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    Summary
    EudraCT Number:2018-004689-32
    Sponsor's Protocol Code Number:SHP675-301
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-08-11
    Trial results View 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 ConcernedPortugal - INFARMED
    A.2EudraCT number2018-004689-32
    A.3Full title of the trial
    A Phase 3, Open-label Study to Evaluate the Efficacy and Safety of REPLAGAL® in Treatment-naïve Subjects with Fabry Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Evaluate the Efficacy and Safety of REPLAGAL® in Treatment-naïve Subjects with Fabry Disease
    A.4.1Sponsor's protocol code numberSHP675-301
    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 SponsorShire Human Genetic Therapies, 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 supportShire Human Genetic Therapies, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationShire Human Genetic Therapies, Inc.
    B.5.2Functional name of contact pointChemmene Cassidy
    B.5.3 Address:
    B.5.3.1Street Address300 Shire Way
    B.5.3.2Town/ cityLexington
    B.5.3.3Post code02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1781482-9792
    B.5.6E-mailchemmene.cassidy@takeda.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 Yes
    D.2.1.1.1Trade name REPLAGAL ®
    D.2.1.1.2Name of the Marketing Authorisation holderShire Human Genetic Therapies AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/00/002
    D.3 Description of the IMP
    D.3.1Product nameREPLAGAL
    D.3.2Product code SHP675
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAGALSIDASE ALFA
    D.3.9.1CAS number 104138-64-9
    D.3.9.2Current sponsor codeDRX005B, TAK-675
    D.3.9.3Other descriptive nameGene Activated α-Galactosidase A
    D.3.9.4EV Substance CodeSUB12456MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Fabry disease
    E.1.1.1Medical condition in easily understood language
    REPLAGAL is intended for use in patients with Fabry disease
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 24.1
    E.1.2Level PT
    E.1.2Classification code 10016016
    E.1.2Term Fabry's disease
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the efficacy of REPLAGAL (0.2 mg/kg every other week [EOW] up to 104 weeks) on renal (estimated glomerular filtration rate [eGFR]) and cardiac (left ventricular mass index [LVMI]) parameters in subjects with a confirmed diagnosis of Fabry disease and who are naïve to any Fabry-specific treatment.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of REPLAGAL 0.2 mg/kg EOW on other renal and cardiac variables and PD markers
    To assess the safety and tolerability of REPLAGAL over the study period.

    The exploratory objectives of this study are:
    - To evaluate the effect of REPLAGAL on inflammatory biomarkers relevant to Fabry disease
    - To assess the effect of REPLAGAL on the subject’s overall rating of pain, fatigue, severity of Fabry symptoms and quality of life
    - To evaluate the effects of REPLAGAL on gastrointestinal (GI) symptoms of Fabry disease.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The subject must voluntarily sign an Institutional Review Board (IRB)/Independent Ethics Committee/Research Ethics Board approved informed consent form after all relevant aspects of the study have been explained and discussed with the subject.

    2. The subject has Fabry disease as confirmed at screening by the following criteria using a dried blood spot (DBS) assay:
     For male subjects, Fabry disease is confirmed by a deficiency of GLA activity and a mutation in the GLA gene.
     For female subjects, Fabry disease is confirmed by a mutation in the GLA gene.

    3. The subject is 18 to 65 years of age, inclusive.

    4. Female subjects must have a negative pregnancy test at screening.

    5. Female subjects of child-bearing potential must agree to use a medically acceptable method of contraception at all times during the study and for at least 14 days after the final study infusion; the methods of acceptable contraception are listed in the protocol.

    6. The subject is deemed, as determined by the investigator, to have adequate general health to undergo the specified protocol-related procedures and to have no safety or medical contraindications for participation.

    7. The subject has not received any treatment (approved or investigational) specific to Fabry disease, such as ERT, chaperone therapy, or substrate reduction therapy.

    8. The subject must have an eGFR of 45 to 120 mL/min/1.73 m2; eGFR will be calculated by a Shire-designated laboratory using the CKD-EPI formula. If the eGFR measurement at screening is not within the stipulated range, a second eGFR measurement may be completed and, if in range, used as the screening value. If a second measurement is taken, a minimum of 1 week and maximum of 30 days should separate it from the first. This inclusion criterion follows the European Guidelines for Treatment of Fabry Disease (Biegstraaten et al., 2015) and Kidney Disease Improving Global Outcomes guidelines for classification of renal disease (Kidney Disease Improving Global Outcomes (KDIGO), 2013).

    9. The subject has left ventricular hypertrophy (LVH), where LVH is defined as left ventricular mass index (LVMI) >50 g/m2.7 confirmed by cardiac magnetic resonance imaging (cMRI) at screening. The cMRI value at screening will serve as the baseline value.
    E.4Principal exclusion criteria
    1. In the opinion of the investigator, the subject’s life expectancy is ≤5 years.

    2. The subject has undergone or is scheduled to undergo kidney transplantation or is currently on dialysis, or has any signs or symptoms of end stage renal disease.

    3. Urine Protein/creatinine ratio (PCR) > 1.5 mg/mg.

    4. Subjects who have clinically relevant history of allergy or signs or symptoms of severe hypersensitivity (including hypersensitivity to the REPLAGAL active substance or any of the excipients), which in the investigator’s judgment, will substantially increase the subject’s risk if he or she participates in the study.

    5. Cardiac fibrosis involving more than 2 segments, as determined by cMRI at screening.

    6. In the opinion of the investigator, the subject has non-Fabry disease-related cause of end-organ (renal, cardiac, central nervous system) dysfunction/failure or is receiving medications that may affect the rate of disease progression, as assessed by cardiac and/or renal measures.

    7. The subject has a positive test at screening for hepatitis B surface antigen (HBsAg), positive test for hepatitis B core antibody (HBcAb), positive test for hepatitis C (HCV) antibody with confirmation by HCV-ribonucleic acid polymerase chain reaction testing, or positive test for human immunodeficiency virus (HIV) antibody.

    8. Treatment with REPLAGAL at any time prior to the study with REPLAGAL.

    9. Prior treatment with any of the following medications:
     FABRAZYME (agalsidase beta) and its biosimilars
     GLYSET® (miglitol)
     ZAVESCA® (miglustat)
     CERDELGA® (eliglustat)
     GALAFOLD® (migalastat)
     Any investigational product for treatment of Fabry disease.
     Chloroquine
     Amiodarone
     Monobenzone
     Gentamicin.

    10. The subject is pregnant or lactating.

    11. The subject has a body mass index >39 kg/m2. (BMI = kg/m2).

    12. The subject is treated or has been treated with any investigational drug within 30 days prior to study start.

    13. The subject is unable to understand the nature, scope, and possible consequences of the study.

    14. The subject is unable to comply with the protocol, eg, uncooperative with protocol schedule, refusal to agree to all of the study procedures, inability to return for evaluations, or isotherwise unlikely to complete
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoints are:
     Change from baseline at Week 104 in renal function, assessed by eGFR (using the CKD-EPI formula)
     Change from baseline at Week 104 in cardiac structure, assessed by LVMI using cMRI.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 104
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints are:
     Annualized rate of change in eGFR
     Annualized rate of change in LVMI
     Change over time in eGFR
     Change over time in LVMI
     Change over time in proteinuria, measured by PCR
     Change over time of the number of fibrotic segments suggestive of cardiac fibrosis as assessed by volume of fibrosis, measured by cMRI
     Change over time in interventricular septal end-diastolic thickness and posterior wall thickness in diastole,
    measured by cMRI
     Change over time in plasma globotriaosylsphingosine (lyso-Gb3).

    The exploratory efficacy endpoints will include the change over time in serum levels of inflammatory biomarkers including but not limited to Interleukin 1 Beta (INTLK1-β), Tumor Necrosis Factor (TNF-α), Vascular Cell Adhesion Molecule 1 (VCAM 1), and Intercellular Adhesion Molecule 1 (ICAM 1).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Change over time of any of the applicable Secondary End Points
    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 No
    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 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 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA34
    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
    Argentina
    Australia
    Brazil
    Canada
    Finland
    Latvia
    Poland
    Sweden
    Romania
    Spain
    Germany
    Greece
    Italy
    Belgium
    Bosnia and Herzegovina
    Croatia
    Hungary
    Portugal
    Slovenia
    Ukraine
    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
    Safety Follow-up visit of the Last Subject Out will be defined as the end of the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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: 42
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 45
    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)
    No aftercare is planned for this study. Replagal is commercially available.
    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 Decision2021-08-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-09-24
    P. End of Trial
    P.End of Trial StatusOngoing
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