E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Fabry disease |
Malattia di Fabry |
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E.1.1.1 | Medical condition in easily understood language |
Inherited metabolic disorder |
Disordine metabolico ereditario |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10016016 |
E.1.2 | Term | Fabry's disease |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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 (https://lih16.u.hpc.mssm.edu/pipeline/js/dbFabry/Mutation.html). 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 (https://lih16.u.hpc.mssm.edu/pipeline/js/dbFabry/Mutation.html). 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. |
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E.5 End points |
E.5.1 | Primary 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.5.1.1 | Timepoint(s) of evaluation of this end point |
throughout the study |
durante lo studio |
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E.5.2 | Secondary 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. Efficacy: •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. Shedding: •Clearance of vector genomes (vg) in blood, urine, saliva, stool, and semen. Pharmacokinetic: •Change from baseline in plasma aGLA activity at Week 12, 24, and 38. •Overall aGLA activity area under curve from baseline to Week 38. |
Sicurezza - 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. Efficacia - 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. Dispersione - Presenza di genomi vettori (vg) nel sangue, nell'urina, nella saliva, nelle feci e nello sperma. Farmacocinetica - 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. |
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E.5.2.1 | Timepoint(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 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 Farmacocinetica: 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Non applicabile |
Not applicable |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
Denmark |
France |
Germany |
Italy |
Norway |
United Kingdom |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |