.2.2Secondary objectives of the trial
    To test the hypothesis that losartan has a superior beneficial effect on cerebrovascular reactivity compared to atenolol.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Treat-SVDs OxBP: EffecTs of Amlodipine and other Blood PREssure Lowering Agents on Arterial Pulsatility in Small Vessel Diseases. Version 1.
    This substudy will measure aortic blood pressure, aortic stiffness m beat-to-beat blood pressure variability, ECG and continuous middle cerebral artery blood flow in the 15 Oxford patients in Treat-SVDs prior to each MRI scan, to determine the effects of these three antihypertensive medications on aortic pulsatility and its transmission to the brain as well as beat-to-beat variability in BP and cerebral blood flow. These additional monitoring tests will expose the patients to no additional risk, but will add approximately 30 minutes of investigation time to each visit.
    E.3Principal inclusion criteria
    Patients may be enrolled in the trial if all of the following criteria have been met:

    - 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.
    o or cognitive impairment defined as visiting a memory clinic with cognitive complaints, and a clinical dementia rating (CDR) score of ≥0.5, and capacity to consent, and with confluent deep white matter hyperintensities (WMH) on MRI (defined on the Fazekas scale as deep WMH score ≥ 2)
    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 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
    Patients will be excluded from the trial for any of the following reasons:
    o Inclusion criteria are not met
    o Unwillingness or inability to give written consent
    o 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
    (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf) and includes combined (oestrogen and progesterone containing) or progesterone-only contraception associated with inhibition of ovulation, or intrauterine device or bilateral tubal occlusion
    o Contraindications to MRI (pacemaker, aneurysm clip, cochlear implant etc.)
    o Other major neurological or psychiatric conditions affecting the brain and interfering with the trial design (e.g. multiple sclerosis)
    o 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)
    o Other stroke risk factor requiring immediate intervention that would preclude involvement in the trial
    o Renal impairment (eGFR <35ml/min)
    o Life expectancy <2 years
    o Use of >2 antihypertensive drugs for an appropriate BP control
    o Contraindications to the applied antihypertensive drugs as known
    o Severe aortic stenosis
    o Bilateral renal artery stenosis
    o Severe arterial circulatory disorders
    o Atrioventricular block II° or III° or sick sinus syndrome
    o Heart failure (NYHA III or IV)
    o Bradycardia, resting heart rate <50/min
    o Bronchospastic diseases such as severe bronchial asthma
    o Severe hepatic dysfunction such as liver cirrhosis
    o Use of monoamine oxidase (MAO)-A-blockers
    o Use of simvastatin >20mg/d
    o Metabolic acidosis
    o Disturbed electrolyte homeostasis such as hypercalcaemia, hypokalaemia, and hyponatraemia
    o Symptomatic hyperuricaemia (gout)
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is cerebrovascular reactivity (CVR) as determined by BOLD MRI (T2*) brain scan response to hypercapnic challenge at the end of the 2 week run-in phase and after 4 weeks of monotherapy while still on medication.
    E.5.1.1Timepoint(s) of evaluation of this end point
    MRI imaging will be performed at baseline (day 14), and after one month of treatment with each drug (days 42, 70, 98)
    E.5.2Secondary end point(s)
    Effect of drug treatment of day-to-day BP variability on home blood pressure monitoring, expressed as the coefficient of variation
    E.5.2.1Timepoint(s) of evaluation of this end point
    Analysis will be performed on 7 days of data preceding each study visit (day 7-14, 35-42, 63-70, 91-98)
    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 No
    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 Yes
    E.8.1.7.1Other trial design description
    rater-blinded endpoint assessment
    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.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    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 No
    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
    Last visit of the last subject undergoing the trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 No
    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 state30
    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. If during the course of the study, one antihypertensive agent is clearly better suited for and individual due to side effect profile or efficacy, although this is not a primary aim of the study, this will be communicated to the GP.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-09-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-08-02
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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