Study of the Safety and Efficacy of PRX-102 Compared to Agalsidase Beta on Renal Function

Fabry Disease Clinical Trial

— BALANCE  

Official title:

A Randomized, Double Blind, Active Control Study of the Safety and Efficacy of PRX-102 Compared to Agalsidase Beta on Renal Function in Patients With Fabry Disease Previously Treated With Agalsidase Beta

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02795676
• Other study ID #: PB-102-F20
• Status: Completed
• Phase: Phase 3
• Start date: June 2016
• Est. completion date: July 2022

Study information

• Verified date: September 2023
• Source: Protalix
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This was a randomized, double-blind, active control study of the enzyme replacement therapy (ERT) drug PRX-102 (pegunigalsidase alfa) in Fabry disease patients with impaired renal function. Patients who had been treated for approximately 1 year with agalsidase beta and who had been on a stable dose of that product for at least 6 months were randomized in a 2:1 ratio to either switch to PRX-102 or to continue treatment with agalsidase beta. Both treatments were delivered by intravenous infusions every two weeks, at a dosage of 1 mg/kg.

Description:

This was a randomized, double-blind, active control study examining the safety and efficacy of pegunigalsidase alfa (PRX-102) in Fabry disease patients with impaired renal function. Participants had to have been taking the licensed ERT drug agalsidase beta (Fabrazyme®) for at least 1 year prior to study entry, and to have been on a stable dose of that product for at least the last 6 months. Since the disease expresses itself differently in males and females, gender could have an impact on the therapeutic effect; thus, there was additionally a requirement that no more than 50% of the patients could be female. Following screening, eligible patients were randomized in a 2:1 ratio to either switch to PRX-102 or continue treatment with agalsidase beta, with randomization stratified according to whether the urine protein-to-creatinine ratio (UPCR), a measure of kidney function, was above or below a specified threshold. Both products were administered as an intravenous infusion every 2 weeks, at a dosage of 1 mg/kg, for up to 24 months. Both patients and study staff were blinded as to which treatment was being given. Patients who completed the study were invited to continue in a long-term open-label extension study, PB-102-F60, in which all participants would receive PRX-102 1 mg/kg every 2 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 78
• Est. completion date: July 2022
• Est. primary completion date: October 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Symptomatic adult Fabry disease patients, age 18-60 years

1. Males: Plasma and/or leucocyte alpha galactosidase activity (by activity assay) less than 30% mean normal levels and one or more of the characteristic features of Fabry disease i. neuropathic pain ii. cornea verticillata iii. clustered angiokeratoma

2. Females:

a. historical genetic test results consistent with Fabry pathogenic mutation and one or more of the described characteristic features of Fabry disease: i. neuropathic pain ii. cornea verticillata iii. clustered angiokeratoma b. or in the case of novel mutations a first degree male family member with Fabry disease with the same mutation, and one or more of the characteristic features of Fabry disease i. neuropathic pain ii. cornea verticillata iii. clustered angiokeratoma

• Screening eGFR by CKD-EPI equation 40 to 120 mL/min/1.73 m²
• Linear negative slope of eGFR based on at least 3 serum creatinine values over approximately 1 year (range of 9 to 18 months, including the value obtained at the screening visit) of = 2 mL/min/1.73 m²/year
• Treatment with a dose of 1 mg/kg agalsidase beta per infusion every 2 weeks for at least one year and at least 80% of 13 (10.4) mg/kg total dose over the last 6 months.
• Female patients and male patients whose co-partners are of child-bearing potential agree to use a medically accepted method of contraception, not including the rhythm method.

Exclusion Criteria:

• History of anaphylaxis or Type 1 hypersensitivity reaction to agalsidase beta
• Known non-pathogenic Fabry mutations
• History of renal dialysis or transplantation
• History of acute kidney injury in the 12 months prior to screening, including specific kidney diseases (e.g., acute interstitial nephritis, acute glomerular and vasculitic renal diseases); non-specific conditions (e.g, ischemia, toxic injury); as well as extrarenal pathology (e.g., prerenal azotemia, and acute postrenal obstructive nephropathy)
• Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy initiated or dose changed in the 4 weeks prior to screening
• Patient with a screening eGFR value between 91-120 mL/min/1.73 m², having an historical eGFR value higher than 120 mL/min/1.73 m² (during 9 to 18 months before screening)
• Urine protein to creatinine ratio (UPCR) > 0.5 g/g and not treated with an ACE inhibitor or ARB
• Cardiovascular event (myocardial infarction, unstable angina) in the 6 month period before randomization
• Congestive heart failure NYHA Class IV
• Cerebrovascular event (stroke, transient ischemic attack) in the 6 month period before randomization
• Known history of hypersensitivity to Gadolinium contrast agent that is not managed by the use of pre-medication
• Female subjects who are pregnant, planning to become pregnant during the study, or are breastfeeding
• Presence of any medical, emotional, behavioral or psychological condition that, in the judgment of the Investigator and/or Medical Director, would interfere with the patient's compliance with the requirements of the study

Related Conditions & MeSH terms

• Fabry Disease

Intervention

Biological:
• PRX-102 (pegunigalsidase alfa)
PRX-102 1 mg/kg every 2 weeks
• agalsidase beta
agalsidase beta 1 mg/kg every 2 weeks

Locations

Country	Name	City	State
Czechia	Vseobecna fakultni nemocnice v Praze	Prague	Czech Republic
Finland	Turku University Central Hospital	Turku
France	Hôpital Raymond Poincaré	Paris
Hungary	Semmelweis Egyetem	Budapest
Italy	Azienda Ospedaliera Universitaria "Federico II"	Napoli
Netherlands	Academisch Medisch Centrum	Amsterdam
Norway	Haukeland University Hospital Klinisk Forskningspost	Bergen
Slovenia	General Hospital Slovenj Gradec	Slovenj Gradec
Spain	Hospital de Dia Quiron Zaragoza	Zaragoza
Switzerland	Klinik und Poliklinik für Innere Medizin UniversitätsSpital Zürich	Zürich
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	Institute of Metabolism and Systems Research	Edgbaston	Birmingham
United Kingdom	The Royal Free Hospital	London
United Kingdom	Salford Royal NHS Foundation Trust	Salford
United States	Emory University School of Medicine	Atlanta	Georgia
United States	UAB Medicine	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Institute of Metabolic Disease, Baylor Healthcare	Dallas	Texas
United States	Renal Disease Research Institute, LLC - Dallas	Dallas	Texas
United States	O+O Alpan LLC	Fairfax	Virginia
United States	Infusion Associates	Grand Rapids	Michigan
United States	University of Iowa Hosptials and Clinics	Iowa City	Iowa
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of California Irvine Center	Orange	California
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Eccles Primary Children's Outpatient Services Building	Salt Lake City	Utah
United States	University of California San Diego	San Diego	California

Sponsors (2)

Lead Sponsor	Collaborator
Protalix	Chiesi Farmaceutici S.p.A.

Countries where clinical trial is conducted

United States,  Czechia,  Finland,  France,  Hungary,  Italy,  Netherlands,  Norway,  Slovenia,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Annualized Change (Slope) in Estimated Glomerular Filtration Rate (eGFR)	The individual annualized mean change (slope) in eGFR (mL/min/1.73 m^2/year) is an estimate of the individual patient's annualized change in eGFR, which is derived from the eGFR assessments over time, for up to 24 months.; The individual annualized mean change (slope) in eGFR is estimated for each patient with at least 4 eGFR observations. For patients with fewer than 4 eGFR observations, the slope will be missing.	24 months
Secondary	Estimated Glomerular Filtration Rate (eGFR)	eGFR was calculated based on measured serum creatinine levels according to the CKD-EPI formula. The median values obtained at baseline and at Month 24 are reported.; The change in eGFR from baseline measurement prior to first infusion to last measurement at Month 24 was summarized using descriptive statistics.; The change was calculated for each subject and the reported value is the median (full range) of these changes.	Baseline and Month 24
Secondary	Plasma Lyso-Gb3	Globotriaosylsphingosine (lyso-Gb3) is a Fabry disease-specific biomarker measured in the plasma. The median concentrations obtained at baseline and at Month 24, and the change from baseline to Month 24 in median concentration, are reported.; The change in Lyso-Gb3 from baseline measurement prior to first infusion to last measurement at Month 24 was summarized using descriptive statistics.; The change was calculated for each subject and the reported value is the median (full range) of these changes.	Baseline and Month 24
Secondary	Short Form Brief Pain Inventory (BPI)	The Short Form Brief Pain Inventory ( BPI) questioner is self-completed by patients regarding pain severity and interference.; Descriptive statistics summarize the findings for the change from baseline at Week 104 for "Pain at Its Worst in Last 24 Hours".; The severity of various aspects of pain scored on a scale of 0 to 10 ( no pain / pain as bad as you can imagine).; The change in BPI from baseline measurement prior to first infusion to the last measurement at Month 24 was summarized using descriptive statistics.; The change was calculated for each subject and the reported value is the mean (Standard Error) of these changes.	Baseline and Month 24
Secondary	Mainz Severity Score Index (MSSI)	The Mainz Severity Score Index (MSSI) is an instrument that is specifically designed to measure the severity of Fabry disease signs/symptoms and to monitor the clinical course of the disease. The MSSI is administered by the investigator, and yields scores for general, neurological, cardiovascular, renal, and overall assessments. The overall score range from 0 to 76. An overall score of less than 20 points is considered mild signs and symptoms of Fabry disease, 20 to 40 is considered moderate, and greater than 40 is considered severe.; The change in overall MSSI score from baseline measurement prior to first infusion to the last measurement at Month 24 was summarized using descriptive statistics.; The change was calculated for each subject and the reported value is the mean (Standard Error) of these changes.	Baseline and Month 24
Secondary	Urine Protein/Creatinine Ratio (UPCR)	The UPCR provides an estimate of protein excretion in urine, and is used as an indicator of the extent of chronic kidney disease. It was classified into three categories: 1) UPCR = 0.5 gr/gr, 2) 0.5 gr/gr < UPCR < 1 gr/gr, 3) 1 gr/gr = UPCR. The results are presented as the percentage of patients (%) in each category at baseline and Month 24.; There are no statistical analyses for this endpoint.	Baseline and Month 24
Secondary	Left Ventricular Mass Index With Hypertrophy at Baseline	Left Ventricular Mass Index (LVMI) based on cardiac MRI for patients with hypertrophy at baseline (for males, hypertrophy is above 91 g/m^2 and for females, above 77 g/m^2).; The change in LVMI from baseline measurement prior to first infusion to the last measurement at Month 24 was summarized using descriptive statistics.; The change was calculated for each subject and the reported value is the median (full range) of these changes.	Baseline and Month 24
Secondary	Left Ventricular Mass Index Without Hypertrophy at Baseline	Left Ventricular Mass Index (LVMI) based on cardiac MRI for patients without hypertrophy at baseline (for males, hypertrophy is above 91 g/m^2 and for females, above 77 g/m^2).; The change in LVMI from baseline measurement prior to first infusion to the last measurement at Month 24 was summarized using descriptive statistics.; The change was calculated for each subject and the reported value is the median (full range) of these changes.	Baseline and Month 24