E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Inherited metabolic disorder |
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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. |
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E.2.2 | Secondary 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 the αGLA transgene product following systemic administration of 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 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. Plasma LysoGb3 levels > 83ng/ml at screening (Part 2 only).
6. Estimated glomerular filtration rate (eGFR) ≥60mL/min/1.73m2 at screening, per serum, using CKD Epidemiology Collaboration (CKD-EPI) equation.
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. |
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E.4 | Principal 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. (https://lih16.u.hpc.mssm.edu/pipeline/js/dbFabry/Mutation.html).
2. Presence of antibodies to αGLA, 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. Persistently elevated ALT or aspartate aminotransferase (AST); or 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 any 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 positive subjects who are CMV polymerase chain reaction (PCR) positive at screening.
19. Current or relevant history of a physical or psychiatric illness or any medical condition that in the opinion of the investigator could affect the patients safety or interfere with the study assessments. |
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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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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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 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 at Week 12, 24, and 38.
•Overall αGLA activity area under curve from baseline to Week 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 αGLA activity at week 12, 24, and 38.
• Overall αGLA activity area under curve from baseline to week 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 | No |
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 | No |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | No |
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 |
Austria |
Denmark |
France |
Germany |
Italy |
Norway |
United Kingdom |
United States |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |