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    Summary
    EudraCT Number:2018-002097-51
    Sponsor's Protocol Code Number:FLT190-01
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-02-28
    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 - PEI
    A.2EudraCT number2018-002097-51
    A.3Full title of the trial
    A Phase 1/2, Baseline-controlled, Non-randomized, Open-label, Single-ascending Dose Study of a Novel Adeno-associated Viral Vector (FLT190) in Patients With Fabry disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Fabry Disease Gene Therapy Study (MARVEL 1)
    A.3.2Name or abbreviated title of the trial where available
    MARVEL1
    A.4.1Sponsor's protocol code numberFLT190-01
    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 SponsorFreeline Therapeutics Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportFreeline Therapeutics Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFreeline Therapeutics Ltd
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressStevenage Bioscience Catalyst, Gunnels Wood Road
    B.5.3.2Town/ cityStevenage
    B.5.3.3Post codeSG1 2FX
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailcontact@freeline.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/20/2248
    D.3 Description of the IMP
    D.3.1Product nameFLT190
    D.3.2Product code FLT190
    D.3.4Pharmaceutical form Concentrate for solution for 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 INNNA
    D.3.9.2Current sponsor codeFLT190
    D.3.9.3Other descriptive nameFLT190
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1.5e12 to 4.0e12
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    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
    Inherited metabolic disorder
    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
    To investigate the safety of systemic administration of FLT190 in adult males with Fabry disease.
    E.2.2Secondary objectives of the trial
    • To investigate endogenous production of αGLA (plasma) following systemic administration of FLT190 in adult males with Fabry disease.
    • To investigate the clearance of Gb3 and LysoGb3 measured in plasma and urine.
    • To establish a baseline for long-term follow up of cellular Gb3 inclusions in skin and renal biopsies.
    • To assess viral shedding in various body fluids after systemic administration of FLT190
    • To describe the immune responses to endogenous production of αGLA following systemic administration of FLT190.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adult males, ≥18 years of age with classic Fabry disease.
    2. Confirmed diagnosis of classic Fabry disease (including historical documentation of a classic pathological GLA mutation).
    3. Plasma αGLA activity at screening (measured by central laboratory activity assay at trough) less than 5% of normal according to the central laboratory reference ranges.
    4. One or more of the characteristic features of classic Fabry disease: neuropathic pain, corneal verticillata, clustered skin angiokeratoma.
    5. Estimated glomerular filtration rate (eGFR) ≥60mL/min/1.73m2 at screening, per serum, using CKD Epidemiology Collaboration (CKD-EPI) equation.
    6. <500mg/g UPCR in a spot urine sample OR if =500 mg/g, <1 g/24 hours of urinary protein (24-hour urine analysis), at screening.
    7. Provision of full informed consent and able to comply with all requirements of the study and willingness to consider participating in the including 5-year long term follow-up.
    8. Willingness to practice barrier contraception (as specified in the
    protocol).
    9. Lack of neutralising anti-AAVS3 antibodies using an in vitro transduction inhibition assay within 6 weeks prior to vector administration.
    10. For inclusion in Part 1, subjects must have received either a licensed ERT or PCT for at least 12 months prior to FLT190 dosing, at a stable dose (subjects receiving both ERT and PCT will be ineligible). For inclusion in Part 2, subjects must have never previously received treatment with either ERT or PCT (licensed or investigational).
    11. Willingness to avoid strenuous exercise during first 3 months after
    FLT190 dosing
    E.4Principal exclusion criteria
    1. Presence of GLA mutations leading to non-classical Fabry disease manifestation and any mutations that have not yet been classified. NOTE: Refer to Fabry Disease mutation database to determine classic and non-classical mutations. E.g., International Fabry Disease Genotype-Phenotype Database. If there is any uncertainty around the mutation classification discuss with Medical Monitor. (http://www.dbfgp.org/dbFgp/fabry/Mutation.html).
    2. Prior hypersensitivity or intolerance to ERT.
    3. Prior lack of response to ERT.
    4. Subjects with a history of chronic kidney disease, stages 3-5 Kidney Disease: Improving Global Outcomes (KDIGO 2012 classification), documented in medical records for a minimum of 3 months.
    5. Subjects with myocardial fibrosis (≥3 segments) identified by MRI at screening.
    6. Use of investigational therapy for Fabry disease within 60 days before enrolment. In addition, participation in any other clinical study of an investigational medicinal product (IMP), and/or receiving any other IMP during the study.
    7. Persistently elevated ALT or aspartate aminotransferase (AST); or bilirubin >1.5 x upper limit of normal, during screening).
    8. Platelet count < 100 x 109/L.
    9. Subjects receiving warfarin or other anticoagulants interfering with the ability to perform renal or skin biopsies, or subjects with a clinically significant bleeding disorder.
    10. A history of hepatitis B infection, or a positive serology test at
    screening for hepatitis B surface antigen (HBsAg) or hepatitis B core
    antibody (HBcAb), or negative for hepatitis B surface antibody (HBsAb).
    11. A positive serology test at screening for hepatitis C antibody (HCAb)
    with a positive HCV-RNA load assay, or currently undergoing anti-viral
    therapy for hepatitis C
    12. A negative test at screening for anti-varicella zoster virus (VZV) IgG
    13. Either history of HIV infection, or a positive serology test at
    screening for human immunodeficiency virus (HIV)
    14. A history of tuberculosis, or a positive screening test for tuberculosis
    at screening. The screening test may be repeated once following an
    indeterminate result.
    15. Subjects who have received live attenuated vaccination within 12
    weeks prior to screening, or intend to receive such vaccination during
    the course of the study
    16. Uncontrolled glaucoma, diabetes mellitus, or hypertension.
    17. History of any malignancy requiring treatment.
    18. History or detection of significant arrhythmia on screening assessments with ECG/24-hour Holter monitoring. A significant arrhythmia includes those deemed clinically significant by the investigator e.g. advanced heart block (2nd or 3rd degree),
    supraventricular or ventricular arrhythmias.
    19. Subjects with uncontrolled cardiac failure, unstable angina, myocardial infarction or other cardiac presentations deemed significant by the investigator in the past 6 months.
    20. History of acute myocarditis or presence of acute myocarditis during screening.
    21. Prior treatment with any gene therapy medicinal product.
    22. Known or suspected intolerance, hypersensitivity or contraindication to gadolinium, tacrolimus and other macrolides, steroids, local anesthetics used for skin or renal biopsies, the IMP and non-investigational medicinal products (NIMPs) or their excipients.
    23. Subjects who are assessed as having any contraindications to MRI. Including subjects with ferromagnetic metallic implants, including pacing and defibrillator devices, nerve stimulators and cochlear implants.
    24. Subjects who have had a renal transplant.
    25. Cytomegalovirus (CMV) Immunoglobulin (Ig)G postive subjects who are CMV polymerase chain reaction (PCR) positive at screening.
    26. Current or relevant history of a physical or psychiatric illness or any medical condition that in the opinion of the investigator could affect the subjects safety or interfere with the study assessments.
    27. History of substance abuse including alcohol abuse or alcohol
    dependence
    E.5 End points
    E.5.1Primary end point(s)
    Safety as assessed by the reporting of AEs
    E.5.1.1Timepoint(s) of evaluation of this end point
    throughout the study
    E.5.2Secondary end point(s)
    Safety :
    •Safety as assessed by reporting of abnormal or change from baseline findings from safety assessments including, laboratory assessments, vital signs, ECG, 24-hour Holter monitoring, echocardiogram, cardiac
    MRI, physical examination, and liver ultrasound.

    Efficacy:
    •Change from baseline in Gb3 and LysoGb3 in plasma and urine, up to 38 weeks following systemic administration of FLT190.
    •Volume fraction of Gb3 inclusions per cell, by renal/skin cell type.

    Immune Response to αGLA:
    •Immune response to the human αGLA transgene product will be assessed by measurement of antibodies up to Week 38 following systemic administration of FLT190.

    Shedding:
    •Clearance of vector genomes (vg) in blood, urine, saliva, stool, and semen.

    Pharmacokinetic:
    •Change from baseline in plasma αGLA activity and concentration at Week 12, 24, and 38.
    •Overall αGLA activity and concentration area under curve from baseline to Week 38.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy: change from baseline towards end of the study
    Immune Response: throughout the study
    Shedding: throughout the study
    Pharmacokinetic:
    • Change from baseline in mean plasma αGLA activity and concentration at week 12, 24, and 38.
    • Comparision of overall αGLA activity and concentration area under curve from baseline to week 38.
    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 Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    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 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.8.2.4Number of treatment arms in the trial1
    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 EEA10
    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
    Austria
    Denmark
    France
    Germany
    Italy
    Norway
    Switzerland
    United Kingdom
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 13
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    F.2 Gender
    F.2.1Female No
    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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 15
    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)
    Treatment/care after study ends will be according to medical needs and local practice. Patients will be consented for a long-term follow-up trial, conducted under a separate extension protocol.
    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 Decision2020-02-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-24
    P. End of Trial
    P.End of Trial StatusOngoing
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