Dose-ranging Study of PRX-102 in Adult Fabry Disease Patients

Fabry Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01678898
• Other study ID #: PB-102-F01 & PB-102-F02
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: October 2012
• Est. completion date: March 6, 2016

Study information

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

Clinical Trial 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.

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).

Other known NCT identifiers

• NCT01769001

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: March 6, 2016
• Est. primary completion date: March 6, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Fabry Disease

Intervention

Drug:
• PRX-102

Locations

Country	Name	City	State
Australia	Royal Melbourne Hospital	Victoria Park
Paraguay	Hematology and Clinical Research Private Institute	Asuncion
Serbia	Clinical Center of Serbia	Belgrade
Spain	Hospital de Dia Quiron Zaragoza	Zaragoza
United Kingdom	The Royal Free Hospital	London
United States	Department of Human Genetics, Emory University School of Medicine	Atlanta	Georgia
United States	Johns Hopkins University School of Medicine	Baltimore	Maryland
United States	Research Baylor Institute of Metabolic Disease	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	O & O Alpan LLC	Fairfax	Virginia
United States	University of Iowa Health Clinics	Iowa City	Iowa
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	UC Davis Medical Center, MIND Institute Department of Pediatrics, Section of Genetics	Sacramento	California

Sponsors (2)

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

Countries where clinical trial is conducted

United States,  Australia,  Paraguay,  Serbia,  Spain,  United Kingdom, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Plasma Gb3 Concentrations	Results are presented as mean percent change from baseline (visit 1) to 12 months +/- standard error.	Plasma Gb3 concentration (ug/mL) was measured at baseline and every 3 months up to 12 months.
Other	Kidney Function - Change in eGFR	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.	eGFR is performed at baseline (day 1) weeks 4, 8, 12, 26, 38 and 52 (12 months)
Other	Plasma Lyso-Gb3 Levels	Results are presented as mean percent change from baseline (visit 1) to 12 months +/- standard error.	Plasma Lyso-Gb3 concentration (ng/mL) was measured at baseline and every 3 months up to 12 months.
Other	Change in Kidney Gb3 Accumulation	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.	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).
Other	Cardiac Fibrosis Per MRI	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.	Cardiac MRI was performed in order to assess myocardial fibrosis at baseline, 6 months and 12 months visit.
Other	Cardiac MRI - Ejection Fraction	Results are presented as mean percent change from baseline (visit 1) to 12 months.	Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
Other	Cardiac MRI - LVM	Results are presented as mean percent change from baseline (visit 1) to 12 months.	Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
Other	Cardiac MRI - LVMI	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.	Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
Other	Pharmacokinetics - AUC	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.	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.
Other	Pharmacokinetics - Terminal Half Life	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.	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.
Other	Pharmacokinetics - Clearance of Drug (Cl)	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.	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.
Other	Pharmacokinetics - Volume of Distribution (Vz)	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.	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.
Other	Pharmacokinetics - Cmax	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.	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.
Other	Number of Participants With Anti-Drug Antibodies	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.	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.
Other	Change in Short Form Brief Pain Inventory (BPI)	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.	The Short Form Brief Pain Inventory (BPI) is assessed at baseline, 3-month, 6-month, and 12-month visits.
Other	Urine Creatinine Level	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.	Urine creatinine level is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits using spot urine tests.
Other	Urine Protein/Creatinine Ratio	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.	Protein/.creatinine ratio is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits
Other	Total Urine Protein Level	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.	Total urine protein level is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits.
Other	Brain MRI	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.	Brain MRI is performed at baseline and 12-month visit.
Other	Change in Mainz Severity Score Index (MSSI)	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.	The MSSI is performed at baseline, 6-month, and 12-month
Other	Gastrointestinal Symptoms Questionnaire - Severity of Abdominal Pain	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.	The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits.
Other	Gastrointestinal Symptoms Questionnaire - Frequency of Abdominal Pain	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.	The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits.
Other	Gastrointestinal Symptoms Questionnaire - Frequency of Diarrhea	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.	The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits.
Primary	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.	12 months