Clinical trial NCT01678898: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Fabry Disease
Keywords: Fabry disease
Alpha galactosidase deficiency
Metabolic storage disease
Lead sponsor: Protalix
Sponsor class: INDUSTRY
Collaborators: name: Chiesi Farmaceutici S.p.A.
First posted: 2012-09-05
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Adverse Events
timeFrame: 12 months
Secondary outcomes:
Other outcomes:
measure: Plasma Gb3 Concentrations
timeFrame: Plasma Gb3 concentration (ug/mL) was measured at baseline and every 3 months up to 12 months.
measure: Kidney Function - Change in eGFR
timeFrame: eGFR is performed at baseline (day 1) weeks 4, 8, 12, 26, 38 and 52 (12 months)
measure: Plasma Lyso-Gb3 Levels
timeFrame: Plasma Lyso-Gb3 concentration (ng/mL) was measured at baseline and every 3 months up to 12 months.
measure: Change in Kidney Gb3 Accumulation
timeFrame: 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).
measure: Cardiac Fibrosis Per MRI
timeFrame: Cardiac MRI was performed in order to assess myocardial fibrosis at baseline, 6 months and 12 months visit.
measure: Cardiac MRI - Ejection Fraction
timeFrame: Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
measure: Cardiac MRI - LVM
timeFrame: Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
measure: Cardiac MRI - LVMI
timeFrame: Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
measure: Pharmacokinetics - AUC
timeFrame: 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.
measure: Pharmacokinetics - Terminal Half Life
timeFrame: 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.
measure: Pharmacokinetics - Clearance of Drug (Cl)
timeFrame: 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.
measure: Pharmacokinetics - Volume of Distribution (Vz)
timeFrame: 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.
measure: Pharmacokinetics - Cmax
timeFrame: 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.
measure: Number of Participants With Anti-Drug Antibodies
timeFrame: 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.
measure: Change in Short Form Brief Pain Inventory (BPI)
timeFrame: The Short Form Brief Pain Inventory (BPI) is assessed at baseline, 3-month, 6-month, and 12-month visits.
measure: Urine Creatinine Level
timeFrame: Urine creatinine level is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits using spot urine tests.
measure: Urine Protein/Creatinine Ratio
timeFrame: Protein/.creatinine ratio is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits
measure: Total Urine Protein Level
timeFrame: Total urine protein level is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits.
measure: Brain MRI
timeFrame: Brain MRI is performed at baseline and 12-month visit.
measure: Change in Mainz Severity Score Index (MSSI)
timeFrame: The MSSI is performed at baseline, 6-month, and 12-month
measure: Gastrointestinal Symptoms Questionnaire - Severity of Abdominal Pain
timeFrame: The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits.
measure: Gastrointestinal Symptoms Questionnaire - Frequency of Abdominal Pain
timeFrame: The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits.
measure: Gastrointestinal Symptoms Questionnaire - Frequency of Diarrhea
timeFrame: The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits.
Locations:
city: Sacramento
country: United States
facility: UC Davis Medical Center, MIND Institute Department of Pediatrics, Section of Genetics
state: California
city: Atlanta
country: United States
facility: Department of Human Genetics, Emory University School of Medicine
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Health Clinics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Dallas
country: United States
facility: Research Baylor Institute of Metabolic Disease
state: Texas
city: Fairfax
country: United States
facility: O & O Alpan LLC
state: Virginia
city: Victoria Park
country: Australia
facility: Royal Melbourne Hospital
city: Asuncion
country: Paraguay
facility: Hematology and Clinical Research Private Institute
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia
city: Zaragoza
country: Spain
facility: Hospital de Dia Quiron Zaragoza
city: London
country: United Kingdom
facility: The Royal Free Hospital
Study officials:
References:
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.