|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Medical condition in easily understood language
|REPLAGAL is intended for use in patients with Fabry disease
|Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|10010331 - Congenital, familial and genetic disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main 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.
|Secondary 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.
|Trial contains a sub-study
|Principal 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.
|Principal 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
Any investigational product for treatment of Fabry disease.
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
|Primary 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.
|Timepoint(s) of evaluation of this end point
|Secondary 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).
|Timepoint(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
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Bosnia and Herzegovina
|Trial has a data monitoring committee
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
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months