Back to resultsStudy of the Safety and Efficacy of PRX-102 Compared to Agalsidase Beta on Renal Function (BALANCE)
Primary Purpose
Fabry Disease
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
PRX-102 (pegunigalsidase alfa)
agalsidase beta
Sponsored by
About this trial
This is an interventional treatment trial for Fabry Disease focused on measuring Glomerular filtration rate, Proteinuria, PRX-102, pegunigalsidase alfa, Fabry Disease
Eligibility Criteria
Inclusion Criteria:
Symptomatic adult Fabry disease patients, age 18-60 years
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
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
Sites / Locations
- UAB Medicine
- Phoenix Children's Hospital
- University of California Irvine Center
- University of California San Diego
- Emory University School of Medicine
- University of Iowa Hosptials and Clinics
- Massachusetts General Hospital
- Infusion Associates
- Cincinnati Children's Hospital Medical Center
- Children's Hospital of Pittsburgh
- Institute of Metabolic Disease, Baylor Healthcare
- Renal Disease Research Institute, LLC - Dallas
- Eccles Primary Children's Outpatient Services Building
- O+O Alpan LLC
- Medical College of Wisconsin
- Vseobecna fakultni nemocnice v Praze
- Turku University Central Hospital
- Hôpital Raymond Poincaré
- Semmelweis Egyetem
- Azienda Ospedaliera Universitaria "Federico II"
- Academisch Medisch Centrum
- Haukeland University Hospital Klinisk Forskningspost
- General Hospital Slovenj Gradec
- Hospital de Dia Quiron Zaragoza
- Klinik und Poliklinik für Innere Medizin UniversitätsSpital Zürich
- Institute of Metabolism and Systems Research
- Addenbrooke's Hospital
- The Royal Free Hospital
- Salford Royal NHS Foundation Trust
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
PRX-102 (pegunigalsidase alfa)
agalsidase beta
Arm Description
PRX-102 infusion every 2 weeks
agalsidase beta infusion every 2 weeks
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
Full Information
NCT ID
NCT02795676
First Posted
June 2, 2016
Last Updated
September 10, 2023
Sponsor
Protalix
Collaborators
Chiesi Farmaceutici S.p.A.
1. Study Identification
Unique Protocol Identification Number
NCT02795676
Brief Title
Study of the Safety and Efficacy of PRX-102 Compared to Agalsidase Beta on Renal Function
Acronym
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
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Completed
Study Start Date
June 2016 (Actual)
Primary Completion Date
October 2021 (Actual)
Study Completion Date
July 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Protalix
Collaborators
Chiesi Farmaceutici S.p.A.
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief 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.
Detailed 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fabry Disease
Keywords
Glomerular filtration rate, Proteinuria, PRX-102, pegunigalsidase alfa, Fabry Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
78 (Actual)
8. Arms, Groups, and Interventions
Arm Title
PRX-102 (pegunigalsidase alfa)
Arm Type
Experimental
Arm Description
PRX-102 infusion every 2 weeks
Arm Title
agalsidase beta
Arm Type
Active Comparator
Arm Description
agalsidase beta infusion every 2 weeks
Intervention Type
Biological
Intervention Name(s)
PRX-102 (pegunigalsidase alfa)
Other Intervention Name(s)
pegunigalsidase alfa, Recombinant human alpha galactosidase-A
Intervention Description
PRX-102 1 mg/kg every 2 weeks
Intervention Type
Biological
Intervention Name(s)
agalsidase beta
Other Intervention Name(s)
Fabrazyme
Intervention Description
agalsidase beta 1 mg/kg every 2 weeks
Primary Outcome Measure Information:
Title
Annualized Change (Slope) in Estimated Glomerular Filtration Rate (eGFR)
Description
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.
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Estimated Glomerular Filtration Rate (eGFR)
Description
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.
Time Frame
Baseline and Month 24
Title
Plasma Lyso-Gb3
Description
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.
Time Frame
Baseline and Month 24
Title
Short Form Brief Pain Inventory (BPI)
Description
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.
Time Frame
Baseline and Month 24
Title
Mainz Severity Score Index (MSSI)
Description
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.
Time Frame
Baseline and Month 24
Title
Urine Protein/Creatinine Ratio (UPCR)
Description
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.
Time Frame
Baseline and Month 24
Title
Left Ventricular Mass Index With Hypertrophy at Baseline
Description
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.
Time Frame
Baseline and Month 24
Title
Left Ventricular Mass Index Without Hypertrophy at Baseline
Description
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.
Time Frame
Baseline and Month 24
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Symptomatic adult Fabry disease patients, age 18-60 years
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
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
Facility Information:
Facility Name
UAB Medicine
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
Phoenix Children's Hospital
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85016
Country
United States
Facility Name
University of California Irvine Center
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
University of California San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
Emory University School of Medicine
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
University of Iowa Hosptials and Clinics
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Infusion Associates
City
Grand Rapids
State/Province
Michigan
ZIP/Postal Code
49525
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Children's Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Institute of Metabolic Disease, Baylor Healthcare
City
Dallas
State/Province
Texas
ZIP/Postal Code
75226
Country
United States
Facility Name
Renal Disease Research Institute, LLC - Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235
Country
United States
Facility Name
Eccles Primary Children's Outpatient Services Building
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
O+O Alpan LLC
City
Fairfax
State/Province
Virginia
ZIP/Postal Code
22030
Country
United States
Facility Name
Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226-3596
Country
United States
Facility Name
Vseobecna fakultni nemocnice v Praze
City
Prague
State/Province
Czech Republic
ZIP/Postal Code
12808
Country
Czechia
Facility Name
Turku University Central Hospital
City
Turku
ZIP/Postal Code
20520
Country
Finland
Facility Name
Hôpital Raymond Poincaré
City
Paris
ZIP/Postal Code
92380
Country
France
Facility Name
Semmelweis Egyetem
City
Budapest
ZIP/Postal Code
1083
Country
Hungary
Facility Name
Azienda Ospedaliera Universitaria "Federico II"
City
Napoli
Country
Italy
Facility Name
Academisch Medisch Centrum
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
Haukeland University Hospital Klinisk Forskningspost
City
Bergen
ZIP/Postal Code
5021
Country
Norway
Facility Name
General Hospital Slovenj Gradec
City
Slovenj Gradec
ZIP/Postal Code
2380
Country
Slovenia
Facility Name
Hospital de Dia Quiron Zaragoza
City
Zaragoza
ZIP/Postal Code
50012
Country
Spain
Facility Name
Klinik und Poliklinik für Innere Medizin UniversitätsSpital Zürich
City
Zürich
Country
Switzerland
Facility Name
Institute of Metabolism and Systems Research
City
Edgbaston
State/Province
Birmingham
Country
United Kingdom
Facility Name
Addenbrooke's Hospital
City
Cambridge
ZIP/Postal Code
CB2 0QQ
Country
United Kingdom
Facility Name
The Royal Free Hospital
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
Facility Name
Salford Royal NHS Foundation Trust
City
Salford
ZIP/Postal Code
M6 8HD
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Study of the Safety and Efficacy of PRX-102 Compared to Agalsidase Beta on Renal Function
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