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    Summary
    EudraCT Number:2021-000183-29
    Sponsor's Protocol Code Number:REVISION
    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:2021-07-21
    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 number2021-000183-29
    A.3Full title of the trial
    Early Reperfusion Therapy with Intravenous Alteplase for Recovery of VISION in Acute Central Retinal Artery Occlusion (REVISION) - A double-blind randomized placebo-controlled phase III proof-of-concept trial
    Frühzeitige Reperfusionstherapie mit intravenöser Alteplase zur Wiederherstellung der Sehleistung (VISION) bei akutem Zentralarterienverschluss der Netzhaut (REVISION)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Early Reperfusion Therapy for Recovery of Vision in Acute Central Retinal Artery Occlusion
    Frühzeitige Reperfusionstherapie zur Wiederherstellung der Sehleistung bei akutem Zentralarterien-verschluss der Netzhaut
    A.4.1Sponsor's protocol code numberREVISION
    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 SponsorEberhard-Karls University Tübingen, Med. Fac. rep. by University Hospital and its Commercial Director
    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 supportBMBF
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Tübingen
    B.5.2Functional name of contact pointDept. of Neurology and Stroke
    B.5.3 Address:
    B.5.3.1Street AddressHoppe-Seyler-Str. 3
    B.5.3.2Town/ cityTübingen
    B.5.3.3Post code72076
    B.5.3.4CountryGermany
    B.5.4Telephone number+491724682284
    B.5.5Fax number+4970712925047
    B.5.6E-mailsven.poli@med.uni-tuebingen.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 Actilyse
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim Pharma
    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 Powder and solvent for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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 Yes
    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 placeboPowder and solvent for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute non-arteritic central retinal artery occlusion (CRAO)
    E.1.1.1Medical condition in easily understood language
    central artery occulasion
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10007971
    E.1.2Term Central retinal artery occlusion
    E.1.2System Organ Class 10015919 - Eye disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Functional recovery to best corrected visual acuity (BCVA) of Logarithm of the Minimum Angle of Resolution (LogMAR) ≤ 0.5 (normal to mild vision impairment according to WHO ICD-11 (WHO, 2019)) in the affected eye at Visit (V) 3 (30 ± 5 days), dichotomized ITT analysis (functional recovery to LogMAR ≤ 0.5 vs. no functional recovery, i.e., LogMAR > 0.5)
    E.2.2Secondary objectives of the trial
    To investigate efficacy of IVT using alternative endpoints as well as to investigate safety of IVT in non-arteritic CRAO.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ● Age ≥ 18 years
    ● Acute non-arteritic CRAO (i.e. sudden, painless monocular vision loss) ≤ 12 hours after symptom onset confirmed by an experienced ophthalmologist through assessment of: BCVA, intraocular pressure, swinging flash light test (relative afferent pupil defect), slit-lamp biomicroscopy, fundoscopy, and OCT of the macula of both eyes* (*within the 4.5-hour time window: to be skipped if not feasible ≤ 10 minutes; beyond the 4.5-hour time window: mandatory)
    ● BCVA of LogMAR ≥ 1.3 in the affected eye (functional blindness according to WHO ICD-11)
    ● Reading must have been possible with the affected eye before CRAO (LogMAR ≤ 0.5)
    ● Neurological examination performed by an experienced stroke neurologist
    ● Brain imaging as per local standard for acute retinal ischemia/stroke assessment, either cranial computed tomography (CT) or cranial magnetic resonance imaging (MRI)
    Additional inclusion criteria for interventional study:
    ● Initiation of study treatment (IVT or placebo) by an experienced stroke neurologist within ≤ 4.5 hours of certain symptom onset
    ● Written informed consent (interventional study) given by the patient
    Additional inclusion criteria for observational study:
    ● Participation of patients within ≤ 4.5 hours of symptom onset is only allowed in case of contraindication(s) for IVT of contraindication(s) for IVT or history of hypersensitivity to Acitlyse® or in case of pregnancy or laction
    ● Written informed consent (observational study) given by the patient
    E.4Principal exclusion criteria
    ● Suspected giant cell arteritis
    ● Other-than-CRAO cause of acute visual loss (e.g., retinal detachment, vitreous hemorrhage, acute glaucoma, acute optic neuritis)
    ● Rapidly improving vision in the affected eye
    ● Acute ischemic stroke with indication for on-label intravenous thrombolysis (IVT)
    ● Any co-existing or terminal disease with anticipated life expectancy of < 3 months
    ● Prior participation in the REVISION trial
    Additional exclusion criteria for interventional study:
    ● Pregnancy or lactation
    ● History of hypersensitivity to Actilyse®
    ● Contraindications for IVT:
    o intracranial hemorrhage or subacute infarct on brain imaging
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoint of the interventional study:
    Functional recovery to best corrected visual acuity (BCVA) of Logarithm of the Minimum Angle of Resolution (LogMAR) ≤ 0.5 (normal to mild vision impairment according to WHO ICD-11) in the affected eye at Visit (V) 3 (30 ± 5 days), intention-to-treat (ITT) analysis
    E.5.1.1Timepoint(s) of evaluation of this end point
    Visit 3 (30 ± 5 days)
    E.5.2Secondary end point(s)
    Secondary endpoints of the interventional study:
    ITT and per protocol (PP) analyses of all endpoints
    Secondary efficacy endpoints of the interventional study:
    ● Functional recovery to LogMAR ≤ 0.5 at V3, PP analysis
    ● Functional recovery to LogMAR ≤ 0.5 at V2 (18 – 72 hours), and V4 (90 ± 10 days)
    ● Shift in visual outcome categories (according to WHO ICD-11: normal vision (LogMAR ≤ 0), mild vision impairment (LogMAR > 0 and ≤ 0.5), moderate vision impairment (LogMAR > 0.5 and ≤ 1.0), severe vision impairment (LogMAR > 1.0 and ≤ 1.3), counting fingers (LogMAR > 1.3 and ≤ counting fingers), hand motion or light perception, and no light perception) at V2 , V3, and V4
    ● Dichotomized analysis visual outcome: ‘normal vision to moderate visual impairment’ vs. ‘severe visual impairment or functional blindness’ and ‘normal vision to severe visual impairment’ vs. ‘functional blindness’ at V2, V3, and V4
    ● Kinetic visual field using III4e mark at V3 and V4
    ● Central retinal artery recanalization assessed using optical coherence tomography angiography (OCT/A) of the optic nerve head and the macula at V2, V3, and V4
    ● Retinal arterial perfusion assessed using fluorescein angiography at V3 and V4
    ● National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) at V3 and V4
    ● National Institutes of Health Stroke Scale score (NIHSS) at V2
    ● modified Rankin Scale score (mRS) at V3, and V4 (dichotomized into categories 0 – 1 vs. 2 – 6, 0 – 2 vs. 3 – 6, and shift analysis)
    ● Fraction of patients with and number of acute ischemic lesions on follow-up diffusion-weighted (DWI) cranial magnetic resonance imaging (MRI) at V2
    Secondary safety endpoints of the interventional study:
    ● All-cause and stroke-related death at V3 and V4
    ● mRS at V3 and V4 (dichotomized into categories 0 – 3 vs. 4 – 6, and 0 – 4 vs. 5 – 6)
    ● any intracranial hemorrhage (ICH) on follow-up MRI at V2
    ● symptomatic ICH (as per ECASS III and Heidelberg bleeding classification) within 5 days after randomization
    ● intraocular hemorrhage in the affected eye at V2
    ● major bleeding (decrease of ≥ 2 g hemoglobin per dL, requiring transfusion, at critical site or resulting in death) within 5 days after randomization
    ● retinal neovascularization requiring therapy at V3 and V4
    ● Adverse events (AE) until V2, AE of special interest (AESI) and serious AE (SAE) until V3 and V4
    E.5.2.1Timepoint(s) of evaluation of this end point
    ● Functional recovery to LogMAR ≤ 0.5 at V3 (30 ± 5 days) (dichotomized)
    ● Functional recovery to LogMAR ≤ 0.5 at V2 (18 – 72 hours), and V4 (90 ± 10 days) (dichotomized)
    ● Shift in visual outcome categories (according to WHO ICD-11 (WHO, 2019): normal vision (LogMAR ≤ 0), mild visual impairment (LogMAR > 0 and ≤ 0.5), moderate visual impairment (LogMAR > 0.5 and ≤ 1.0), severe visual impairment (LogMAR > 1.0 and ≤ 1.3), counting fingers (LogMAR > 1.3 and ≤ counting fingers), hand motion or light perception, and no light perception) at V2, V3, and V4
    ● Dichotomized analysis of visual outcome: ‘normal vision to moderate visual impairment’ vs. ‘severe visual impairment or functional blindness’ and ‘normal vision to severe visual impairment’ vs. ‘functional blindness’ at V2, V3, and V4
    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 No
    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 No
    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 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 concerned18
    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 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
    Last patient out
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months50
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months50
    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: 1300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 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 state1400
    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)
    After trial participation all patients of the interventional study continue to be treated in regular routine. Further treatment decisions are at the discretion of the treating physicians.
    The investigator will continue to observe all patients (also withdrawals) because of intolerable AEs/ SAEs until the findings have been clarified or became stable.
    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 Decision2022-03-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-13
    P. End of Trial
    P.End of Trial StatusOngoing
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