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    EudraCT Number:2018-002097-51
    Sponsor's Protocol Code Number:FLT190-01
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-19
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-002097-51
    A.3Full title of the trial
    A Phase 1/2, Baseline-controlled, Non-randomised, Open-label, Singleascending Dose Study of a Novel Adeno-associated Viral Vector (FLT190) in Patients With Fabry disease
    Studio di fase 1/2, controllato verso il basale, non randomizzato, in aperto, a incremento di dose singola, di un nuovo vettore virale adeno-associato (FLT190) in pazienti con malattia di Fabry
    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)
    Uno studio sulla malattia di Fabry con terapia genica (MARVEL 1)
    A.3.2Name or abbreviated title of the trial where available
    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 Limited
    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.5.4Telephone number00000000000000000
    B.5.5Fax number0000000000000000
    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 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.3.9.2Current 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 to 4
    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. cell therapy medicinal product No
    D. therapy medical product Yes
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Malattia di Fabry
    E.1.1.1Medical condition in easily understood language
    Inherited metabolic disorder
    Disordine metabolico ereditario
    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 20.0
    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.
    Studiare la sicurezza della somministrazione sistemica di FLT190 in maschi adulti con malattia di Fabry.
    E.2.2Secondary objectives of the trial
    To investigate endogenous production of aGLA (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 FLT190To describe the immune responses to the aGLA transgene product following systemic administration of FLT190.
    Studiare la produzione endogena di aGLA (plasma) in seguito a somministrazione sistemica di FLT190 in maschi adulti con malattia di Fabry.
    Studiare la clearance di Gb3 e LysoGTb3 misurata nel plasma e nell’urina.
    Stabilire un riferimento per il follow up a lungo termine delle inclusioni cellulari di Gb3 in biopsie cutanee e renali.
    Valutare la dispersione virale in vari fluidi corporei dopo la somministrazione sistemica di FLT190.
    Descrivere le risposte immunitarie al prodotto transgenico aGLA in seguito alla somministrazione sistemica di 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 and/or leucocyte alpha galactosidase 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. Plasma LysoGb3 levels > 83ng/ml at screening (Part 2 only)
    6. Estimated glomerular filtration rate (eGFR) =60mL/min/1.73m2 at screening, per serum creatinine Epidemiology Collaboration (CKD-EPI).
    7. <500mg/g UPCR in a spot urine sample OR <1g/24 hours of urinary protein (24 hour urine analysis), at screening.
    8. Provision of full informed consent and able to comply with all requirements of the study including 5-year long term follow-up.
    9. Willing to practice barrier contraception until at least three consecutive semen samples taken at separate visits at least 1 week apart (as specified in the study schedule of assessments) after vector
    administration are negative for vector sequences.
    10. Lack of neutralising anti-AAVS3 antibodies using an in vitro transduction inhibition assay within 6 weeks prior to vector administration.
    1. Maschi adulti, di età pari o superiore a 18 anni, affetti da malattia di Fabry classica.
    2. Diagnosi confermata di malattia di Fabry classica (compresa documentazione storica di una mutazione classica patologica del GLA).
    3. Attività plasmatica e/o leucocitaria dell’alfa-galattosidasi allo screening (misurata da un test di attività presso il laboratorio centrale al livello minimo) inferiore al 5% del normale secondo gli intervalli di riferimento del laboratorio centrale.
    4. Una o più delle caratteristiche tipiche della malattia di Fabry classica: dolore neuropatico, cornea verticillata, angiocheratoma cutaneo a grappolo.
    5. Livelli plasmatici di LysoGb3 >83 ng/mL allo screening (solo Parte 2).
    6. Velocità di filtrazione glomerulare stimata (eGFR) =60 mL/min/1,73 m2 allo screening secondo l’equazione CKD Epidemiology Collaboration (relativa alla malattia renale cronica) per la creatinina sierica.
    7. Proteine urinarie <1 g/24 ore (analisi delle urine su 24 ore) O <500 mg/g UPCR (rapporto proteine urinarie/creatinina) su un campione di urina.
    8. Fornitura del pieno consenso informato e di soddisfazione di tutti i requisiti dello studio, incluso il follow-up a lungo termine di 5 anni.
    9. Disponibilità a utilizzare un contraccettivo a barriera finché almeno 3 campioni consecutivi di sperma raccolti in visite separate ad almeno 1 settimana di distanza (come specificato nel calendario delle valutazioni dello studio) dopo la somministrazione del vettore non risultino negativi per le sequenze del vettore.
    10. Assenza di anticorpi neutralizzanti anti-AAVS3 mediante un saggio di inibizione della trasduzione in vitro nelle 6 settimane precedenti la somministrazione del vettore.
    E.4Principal exclusion criteria
    1. Presence of either R118C, A143T, or other 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
    2. Presence of antibodies to aGLA, Replagal, or Fabrazyme as defined by a positive result in the screening assay.
    3. 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.
    4. Subjects with severe myocardial fibrosis (=3 segments) identified by MRI at screening.
    5. 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 course of the study
    6. Elevated ALT, aspartate aminotransferase (AST) and bilirubin >1.5 x upper limit of normal, during screening).
    7. Platelet count < 100 x 109/L.
    8. Subjects receiving warfarin or other anticoagulants interfering with the ability to perform renal or skin biopsies, or subjects with a clinically significant bleeding disorder.
    9. Either history of, or a positive serology test at screening for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCAb), or human immunodeficiency virus (HIV).
    10. Uncontrolled glaucoma, diabetes mellitus, or hypertension.
    11. History of malignancy requiring treatment.
    12. Subjects with uncontrolled cardiac failure, unstable angina, or myocardial infarction in the past 6 months.
    13. History of acute myocarditis or presence of acute myocarditis during screening.
    14. Prior treatment with any gene transfer medicinal product.
    15. Known or suspected intolerance, hypersensitivity or contraindication to replagal, fabrazyme, the IMP and non-investigational medicinal products (NIMPs) or their excipients.
    16. 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.
    17. Subjects who have had a renal transplant.
    18. Cytomegalovirus (CMV) Immunoglobulin (Ig)G postive subjects who are CMV polymerase chain reaction (PCR) positive at screening.
    1. Presenza della mutazione R118C, A143T o di altre mutazioni del GLA che portino alla manifestazione della malattia di Fabry in forma non classica e mutazioni non ancora classificatea. NOTE: Refer to Fabry Disease mutation database to determine classic and non-classical mutations. E.g., International Fabry Disease Genotype-Phenotype Database
    2. Presenza di anticorpi anti-aGLA, Replagal o Fabrazyme, definita come risultato positivo al saggio di screening.
    3. Soggetti con anamnesi di malattia renale cronica di stadio 3-5 [classificazione Kidney Disease: Improving Global Outcomes (KDIGO 2012), documentata in cartelle mediche per almeno 3 mesi].
    4. Soggetti con fibrosi miocardica grave (=3 segmenti) misurata mediante risonanza magnetica (RM).
    5. Utilizzo di una terapia sperimentale per la malattia di Fabry nei 60 giorni precedenti l'arruolamento. In aggiunta, partecipazione ad altri studi clinici su medicinali sperimentali (Investigational Medicinal Product, IMP) e/o assunzione di altri IMP durante il corso dello studio.
    6. Alanina aminotransaminasi (ALT), aspartato aminotransferasi (AST) e bilirubina elevate, >1,5 volte il limite superiore di normalità, durante lo screening.
    7. Conta piastrinica < 100 × 109/L.
    8. Soggetti che assumono warfarin o altri anticoagulanti che interferiscono con la possibilità di effettuare biopsie renali o cutanee, o soggetti con un disturbo della coagulazione clinicamente significativo.
    9. Precedenti di o test sierologico positivo allo screening per l’antigene di superficie dell’epatite B (HBsAg), l’anticorpo anti-epatite C (HCAb) o il virus dell’immunodeficienza umana (HIV).
    10. Glaucoma, diabete mellito o ipertensione non controllato.
    11. Anamnesi di neoplasia che richiede un trattamento.
    12. Soggetti con insufficienza cardiaca non controllata, angina instabile o infarto miocardico negli ultimi 6 mesi.
    13. Anamnesi di miocardite acuta o presenza di miocardite acuta durante lo screening.
    14. Precedente trattamento con un farmaco transgenico.
    15. Intolleranza, ipersensibilità o controindicazione nota o sospetta a Replagal, a Fabrazyme, all’IMP e ai medicinali non sperimentali (Non-IMP, NIMP) o ai loro eccipienti.
    16. Soggetti in cui sono state riscontrate controindicazioni alla RM. Inclusi soggetti con impianti metallici ferromagnetici, compresi pacemaker e defibrillatori, stimolatori nervosi e impianti cocleari.
    17. Soggetti che sono stati sottoposti a trapianto renale.
    18. Pazienti positivi agli anticorpi del citomegalovirus (CMV IgG) che risultino positivi alla reazione a catena della polimerasi (PCR) per il CMV allo screening.
    E.5 End points
    E.5.1Primary end point(s)
    Safety as assessed by the reporting of AEs according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
    La sicurezza sarà valutata mediante la segnalazione di AE secondo i CTCAE versione 5.0.
    E.5.1.1Timepoint(s) of evaluation of this end point
    throughout the study
    durante lo studio
    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, physical exam and liver ultrasound.
    •Change from baseline in Gb3 and LysoGb3 in plasma and urine, up to 38
    weeks following systemic administration of FLT190.
    Immune Response:
    •Immune response to the human aGLA transgene product will be
    assessed by measurement of antibodies up to Week 38 following
    systemic administration of FLT190.
    •Clearance of vector genomes (vg) in blood, urine, saliva, stool, and
    •Change from baseline in plasma aGLA activity at Week 12, 24, and 38.
    •Overall aGLA activity area under curve from baseline to Week 38.
    - La sicurezza sarà valutata mediante la segnalazione di risultati anomali o diversi rispetto al basale provenienti da valutazioni di laboratorio, segni vitali, ECG, esame fisico ed ecografia al fegato.
    - Variazione rispetto al basale di Gb3 e LysoGb3 in plasma e urina fino a 38 settimane dopo la somministrazione sistemica di FLT190.
    Risposta immunitaria
    - La risposta immunitaria al prodotto transgenico umano aGLA sarà valutata mediante la misurazione di anticorpi fino a 38 settimane dopo la somministrazione sistemica di FLT190.
    - Presenza di genomi vettori (vg) nel sangue, nell'urina, nella saliva, nelle feci e nello sperma.
    - Variazione rispetto al basale dell’attività plasmatica di aGLA alle Settimane 12, 24 e 38.
    - Area sotto la curva dell’attività globale di aGLA dal basale alla Settimana 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
    • Change from baseline in mean plasma aGLA activity at week 12, 24 and 38.
    • Overall aGLA activity area under curve from baseline to week 38.
    Efficacia: passaggio dal basale alla fine dello studio
    Risposta immunitaria: durante lo studio
    Dispersione: durante lo studio
    Variazione rispetto al basale dell’attività plasmatica media di aGLA alle settimane 12, 24 e 38.
    Area sotto la curva dell’attività globale di aGLA dal basale alla settimana 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. 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 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 Yes
    E. description
    Non applicabile
    Not applicable
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    United Kingdom
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months2
    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 months2
    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: 10
    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 12
    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.
    Il trattamento / cura dopo lo studio sarà in base alle esigenze mediche e alla pratica locale. I pazienti spotranno partecipare ad una sperimentazione di follow-up a lungo termine, condotta secondo un protocollo di estensione separato.
    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 Decision2019-06-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-18
    P. End of Trial
    P.End of Trial StatusOngoing
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