A Study of Replagal in Treatment-naïve Adults With Fabry Disease

Study Overview
=================
Brief Summary
-----------------
In this study, adults with Fabry Disease who have not had any treatment for this condition will be treated with Replagal. The main aim of the study is to check if Replagal improves kidney function and heart structure of participants with Fabry Disease. Participants will receive one Replagal infusion every other week for up to 104 weeks. They will visit the clinic every 12 to 14 weeks during treatment with a follow-up visit 2 weeks after treatment.

Official Title
-----------------
A Phase 3, Open-label Study to Evaluate the Efficacy and Safety of REPLAGAL® in Treatment-naïve Subjects With Fabry Disease

Conditions
-----------------
Fabry Disease

Intervention / Treatment
-----------------
* Drug: REPLAGAL


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The participant 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 participant. The participant has Fabry disease as confirmed at screening by the following criteria using a dried blood spot (DBS) assay: For male participants, Fabry disease is confirmed by a deficiency of alpha-galactosidase A (GLA) activity and a mutation in the GLA gene For female participants, Fabry disease is confirmed by a mutation in the GLA gene The participant is 18 to 65 years of age, inclusive. Female participants must have a negative pregnancy test at screening. Female participants 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. The participant 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. The participant has not received any treatment (approved or investigational) specific to Fabry disease, such as enzyme replacement therapy (ERT), chaperone therapy, or substrate reduction therapy. The participant must have an eGFR of 45 to 120 milliliter per minute per 1.73 square meter (mL/min/1.73 m^2); eGFR will be calculated by a Shire-designated laboratory using the CKD-EPI formula. If the eGFR measurement at screening is not within the 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 and Kidney Disease Improving Global Outcomes guidelines for classification of renal disease. The participant has left ventricular hypertrophy (LVH), where LVH is defined as left ventricular mass index (LVMI) greater than (>) 50 gram per square meter (g/m^2.7) confirmed by cardiac magnetic resonance imaging (cMRI) at screening. The cMRI value at screening will serve as the baseline value. Exclusion Criteria: In the opinion of the investigator, the participant's life expectancy is less than or equal to (<=) 5 years. The participant 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. Urine protein/creatinine ratio (PCR) greater than (>) 1.5 milligram per milligram (mg/mg). Participants 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 participant's risk if he or she participates in the study. Cardiac fibrosis involving more than 2 segments, as determined by cMRI at screening. In the opinion of the investigator, the participant 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. The participant has a positive test at screening for hepatitis B surface antigen, positive test for hepatitis B core antibody, positive test for hepatitis C (HCV) antibody with confirmation by HCV-ribonucleic acid polymerase chain reaction testing, or positive test for human immunodeficiency virus antibody. Treatment with REPLAGAL at any time prior to the study. Prior treatment with any of the following medications: FABRAZYME (agalsidase beta) and its biosimilars GLYSET (miglitol) ZAVESCA (miglustat) CERDELGA (eliglustat) GALAFOLD (migalastat) Any investigational product for treatment of Fabry disease Treatment at any time during the study with the following medications: Chloroquine Amiodarone Monobenzone Gentamicin The participant is pregnant or lactating. The participant has a body mass index > 39 kilogram per square meter (kg/ m^2). (Body mass index [BMI] = kg/ m^2). The participant is treated or has been treated with any investigational drug within 30 days of study start. The participant is unable to understand the nature, scope, and possible consequences of the study. The participant 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 is otherwise unlikely to complete the study, as determined by the investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: REPLAGAL<br>Participants will receive REPLAGAL 0.2 milligram per kilogram (mg/kg) body weight of intravenous (IV) infusion Every Other Week (EOW) for 104 weeks. | Drug: REPLAGAL<br>* Participants will receive REPLAGAL 0.2 mg/kg body weight of IV infusion for 104 weeks.<br>* Other names: SHP675;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Renal Function at Week 104 | Renal function is assessed by estimated glomerular filtration rate (eGFR) using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. The eGFR will be calculated by CKD-EPI formula: eGFR = 141 x min (Serum Creatinine [Scr]/κ,1)^(α) x max(Scr/κ,1)^(-1.209) x 0.993^(Age) x 1.018 (if female) x 1.159 (if black) where: Scr is serum creatinine (mg/dL); κ is 0.7 for females and 0.9 for males; α is -0.329 for females and -0.411 for males; min indicates the minimum of Scr/κ or 1; max indicates the maximum of Scr /κ or 1. Change from baseline in renal function at Week 104 will be assessed. | Baseline, Week 104 | 
| Change From Baseline in Cardiac Structure at Week 104 | Cardiac structure is assessed by left ventricular mass index (LVMI) using cardiac magnetic resonance imaging (cMRI). Change from baseline in cardiac structure at Week 104 will be assessed. | Baseline, Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Rate of Change in Estimated Glomerular Filtration Rate (eGFR) up to Week 104 | Annualized rate of change in eGFR up to Week 104 will be assessed. | Baseline, up to Week 104 | 
| Annualized Rate of Change in Left Ventricular Mass Index (LVMI) up to Week 104 | Annualized rate of change in LVMI up to Week 104 will be assessed. | Baseline, up to Week 104 | 
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) up to Week 104 | Change from baseline in eGFR up to Week 104 will be assessed. | Baseline, up to Week 104 | 
| Change From Baseline in Left Ventricular Mass Index (LVMI) up to Week 104 | Change from baseline in LVMI up to Week 104 will be assessed. | Baseline, up to Week 104 | 
| Change From Baseline in Proteinuria up to Week 104 | Proteinuria will be measured based on protein/creatinine ratio (PCR). Change from baseline in proteinuria up to Week 104 will be assessed. | Baseline, up to Week 104 | 
| Change From Baseline in Cardiac Fibrotic Segments up to Week 104 | Change from baseline in cardiac fibrotic segments suggestive of cardiac fibrosis up to Week 104 will be assessed by volume of fibrosis, measured by cMRI. | Baseline, up to Week 104 | 
| Change From Baseline in Interventricular Septal End-Diastolic Thickness and Posterior Wall Thickness in Diastole up to Week 104 | Change from baseline in interventricular septal end-diastolic thickness and posterior wall thickness in diastole up to Week 104 will be measured by cMRI. | Baseline, up to Week 104 | 
| Change From Baseline in Plasma Globotriaosylsphingosine (lyso-Gb3) up to Week 104 | Change from baseline in lyso-Gb3 up to Week 104 will be assessed. | Baseline, up to Week 104 | 
| Number of Participants with Adverse Events (AEs) | An adverse event (AE) is any untoward medical occurrence in a clinical investigation participants administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. | From start of study drug administration up to follow-up (Week 106) | 
| Number of Participants Who Will Develop Anti-drug Antibodies (ADA) to REPLAGAL | Number of participants who will develop ADA to REPLAGAL will be assessed. | Baseline, up to Week 104 |