Clinical trial NCT02795676: Study of the Safety and Efficacy of PRX-102 Compared to Agalsidase Beta on Renal Function
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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Fabry Disease
Keywords: Glomerular filtration rate
Proteinuria
PRX-102
pegunigalsidase alfa
Fabry Disease
Lead sponsor: Protalix
Sponsor class: INDUSTRY
Collaborators: name: Chiesi Farmaceutici S.p.A.
First posted: 2016-06-10
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Annualized Change (Slope) in Estimated Glomerular Filtration Rate (eGFR)
timeFrame: 24 months
Secondary outcomes:
measure: Estimated Glomerular Filtration Rate (eGFR)
timeFrame: Baseline and Month 24
measure: Plasma Lyso-Gb3
timeFrame: Baseline and Month 24
measure: Short Form Brief Pain Inventory (BPI)
timeFrame: Baseline and Month 24
measure: Mainz Severity Score Index (MSSI)
timeFrame: Baseline and Month 24
measure: Urine Protein/Creatinine Ratio (UPCR)
timeFrame: Baseline and Month 24
measure: Left Ventricular Mass Index With Hypertrophy at Baseline
timeFrame: Baseline and Month 24
measure: Left Ventricular Mass Index Without Hypertrophy at Baseline
timeFrame: Baseline and Month 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: UAB Medicine
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Orange
country: United States
facility: University of California Irvine Center
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Hosptials and Clinics
state: Iowa
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Grand Rapids
country: United States
facility: Infusion Associates
state: Michigan
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: Institute of Metabolic Disease, Baylor Healthcare
state: Texas
city: Dallas
country: United States
facility: Renal Disease Research Institute, LLC - Dallas
state: Texas
city: Salt Lake City
country: United States
facility: Eccles Primary Children's Outpatient Services Building
state: Utah
city: Fairfax
country: United States
facility: O+O Alpan LLC
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Prague
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
state: Czech Republic
city: Turku
country: Finland
facility: Turku University Central Hospital
city: Paris
country: France
facility: Hôpital Raymond Poincaré
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria "Federico II"
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
city: Bergen
country: Norway
facility: Haukeland University Hospital Klinisk Forskningspost
city: Slovenj Gradec
country: Slovenia
facility: General Hospital Slovenj Gradec
city: Zaragoza
country: Spain
facility: Hospital de Dia Quiron Zaragoza
city: Zürich
country: Switzerland
facility: Klinik und Poliklinik für Innere Medizin UniversitätsSpital Zürich
city: Edgbaston
country: United Kingdom
facility: Institute of Metabolism and Systems Research
state: Birmingham
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: London
country: United Kingdom
facility: The Royal Free Hospital
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
Study officials:
References: