To Assess the Glycosphingolipid Clearance and Clinical Effects of Switching to Agalsidase Beta (Fabrazyme) Versus Continuing on Agalsidase Alfa (Replagal) in Male Patients With Classic Fabry Disease (BCLEAR1)

A Randomized, Open-label, Active Comparator, 2-arm, Prospective Study to Assess the Glycosphingolipid Clearance and Clinical Effects of Switching to Agalsidase Beta (Fabrazyme) Versus Continuing on Agalsidase Alfa (Replagal) in Male Patients With Classic Fabry Disease

Primary Objective:

To assess reduction of plasma lyso-GL3 level after switch to agalsidase beta from agalsidase alfa

Secondary Objectives:

• To assess reduction of kidney podocyte GL3 content after switch to agalsidase beta from agalsidase alfa
• To assess reduction of GL3 content in endothelial skin cells after switch to agalsidase beta from agalsidase alfa
• To assess change in renal function after switch to agalsidase beta from agalsidase alfa
• To assess disease severity and clinical changes after switch to agalsidase beta from agalsidase alfa
• To assess improvement in symptoms of Fabry disease after switch to agalsidase beta from agalsidase alfa

Study Overview

• Status: Withdrawn
• Conditions: Fabry Disease
• Intervention / Treatment: Drug: agalsidase beta (GZ419828); Drug: agalsidase alfa

Detailed Description

The study will have a screening period of up to 9 weeks. Eligible participants will be randomized to switch to agalsidase beta or to continue agalsidase alfa in a 1:1 ratio for a period of 12 months (52 weeks).

• Study Type: Interventional
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion criteria :

• Male participant must be 16 to 45 years of age inclusive, at the time of signing the informed consent.
• Participants who are diagnosed with classic Fabry disease based on phenotype, presence or absence of characteristic Fabry disease symptoms including neuropathic pain, clustered angiokeratoma and/or cornea verticillata, leucocyte α-GAL A enzyme activity (3% or less compared to control), and genotype (optional).
• Participants who are currently receiving agalsidase alfa for a minimum of 6 months at an average dose of 0.2 mg/kg every other week (ie, every 2 weeks) at baseline.
• Participants who are naïve to agalsidase beta.
• Participants with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m^2 at screening and baseline.
• Proteinuria level as measured by 2 separate, morning, clean-catch urine samples taken a few days apart demonstrating an averaged urine protein-creatinine ratio of <0.5 (ie, <500 mg protein per 1 g creatinine) between the 2 samples. For participants on angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), the criterion is to be met both prior and after a temporary interruption of ACEIs/ARBs for 4 weeks.
• Participants with plasma lyso-GL3 levels >20 ng/mL on 2 consecutive samples taken at least 4 weeks apart.
• Participant's medical records (including eGFR values) available and accessible during the study period.
• Participant and/or participant's legal representative has given signed informed consent as described in the protocol which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. For potential participants age 16 to 18 years, a parent or legal representative is required to sign the ICF, and the potential participant is also required to sign an informed assent form.

Exclusion criteria:

• Participants with severe renal impairment (end-stage renal disease, dialysis, or renal transplantation) and/or nephropathies (including diabetic).
• Participants with rapid renal decline: Loss of >6mL/min/1.73 m^2 at screening compared to the most recent eGFR value approximately 12 months prior to screening.
• Participants with advanced cardiac failure (Stage D).
• Participants with bleeding disorder, prior history of unexplained bleeding episodes, or receiving mandatory anticoagulants or antiplatelets for any indication not allowing interruption of therapy for renal biopsy.
• Participants with diagnosed diabetes.
• Participants with history of anaphylaxis to Enzyme Replacement Therapy (ERT).
• Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.
• Participants treated for more than 5 years with agalsidase alfa at an average dose of 0.2 mg/kg every other week (ie, every 2 weeks) prior to randomization.
• Exposure to migalastat or any investigational study intervention, except agalsidase alfa, for Fabry disease in the last 5 years prior to study participation. Patients who previously participated in any agalsidase alfa clinical study will be eligible if they meet other criteria.
• Exposure to any investigational drugs in the last 4 weeks or 5 half-lives, whichever is longer, prior to screening visit or concomitant enrollment in any other clinical study involving an investigational study treatment.
• Individuals accommodated in an institution because of regulatory or legal order; prisoners or subjects who are legally institutionalized.
• Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures.
• Participants are dependent on the Sponsor or Investigator or deemed vulnerable for any reason (in conjunction with Section 1.61 of the International Council for Harmonisation Good Clinical Practice [ICH-GCP] Ordinance E6).
• Participants who are employees of the clinical study center or other individuals directly involved in the conduct of the study, or immediate family members of such individuals.
• Any specific situation during study implementation/course that may raise ethics consideration

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: agalsidase beta; Commercially available agalsidase beta treatment at approved dose and regimen;administered once every 2 weeks as an IV infusion	Drug: agalsidase beta (GZ419828); Pharmaceutical form:Powder for concentrate for solution for infusion Route of administration: Intravenous (IV) infusion,
Active Comparator: agalsidase alfa; Commercially available agalsidase alfa treatment at approved dose and regimen; administered once every 2 weeks as an IV infusion	Drug: agalsidase alfa; Pharmaceutical form:concentrate for solution for infusion Route of administration: Intravenous (IV) infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Plasma globotriaosylsphingosine (lyso-GL3) level	Change from baseline to 12 months (week 52) for plasma lyso-GL3 level	Baseline, 12 months (week 52)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in GL3 content in podocytes	Change from baseline to 12 months (week 52) for GL3 content in podocytes	Baseline, 12 months (week 52)
Change in GL3 content in endothelial skin cells	Change from baseline to 12 months (Week 52) for GL3 content in endothelial skin cells	Baseline, 12 months (week 52)
Change in measured glomerular filtration rate (mGFR)	Change from baseline to 12 months (Week 52) for measured glomerular filtration rate (mGFR) (measured by iohexol clearance)	Baseline, 12 months (week 52)
Change in estimated glomerular filtration rate (eGFR) calculated	Change from baseline to 12 months (Week 52) for estimated glomerular filtration rate (eGFR) calculated using age appropriate formula [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)/ Bedside-Schwartz]	Baseline, 12 months (week 52)
Change in Mainz Severity Score Index (MSSI) total score	Change from baseline to 12 months (Week 52) for Mainz Severity Score Index (MSSI), based on MSSI total score	Baseline, 12 months (week 52)
Change in Fabry Disease Patient Reported Outcomes (FD-PRO) total symptom score	Change from baseline to 12 months (Week 52) in Fabry Disease Patient Reported Outcomes (FD-PRO) score, based on FD-PRO total symptom score	Baseline, 12 months (week 52)

Collaborators and Investigators

• Sponsor: Sanofi

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2020
• Primary Completion (Anticipated): November 1, 2023
• Study Completion (Anticipated): November 1, 2023

Study Registration Dates

• First Submitted: October 28, 2019
• First Submitted That Met QC Criteria: October 28, 2019
• First Posted (Actual): October 30, 2019

Study Record Updates

• Last Update Posted (Actual): April 7, 2023
• Last Update Submitted That Met QC Criteria: April 5, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Fabry Disease
• Other Study ID Numbers: LPS15918; 2019-000064-21 (EudraCT Number); U1111-1223-5105 (Other Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes