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    Summary
    EudraCT Number:2020-002329-27
    Sponsor's Protocol Code Number:ETLAS-2
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-05-25
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2020-002329-27
    A.3Full title of the trial
    Improving cerebral blood flow and cognition in patient with cerebral small vessel disease. The ETLAS-2 Trial.
    Forbedring af hjernens blodgennemstrømningen og kognition hos patienter med cerebral småkarssygdom. ETLAS-2 Studiet.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Tadalafil as a treatment against cerebral small vessel disease and stroke.
    Tadalafil som behandling til sygdom i hjernens små blodkar og stroke.
    A.4.1Sponsor's protocol code numberETLAS-2
    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 SponsorHerlev Gentofte Hospital
    B.1.3.4CountryDenmark
    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 supportHerlev Gentofte Hospital
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHerlev Gentofte Hospital
    B.5.2Functional name of contact pointChristina Kruuse
    B.5.3 Address:
    B.5.3.1Street AddressBorgmester Ib Juuls Vej 1
    B.5.3.2Town/ cityHerlev
    B.5.3.3Post code2730
    B.5.3.4CountryDenmark
    B.5.4Telephone number004538681233
    B.5.6E-mailchristina.kruuse@regionh.dk
    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.2.1.1.1Trade name Tadalafil Stada
    D.2.1.1.2Name of the Marketing Authorisation holderStada Arzneimittel AG
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 Capsule
    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 INNTadalafil
    D.3.9.1CAS number 171596-29-5
    D.3.9.4EV Substance CodeSUB12602MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    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 and stroke.
    Cerebral småkarssygdom og stroke/apopleksi.
    E.1.1.1Medical condition in easily understood language
    Stroke.
    Slagtilfælde.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10070879
    E.1.2Term Cerebral small vessel ischemic disease
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.1
    E.1.2Level PT
    E.1.2Classification code 10076994
    E.1.2Term Lacunar stroke
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    We aim to investigate the feasibility of daily tadalafil for three months compared to placebo in cerebral small vessel disease patients with stroke.
    Vi vil undersøge hvor godt patienter med cerebral småkarssygdom kan tåle daglig tadalafil i tre måneder sammenlignet med placebo.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to investigate if daily tadalafil for three months compared to placebo have any effect on:
    Cerebral blood perfusion
    Cerebrovascular reactivity
    Blood brain barrier function
    Signs of cerebral small vessel disease on MRI
    Cognition
    Blood endothelial and inflammatory biomarkers
    Death in three and five years
    Sekundære formål er at undersøge om daglig tadalafil i tre måneder sammenligned med placebo har nogen effekt på:
    Cerebral blodgennemstrømning
    Cerebrovaskulær reaktivitet
    Blod-hjerne-barrieren
    Tegn på cerebral småkarssygdom på MR-skanninger
    Kognition
    Endothel og inflammatoriske biomarkører i blod
    Død indenfor tre og fem år
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. MRI/computed tomography (CT) evidence of small vessel occlusion stroke(s)/lacunar stroke(s) (involving ≤2 cm in the acute phase and ≤1.5cm in the late phase) and/or confluent deep white matter hyperintensities (≥ grade 2 on Fazekas’s scale).
    2. Clinical evidence of cerebral small vessel disease can be: a) small vessel occlusion stroke (lacunar stroke) syndrome with symptoms lasting > 24 hours, occurring < 5 years ago; OR b) transient ischemic attack (TIA) with symptoms lasting < 24 hours AND with MR-DWI imaging performed acutely showing small vessel occlusion stroke, occurring < 5 years ago; OR c) TIA with symptoms lasting < 24 hours AND no acute MRI-DWI lesion but MRI/CT evidence of CSVD with old small vessel occlusion stroke(s) (involving ≤1.5cm) and/or confluent deep white matter hyperintensities (≥ grade 2 on Fazekas’s scale).
    3. Age ≥ 50 years.
    1. MR/CT-tegn på et lille stroke (≤ 2 cm i akutfase eller ≤ 1,5 cm i kronisk fase) og/eller hvidsubstansforandringer (≥ 2 på Fazekas skala).
    2. Kliniske tegn på cerebral småkarssygdom kan være: a) stroke med symptomer > 24 timer, opstået for < 5 år siden; b) transitorisk cerebral iskæmi (TCI) med symptomer < 24 timer OG akutte MR-DWI forandringer foreneligt med stroke, opstået < 5 år siden; c) TCI med symptomer < 24 timer OG ingen akutte MR-DWI forandringer, men MR/CT-tegn på cerebral småkarssygom med gamle strokes (≤ 1,5 cm) og/eller hvidsubstansforandringer (≥ 2 på Fazekas skala).
    3. Alder ≥ 50 år.
    E.4Principal exclusion criteria
    1. Known diagnosis of dementia, medical treated dementia, or under investigaton for dementia
    2. Pregnancy or nursing
    3. Women of childbearing age not taking contraception
    4. Known cortical infarction (> 1.5 cm maximum diameter)
    5. Known carotid artery stenosis ≥ 50 % with Doppler ultrasound, CT angiography, or MRI angiography diagnosed within the last five years
    6. Known carotid or vertebral dissection as a cause of stroke
    7. Stroke after carotid or heart surgery
    8. Known hypercoagulable disease
    9. Systolic BP < 90 and/or diastolic BP < 50
    10. Known severe renal impairment (eGFR < 30ml/min)
    11. Known severe hepatic impairment (Child-Pugh > B)
    12. History of non-arthritic anterior ischemic optic neuropathy
    13. Concomitant use of PDE5 inhibitors e.g. sildenafil, tadalafil, and vardenafil during trial period
    14. Patients receiving nicorandil and nitrates e.g. isosorbide mononitrate, isosorbide dinitrate, glyceryl trinitrate
    15. History of acute myocardial infarction in the last three months before trial intervention
    16. Body weight > 130kg
    17. Known cardiac failure (NYHA ≥ II)
    18. Known persistent or paroxysmal atrial fibrillation/flutter
    19. History of “sick sinus syndrome” or other supraventricular cardiac conduction conditions such as sinoatrial or atrioventricular block (2nd of 3rd degree)
    20. Other known cardiogenic cause of stroke
    21. Contraindication to CO2 challage, eg severe respiratory disease
    22. MRI not tolerated or contraindicated
    23. Known monogenic causes of stroke i.e. CADASIL
    24. Unable to provide informed consent
    25. The participant does not wish to be informed about results from the MRI
    1. Diagnosticeret med demens, medicinsk behandling for demens eller under udredning for demens
    2. Gravid eller ammende
    3. Kvinder i fødedygtig alder som ikke tager prævention
    4. Kendt kortikal stroke (> 1,5 cm i diameter)
    5. Kendt karotisstenose ≥ 50 % med Ultralyd Doppler, CT angiografi eller MR angiografi diagnosticeret indenfor de sidste fem år
    6. Kendt karotis- eller vertebralisdissektion som forårsaget stroke
    7. Stroke efter karotis- eller hjerteoperation
    8. Kendt hyperkoagulabel tilstand
    9. Systolisk blodtryk < 90 mmHg og/eller diastolisk blodtryk < 50 mmHg
    10. Kendt svær nyresvigt (eGFR < 30 ml/min)
    11. Kendt svær leversvigt (Child-Pugh > B)
    12. Tidligere non-artritisk anterior iskæmisk optisk neuropati
    13. Samtidig brug af PDE5-hæmmere, eg. sildenafil, tadalafil og vardenafil under studiet
    14. Brug af nicroandil og nitrater, eg. isorbid mononitrat, isorbid dinitrat eller nitroglycerin under studiet
    15. Hjerteinfarkt indenfor tre måneder
    16. Vægt > 130 kg
    17. Kendt hjertesvigt (NYHA ≥ II)
    18. Kendt atrieflimren
    19. Syg sinusknude eller andre supraventrikulære hjerterytmeforstyrrelser (sinoatrial eller atriventrikulær blok (2 eller 3 grad)
    20. Anden kendt kardiogen årsag til stroke
    21. Kontraindikation til kuldioxid-challange, f.eks. svær lungesygdom
    22. MR-skanninger kan ikke tåles
    23. Kendt monogen årsag til stroke, ex. CADASIL
    24. Ikke mulighed for at give informeret samtykke
    25. Patienten ønsker ikke at vide hvad MR-skanningerne har vist
    E.5 End points
    E.5.1Primary end point(s)
    Drop-out rate and proportion of participants achieving target dose assessed by diary and pharmacy tablet count.
    Frafaldsrate og hvor mange patienter som opfylder behandlingsmålet ved at tælle tabletter.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After one and three months.
    Efter en og tre måneder.
    E.5.2Secondary end point(s)
    • Cognitive evaluations will be assessed using the well validated Montreal Cognitive Assessment (MoCA) tool and Symbol Digit Modalities Test (SDMT). Different paper- and pencil tests and computerized tests will also be used to assess processing speed, attention, verbal and visual working memory, learning and memory, executive functions, and to estimate premorbid intelligence.
    • Adverse events will be registered during the trial period according to GCP.
    • Blood pressure and heart rate are registered at baseline, after one month, and three months.
    • Anatomical evaluations based on MRI will be performed at baseline and after three months intervention according to the STRIVE criteria. The following sequences will be included: 3D T1-weigthed, diffusion weighted imaging (DWI), T2-weighted, fluid-attenuated inversion recovery (FLAIR), diffusion tensor imaging (DTI), MRI angiography, and susceptibility weighted imaging (SWI).
    • Register based outcome assessment with a composite measure of death, any ischemic event, hemorrhagic event or dementia per patient registry after three and five years respectively from end of trial.
    • Blood biomarkers - endothelial-, inflammatory-, and neuronal biomarkers and micro RNA.

    By use of MRI, dynamical cerebro-vascular evaluations will be performed at baseline and after three months in accordance with previous well documented MRI-protocols. The following MRI sequences will be used for dynamical evaluations: Pseudo-continuous arterial spin labeling (pCASL), Functional MRI (fMRI) - blood-oxygen-level dependent (BOLD), and dynamic contrast enhanced sequence (DCE).
    • Kognitive undersøgelser vil blive undersøgt med Montreal Cognitive Assessment (MoCA) og Symbol Digit Modalities Test (SDMT). Forskellige papir- og computertests vil også blive brugt til at undersøge reaktionsevne, opmærksomhed, verbal og visuel arbejdshukommelse, læring og hukommelse, eksekutive funktioner og test af præmorbid intelligens.
    • Bivirkninger vil blive registreret under forsøgsperioden efter GCPs vejledning.
    • Blodtryk og puls bliver registreret ved baseline, en måned og efter tre måneder.
    • Anatomisk evaluering baseret på MR skanninger vil blive udført ved baseline og efter tre måneder efter STRIVE kriterierne. Følgende sekvenser vil blive brugt: 3D T1-weigthed, diffusion weighted imaging (DWI), T2-weighted, fluid-attenuated inversion recovery (FLAIR), diffusion tensor imaging (DTI), MR angiografi og susceptibility weighted imaging (SWI).
    • Registerbaseret evaluering af død, iskæmisk event, blødning eller demens per patient registreret efter tre og fem år fra afslutning af studiet.
    • Blod biomarkører - endothel-, inflammatoriske- og neuronalebiomarkører samt mikroRNA.

    Ved MR skanninger undersøger vi dynamiske cerebrovaskulære forhold ved baseline og efter tre måneder efter veldokumenterede MR-protokoller. Følgende MR sekvenser vil blive brugt til undersøgelse af dynamiske forhold: Pseudo-continuous arterial spin labeling (pCASL), Functional MRI (fMRI) - blood-oxygen-level dependent (BOLD), and dynamic contrast enhanced sequence (DCE).
    E.5.2.1Timepoint(s) of evaluation of this end point
    After three months.
    Efter tre måneder.
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state100
    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)
    None
    Ingen
    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 Decision2020-06-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-10
    P. End of Trial
    P.End of Trial StatusOngoing
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