Back to resultsDose-ranging Study of PRX-102 in Adult Fabry Disease Patients
Primary Purpose
Fabry Disease
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
PRX-102
Sponsored by
About this trial
This is an interventional treatment trial for Fabry Disease focused on measuring Fabry disease, Alpha galactosidase deficiency, Metabolic storage disease
Eligibility Criteria
Inclusion Criteria:
- Symptomatic adult Fabry patients (≥18 yrs)
- Males: plasma and/or leucocyte alpha galactosidase activity (by activity assay) less than lower limit of normal (LLN in plasma=3.2 nmol/hr/ml, LLN in leucocytes=32 nmol/hr/mg/protein)
- Females: historical genetic test results consistent with Fabry mutations
- Globotriaosylceramide (Gb3) concentration in urine > 1.5 times upper normal limit
- Patients who have never received enzyme replacement therapy (ERT) in the past, or patients who have not received ERT in the past 6 months and have a negative anti alpha galactosidase antibody test
- eGFR ≥ 60 mL/min/1.73m2
- The patient signs informed consent
- Female patients and male patients whose co-partners are of child-bearing potential agree to use a medically acceptable method of contraception, not including the rhythm method
Exclusion Criteria:
- Participation in any trial of an investigational drug within 30 days prior to study screening
- Chronic kidney disease stages 3-5 (CKD 3-5) (Appendix 7)
- History of dialysis or renal transplantation
- Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy initiated or dose changed in the 4 weeks prior to screening
- Severe myocardial fibrosis by MRI (≥2 late-enhancement [LE] positive left ventricular segments) (Weidemann et al. 2009)
- History of clinical stroke
- Pregnant or nursing
- Presence of HIV and/or HBsAg and/or Hepatitis C infections
- Known allergies to ERT
- Known allergy to Gadolinium based contrast agents
- 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
- UC Davis Medical Center, MIND Institute Department of Pediatrics, Section of Genetics
- Department of Human Genetics, Emory University School of Medicine
- University of Iowa Health Clinics
- University of Kansas Medical Center
- Johns Hopkins University School of Medicine
- Duke University Medical Center
- Children's Hospital of Pittsburgh of UPMC
- Research Baylor Institute of Metabolic Disease
- O & O Alpan LLC
- Royal Melbourne Hospital
- Hematology and Clinical Research Private Institute
- Clinical Center of Serbia
- Hospital de Dia Quiron Zaragoza
- The Royal Free Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
0.2 mg/kg
1 mg/kg
2 mg/kg
Arm Description
PRX-102 0.2 mg/kg every 2 weeks
PRX-102 1 mg/kg every 2 weeks
PRX-102 2 mg/kg every 2 weeks
Outcomes
Primary Outcome Measures
Adverse Events
Reportings of adverse events reported by the patient and from monitoring with clinical laboratory, physical examination and ECG. Results represent the number of AEs that were considered possibly, probably, or definitely related to treatment.
Secondary Outcome Measures
Full Information
NCT ID
NCT01678898
First Posted
August 31, 2012
Last Updated
September 10, 2023
Sponsor
Protalix
Collaborators
Chiesi Farmaceutici S.p.A.
1. Study Identification
Unique Protocol Identification Number
NCT01678898
Brief Title
Dose-ranging Study of PRX-102 in Adult Fabry Disease Patients
Official Title
A Phase 1/2, Open Label, Dose Ranging Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Exploratory Efficacy Parameters of PRX-102 Administered by Intravenous Infusion Every 2 Weeks for 12 Months to Adult Fabry Patients
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Completed
Study Start Date
October 2012 (Actual)
Primary Completion Date
March 6, 2016 (Actual)
Study Completion Date
March 6, 2016 (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 is the first human treatment with PRX-102, an enzyme being developed as a long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease (alpha galactosidase deficiency). The safety, tolerability, and exploratory efficacy will be evaluated in this study of increasing doses. Patients will be treated with infusions every two weeks for 12 months.
Detailed Description
Under the PB-102-F01 study protocol, patients will be enrolled into one of three PRX-102 dosing groups (0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg) and receive PRX-102 as an intravenous infusion every 2 weeks for 12 weeks (3 months). Patients who finish the PB-102-F01 study will be enrolled in the PB-102-F02 extension study and receive the same dose they had received in the PB-102-F01 study for an additional 38 weeks (9 months).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fabry Disease
Keywords
Fabry disease, Alpha galactosidase deficiency, Metabolic storage disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
0.2 mg/kg
Arm Type
Experimental
Arm Description
PRX-102 0.2 mg/kg every 2 weeks
Arm Title
1 mg/kg
Arm Type
Experimental
Arm Description
PRX-102 1 mg/kg every 2 weeks
Arm Title
2 mg/kg
Arm Type
Experimental
Arm Description
PRX-102 2 mg/kg every 2 weeks
Intervention Type
Drug
Intervention Name(s)
PRX-102
Other Intervention Name(s)
plant cell expressed recombinant human alpha-galactosidase-A
Primary Outcome Measure Information:
Title
Adverse Events
Description
Reportings of adverse events reported by the patient and from monitoring with clinical laboratory, physical examination and ECG. Results represent the number of AEs that were considered possibly, probably, or definitely related to treatment.
Time Frame
12 months
Other Pre-specified Outcome Measures:
Title
Plasma Gb3 Concentrations
Description
Results are presented as mean percent change from baseline (visit 1) to 12 months +/- standard error.
Time Frame
Plasma Gb3 concentration (ug/mL) was measured at baseline and every 3 months up to 12 months.
Title
Kidney Function - Change in eGFR
Description
Estimated glomerular filtration rate (eGFR) was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Levels of eGFR calculated by the CKD-EPI equation, based on measured serum creatinine on day 1, weeks 4, 8, 12, 26, 38 and 52 are used to determine the annualized slope of eGFR per patient over a 12 months period. The absolute mean change from baseline (visit 1) to 12 months is then derived from the eGFR slope.
Time Frame
eGFR is performed at baseline (day 1) weeks 4, 8, 12, 26, 38 and 52 (12 months)
Title
Plasma Lyso-Gb3 Levels
Description
Results are presented as mean percent change from baseline (visit 1) to 12 months +/- standard error.
Time Frame
Plasma Lyso-Gb3 concentration (ng/mL) was measured at baseline and every 3 months up to 12 months.
Title
Change in Kidney Gb3 Accumulation
Description
Kidney biopsy was performed at baseline of study PB-102-F01 and following 6 months treatment with PRX-102. Approximately 300 capillaries were scored in each specimen. A quantitative Barisoni Lipid Inclusion Scoring System (BLISS) was used for scoring Gb3 inclusions in kidney peritubular capillary (PTC) biopsy samples.The scoring system was implemented by 3 blinded pathologists/readers.The BLISS scoring methodology consists of counting the number of Gb-3 inclusions per capillary previously annotated.The final score of each biopsy was the average number of inclusions per capillary. A decrease in scoring from baseline to 6 Month is considered an indication for clinical improvement.
Time Frame
Visit 1 (day 1) in PB-102-F01 study and after a total of 6 months of treatment (i.e., at 3 months into study PB-102-F02).
Title
Cardiac Fibrosis Per MRI
Description
Cardiac MRI was performed to estimate the percentage and mass of the myocardial fibrotic area.
Results represent the number of subjects with fibrosis after 1 year of treatment.
Time Frame
Cardiac MRI was performed in order to assess myocardial fibrosis at baseline, 6 months and 12 months visit.
Title
Cardiac MRI - Ejection Fraction
Description
Results are presented as mean percent change from baseline (visit 1) to 12 months.
Time Frame
Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
Title
Cardiac MRI - LVM
Description
Results are presented as mean percent change from baseline (visit 1) to 12 months.
Time Frame
Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
Title
Cardiac MRI - LVMI
Description
Cardiac MRI with computer-calculated left ventricular mass index were conducted at baseline, 6 month, and 12 months. Results are presented as mean percent change from baseline (visit 1) to 12 months. LVMI is calculated by dividing the left ventricular mass by body surface area.
Time Frame
Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
Title
Pharmacokinetics - AUC
Description
PK parameters were derived from the plasma concentration versus time profiles. Results reported represent the averaged values following a single dosing of the study drug.
Time Frame
PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion.
Title
Pharmacokinetics - Terminal Half Life
Description
PK parameters were derived from the plasma concentration versus time profiles. Results reported represent the averaged values following a single dosing of the study drug.
Time Frame
PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion.
Title
Pharmacokinetics - Clearance of Drug (Cl)
Description
PK parameters were derived from the plasma concentration versus time profiles. Clearance of drug from plasma represents the volume of plasma cleared of the drug per unit time per Kg.
Results reported represent the averaged values following a single dosing of the study drug.
Time Frame
PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion.
Title
Pharmacokinetics - Volume of Distribution (Vz)
Description
PK parameters were derived from the plasma concentration versus time profiles. Vz is the volume of distribution during the elimination phase. Results reported represent the averaged values following a single dosing of the study drug.
Time Frame
PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion.
Title
Pharmacokinetics - Cmax
Description
Pharmacokinetic (PK) parameters were derived from the plasma concentration versus time profiles.
Cmax is the maximal plasma concentration of a drug after administration. Results reported represent the averaged values following a single dosing of the study drug.
Time Frame
PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion.
Title
Number of Participants With Anti-Drug Antibodies
Description
Results reported represent the number of participants who were tested positive for anti-pegunigalsidase alfa (PRX-102) antibodies, including neutralizing antibodies in patients having a positive IgG antibody response per group, at Visit 1, 2 (Month 1), and then every 2 months during the study, and 2 months after the last infusion.
Time Frame
Anti-pegunigalsidase alfa (PRX-102) antibodies, including neutralizing antibodies in patients having a positive IgG antibody response, were assessed at Visit 1, 2 (Month 1), and then every 2 months during the study, and 2 months after the last infusion.
Title
Change in Short Form Brief Pain Inventory (BPI)
Description
Pain severity (worst, least, average, and right now) is summarized at baseline, 3-month, 6-month and 12-month of the study. The Short Form Brief Pain Inventory (BPI) is based on a 10-point scale, where 0=no pain and 10=pain as bad as you can imagine. A reduction in pain severity score indicated an improvement. The changes from baseline for individual scores and composite scores (a mean severity score) was assessed. The mean change in score from baseline at the 12-month visit is reflected.
Time Frame
The Short Form Brief Pain Inventory (BPI) is assessed at baseline, 3-month, 6-month, and 12-month visits.
Title
Urine Creatinine Level
Description
Proteinuria is assessed using spot urine tests at baseline, 3-month, 6-month, 9-month, and 12-month visits. The percent changes of urine creatinine level at the 12-month visit from baseline is reflected.
Time Frame
Urine creatinine level is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits using spot urine tests.
Title
Urine Protein/Creatinine Ratio
Description
Proteinuria is assessed using spot urine tests at baseline, 3-month, 6-month, 9-month, and 12-month visits. The percent changes of urine protein/creatinine ratio at the 12-month visit from baseline is reflected.
Time Frame
Protein/.creatinine ratio is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits
Title
Total Urine Protein Level
Description
Proteinuria is assessed using spot urine tests at baseline, 3-month, 6-month, 9-month, and 12-month visits. The percent changes of total urine protein level at the 12-month visit from baseline is reflected.
Time Frame
Total urine protein level is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits.
Title
Brain MRI
Description
Qualitative assessments regarding evidence of stroke using brain MRI were summarized at baseline and 12-month visits. Number is subjects with evidence of stoke on the brain MRI at the 12-month visit is reflected.
Time Frame
Brain MRI is performed at baseline and 12-month visit.
Title
Change in Mainz Severity Score Index (MSSI)
Description
The Mainz Severity Score Index (MSSI) is useful for monitoring clinical improvement in patients receiving enzyme replacement therapy. The MSSI scoring system is composed of four sections that cover the general, neurological,cardiovascular and renal signs and symptoms of Fabry disease. Each section includes a group of signs and symptoms that are associated with Fabry disease. The minimal score is 0, and the maximum score for the general section is 18. A higher score indicates more severe clinical manifestations of the disease.The MSSI is performed at baseline, 6-month, and 12-month. The overall mean reduction of the total general score at 12-month from baseline is reflected.
Time Frame
The MSSI is performed at baseline, 6-month, and 12-month
Title
Gastrointestinal Symptoms Questionnaire - Severity of Abdominal Pain
Description
A qualitative assessments regarding abdominal pain and diarrhea at baseline, 3-month, 6-month, 9-month, and 12-month visits. The subjects were asked to report the severity of their abdominal pain as no pain, mild, moderate, severe or really severe. The number of subjects who reported no or mild abdominal pain at the 12-month visit are reflected.
Time Frame
The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits.
Title
Gastrointestinal Symptoms Questionnaire - Frequency of Abdominal Pain
Description
A qualitative assessments regarding abdominal pain and diarrhea at baseline, 3-month, 6-month, 9-month, and 12-month visits. The subjects were asked to report their frequency of abdominal pain as never, rarely, monthly, weekly, or daily. The numbers of subjects who reported never or rarely having abdominal pain at the 12-month visit are reflected.
Time Frame
The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits.
Title
Gastrointestinal Symptoms Questionnaire - Frequency of Diarrhea
Description
A qualitative assessments regarding abdominal pain and diarrhea at baseline, 3-month, 6-month, 9-month, and 12-month visits. The subjects were asked to report their frequency of diarrhea as never, rarely, monthly, weekly, or daily. The number of subjects who reported never or rarely having diarrhea at the 12-month visit is reflected.
Time Frame
The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Symptomatic adult Fabry patients (≥18 yrs)
Males: plasma and/or leucocyte alpha galactosidase activity (by activity assay) less than lower limit of normal (LLN in plasma=3.2 nmol/hr/ml, LLN in leucocytes=32 nmol/hr/mg/protein)
Females: historical genetic test results consistent with Fabry mutations
Globotriaosylceramide (Gb3) concentration in urine > 1.5 times upper normal limit
Patients who have never received enzyme replacement therapy (ERT) in the past, or patients who have not received ERT in the past 6 months and have a negative anti alpha galactosidase antibody test
eGFR ≥ 60 mL/min/1.73m2
The patient signs informed consent
Female patients and male patients whose co-partners are of child-bearing potential agree to use a medically acceptable method of contraception, not including the rhythm method
Exclusion Criteria:
Participation in any trial of an investigational drug within 30 days prior to study screening
Chronic kidney disease stages 3-5 (CKD 3-5) (Appendix 7)
History of dialysis or renal transplantation
Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy initiated or dose changed in the 4 weeks prior to screening
Severe myocardial fibrosis by MRI (≥2 late-enhancement [LE] positive left ventricular segments) (Weidemann et al. 2009)
History of clinical stroke
Pregnant or nursing
Presence of HIV and/or HBsAg and/or Hepatitis C infections
Known allergies to ERT
Known allergy to Gadolinium based contrast agents
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
UC Davis Medical Center, MIND Institute Department of Pediatrics, Section of Genetics
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
Department of Human Genetics, Emory University School of Medicine
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
University of Iowa Health Clinics
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Johns Hopkins University School of Medicine
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Children's Hospital of Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Research Baylor Institute of Metabolic Disease
City
Dallas
State/Province
Texas
ZIP/Postal Code
75226
Country
United States
Facility Name
O & O Alpan LLC
City
Fairfax
State/Province
Virginia
ZIP/Postal Code
22030
Country
United States
Facility Name
Royal Melbourne Hospital
City
Victoria Park
ZIP/Postal Code
3050
Country
Australia
Facility Name
Hematology and Clinical Research Private Institute
City
Asuncion
Country
Paraguay
Facility Name
Clinical Center of Serbia
City
Belgrade
Country
Serbia
Facility Name
Hospital de Dia Quiron Zaragoza
City
Zaragoza
ZIP/Postal Code
50012
Country
Spain
Facility Name
The Royal Free Hospital
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
30834538
Citation
Schiffmann R, Goker-Alpan O, Holida M, Giraldo P, Barisoni L, Colvin RB, Jennette CJ, Maegawa G, Boyadjiev SA, Gonzalez D, Nicholls K, Tuffaha A, Atta MG, Rup B, Charney MR, Paz A, Szlaifer M, Alon S, Brill-Almon E, Chertkoff R, Hughes D. Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1-year Phase 1/2 clinical trial. J Inherit Metab Dis. 2019 May;42(3):534-544. doi: 10.1002/jimd.12080. Epub 2019 Apr 8.
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Dose-ranging Study of PRX-102 in Adult Fabry Disease Patients
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