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    Summary
    EudraCT Number:2019-003280-22
    Sponsor's Protocol Code Number:K-321-201
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-02-05
    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 number2019-003280-22
    A.3Full title of the trial
    A Double-Masked, Randomised, Placebo-Controlled, Parallel-Group,
    12-Week, Phase 2 Study to Investigate the Safety and Efficacy of Ripasudil
    (K-321) Eye Drops After Descemetorhexis in Patients with Fuchs
    Endothelial Corneal Dystrophy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Investigate the Safety and Efficacy of Ripasudil (K-321) Eye Drops After Descemetorhexis in Patients with Fuchs Endothelial Corneal Dystrophy
    A.4.1Sponsor's protocol code numberK-321-201
    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 SponsorKowa Research Institute, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportKowa Research Institute, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKowa Research Institute, Inc.
    B.5.2Functional name of contact pointAkira Hashimoto
    B.5.3 Address:
    B.5.3.1Street Address430 Davis Drive, Suite 200
    B.5.3.2Town/ cityMorrisville
    B.5.3.3Post codeNC 27560
    B.5.3.4CountryUnited States
    B.5.4Telephone number01646905-2292
    B.5.6E-mailahashimoto@kowa.com
    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 No
    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 nameRipasudil
    D.3.2Product code K-321
    D.3.4Pharmaceutical form Eye drops, solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOphthalmic use (Noncurrent)
    Ocular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRIPASUDIL
    D.3.9.2Current sponsor codeK-321
    D.3.9.3Other descriptive nameRipasudil
    D.3.9.4EV Substance CodeSUB185276
    D.3.10 Strength
    D.3.10.1Concentration unit % percent
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.4
    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 placeboEye drops
    D.8.4Route of administration of the placeboOphthalmic use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    In Fuchs endothelial corneal dystrophy (FECD), there is an increased rate of loss of endothelial cells, starting in the centre of Descemet’s membrane and spreading to the periphery, resulting in excrescences known as guttae, which are a marker of the condition. Guttae may coalesce and inhibit the migration of endothelial cells. Eventually the corneal endothelium ceases to function effectively, and the cornea begins to cloud, leading eventually to blindness.
    E.1.1.1Medical condition in easily understood language
    Fuchs endothelial corneal dystrophy (FECD)
    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 PT
    E.1.2Classification code 10011005
    E.1.2Term Corneal dystrophy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to investigate the effect of K-321 dosed for 12 weeks on central ECD in patients with FECD after descemetorhexis.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are the following:
    • to investigate the effect of K-321 on central ECD, corneal thickness, and corneal clarity in patients with FECD at each visit after descemetorhexis out to 52 weeks
    • to assess the safety and tolerability of K-321 in patients with FECD at each visit after descemetorhexis out to 52 weeks
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each patient must meet all of the following criteria to be enrolled in this study:
    1. Is at least 18 years old at the screening visit (Visit 1). Re-screening possible if initial screening was soon before 18th birthday.
    2. Has a diagnosis of FECD at Visit 1. Rescreening is not possible.
    3. Has confluent central guttae in the study eye that can be removed by descemetorhexis of a circular area of 5 mm diameter or less (at Visit 1). Rescreening is not possible.
    4. Has a study eye with best corrected visual acuity (BCVA) of 75 letters or fewer by Early Treatment Diabetic Retinopathy Study (ETDRS) testing (Snellen equivalent of 20/32 or worse) at Visit 1. Rescreening is not possible.
    5. The study eye descemetorhexis at Visit 2 is confirmed to have excised a central area with confluent guttae and a diameter of 4.5 to 5.5 mm. Guidance for performing the study eye descemetorhexis and measurement of the excised area will be provided in the study manual. Rescreening is not possible in that eye but the non-study eye can be used.
    6. Can understand the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements before any study-specific assessment is performed. Rescreening is not possible.
    E.4Principal exclusion criteria
    Patients meeting any of the following criteria will be excluded from the study:
    1. Is a female patient and any of the following is true:
    • is pregnant or lactating/breastfeeding, or
    • is not surgically sterile, not post-menopausal (no menses for the previous 12 months), or not practising an effective method of birth control as determined by the investigator (eg, oral contraceptives, double barrier methods, hormonal injectable or implanted contraceptives, tubal ligation, or partner with vasectomy).
    If a patient is female and of childbearing potential, she must have a negative urine
    pregnancy test result at Visit 2 before the descemetorhexis. Women of childbearing potential must also agree to use effective contraception throughout the study. A female of childbearing potential is defined as a woman who has experienced menarche and has not undergone successful surgical sterilisation or is not post-menopausal, and a post-menopausal woman is defined as having had no menses for the previous 12 months (without a known cause). Rescreening is possible if patient either stops nursing or initiates birth control.
    2. Has a study eye with confluent guttae in the periphery or confluent guttae outside the stripped area (individual guttae are allowed). Note that patients may have individual or small number of guttae remaining outside the stripped area, but there should be no areas of confluent guttae remaining after the descemetorhexis. For example, a patient who had 5 to 10 guttae remaining in a few spots around the circumference of the descemetorhexis would not be excluded by this criterion. Rescreening is not possible.
    3. Has a study eye with a history of cataract surgery within 90 days of Visit 1. Rescreening is possible.
    4. Has a study eye with a history of any previous ocular surgery other than for cataract. Rescreening is not possible.
    5. Has a non-study eye with a history of any previous ocular surgery within 30 days of Visit 1. Rescreening is possible.
    6. Plans to receive any surgical treatment on the study eye during any study period, other than the study descemetorhexis. Re-screening possible if during initial screening subject had plans for surgical treatment on the study eye during the study period, but upon re-screening these plans for surgery were cancelled.
    7. Plans to receive any surgical treatment for FECD or cataract on the non-study eye in the screening or treatment period. – Re-screening possible if during initial screening subject had plans for surgical treatment for FECD or cataract on the non-study eye during the screening or treatment period, but upon re-screening these plans for surgery were cancelled.
    8. Has advanced corneal stromal oedema defined as the presence of widespread haze or bullae on slit-lamp examination. Rescreening is not possible.
    9. Has a study eye with central corneal thickness ≥ 670 μm. Rescreening is not possible.
    10. Has known severe comorbidities that may interfere with descemetorhexis (eg, a bacterial, viral, or fungal ophthalmic infection). Rescreening is not possible.
    11. Has any clinically significant ocular condition other than FECD or cataract that requires medication or ocular surgery. Rescreening is not possible.
    12. Has diabetes with poor blood sugar control (eg, HbA1c value > 8.5%). Rescreening possible if HbA1c has improved at the time of the re-screening.
    13. Has used contact lenses within 7 days of Visit 1. Rescreening is possible.
    14. Has hypersensitivity to any ophthalmic medication used for diagnosis or treatment, including eye drops containing antibiotic(s) or glucocorticoid(s). Rescreening is not possible.
    15. Has known hypersensitivity to any component of the study drugs. Rescreening is not possible.
    16. Has previously used ripasudil, netarsudil, or other ROCK inhibitors.Rescreening is not possible.
    17. Has used any investigational medications within 30 days of Visit 1.Rescreening is possible.
    18. Has a positive urine test result for drugs of abuse (opiates, methadone, cocaine, amphetamines, barbiturates, or benzodiazepines) or alcohol at screening. Rescreening is not possible.
    19. Has donated more than 450 mL of blood within 60 days of Visit 1. Rescreening is possible.
    20. Is a member or a family member of the professional or ancillary personnel working at the study site or the sponsor involved in the study. Rescreening is not possible.
    21. Has a concomitant medical or psychological condition that could interfere with study participation or is otherwise not suitable for entry into the study in the opinion of the investigator. Re-screening possible if investigator provides evidence that the concomitant medical or psychological condition resolved and the subject was suitable for entry into the study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the central corneal ECD at Week 12 as assessed by the CIARC.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints include:
    • Central corneal thickness change from baseline to each subsequent visit
    • Percent change of central corneal thickness from baseline to each subsequent visit
    • Central corneal ECD at each visit
    • Number and percentage of patients who achieve central corneal ECD of
    700 cells/mm2 or more at each visit
    • Time to achieve central corneal ECD 700 cells/mm2 or more
    • Number and percentage of patients who achieve cornea clearance at each visit where corneal clearance is defined as patients achieving a cornea thickness less than or equal to baseline cornea thickness and who have no corneal oedema
    o Number and percentage of patients who achieve cornea thickness less than or
    equal to baseline cornea thickness
    o Number and percentage of patients who achieve no corneal oedema
    • Time to cornea clearance
    o Time to return of cornea thickness to less than or equal to baseline cornea thickness
    o Time to no corneal oedema
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 52
    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 Yes
    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 trial3
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    United States
    Spain
    Germany
    Denmark
    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. Although Kowa Research Institute, Inc. has every intention of completing the study, Kowa Research Institute, Inc. reserves the right to discontinue the study at any time for clinical or administrative reasons.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial 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: 50
    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 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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 60
    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)
    Standard of care at site
    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 Decision2020-02-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-06-27
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