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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01678898
Recruitment Status : Completed
First Posted : September 5, 2012
Results First Posted : January 27, 2020
Last Update Posted : January 27, 2020
Sponsor:
Information provided by (Responsible Party):
Protalix

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.

Condition or disease Intervention/treatment Phase
Fabry Disease Drug: PRX-102 Phase 1 Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 2012
Actual Primary Completion Date : March 6, 2016
Actual Study Completion Date : March 6, 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 0.2 mg/kg
PRX-102 0.2 mg/kg every 2 weeks
Drug: PRX-102
Other Name: plant cell expressed recombinant human alpha-galactosidase-A

Experimental: 1 mg/kg
PRX-102 1 mg/kg every 2 weeks
Drug: PRX-102
Other Name: plant cell expressed recombinant human alpha-galactosidase-A

Experimental: 2 mg/kg
PRX-102 2 mg/kg every 2 weeks
Drug: PRX-102
Other Name: plant cell expressed recombinant human alpha-galactosidase-A




Primary Outcome Measures :
  1. Adverse Events [ Time Frame: 12 months ]
    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.


Other Outcome Measures:
  1. Plasma Gb3 Concentrations [ Time Frame: Plasma Gb3 concentration (ug/mL) was measured at baseline and every 3 months up to 12 months. ]
    Results are presented as mean percent change from baseline (visit 1) to 12 months +/- standard error.

  2. Kidney Function - Change in eGFR [ Time Frame: eGFR is performed at baseline (day 1) weeks 4, 8, 12, 26, 38 and 52 (12 months) ]
    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.

  3. Plasma Lyso-Gb3 Levels [ Time Frame: Plasma Lyso-Gb3 concentration (ng/mL) was measured at baseline and every 3 months up to 12 months. ]
    Results are presented as mean percent change from baseline (visit 1) to 12 months +/- standard error.

  4. Change in Kidney Gb3 Accumulation [ 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). ]
    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.

  5. Cardiac Fibrosis Per MRI [ Time Frame: Cardiac MRI was performed in order to assess myocardial fibrosis at baseline, 6 months and 12 months visit. ]

    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.


  6. Cardiac MRI - Ejection Fraction [ Time Frame: Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months. ]
    Results are presented as mean percent change from baseline (visit 1) to 12 months.

  7. Cardiac MRI - LVM [ Time Frame: Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months. ]
    Results are presented as mean percent change from baseline (visit 1) to 12 months.

  8. Cardiac MRI - LVMI [ Time Frame: Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months. ]
    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.

  9. Pharmacokinetics - AUC [ 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. ]
    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.

  10. Pharmacokinetics - Terminal Half Life [ 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. ]
    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.

  11. Pharmacokinetics - Clearance of Drug (Cl) [ 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. ]

    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.


  12. Pharmacokinetics - Volume of Distribution (Vz) [ 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. ]
    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.

  13. Pharmacokinetics - Cmax [ 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. ]

    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.


  14. Number of Participants With Anti-Drug Antibodies [ 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. ]
    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.

  15. Change in Short Form Brief Pain Inventory (BPI) [ Time Frame: The Short Form Brief Pain Inventory (BPI) is assessed at baseline, 3-month, 6-month, and 12-month visits. ]
    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.

  16. Urine Creatinine Level [ Time Frame: Urine creatinine level is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits using spot urine tests. ]
    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.

  17. Urine Protein/Creatinine Ratio [ Time Frame: Protein/.creatinine ratio is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits ]
    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.

  18. Total Urine Protein Level [ Time Frame: Total urine protein level is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits. ]
    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.

  19. Brain MRI [ Time Frame: Brain MRI is performed at baseline and 12-month visit. ]
    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.

  20. Change in Mainz Severity Score Index (MSSI) [ Time Frame: The MSSI is performed at baseline, 6-month, and 12-month ]
    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.

  21. Gastrointestinal Symptoms Questionnaire - Severity of Abdominal Pain [ Time Frame: The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits. ]
    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.

  22. Gastrointestinal Symptoms Questionnaire - Frequency of Abdominal Pain [ Time Frame: The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits. ]
    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.

  23. Gastrointestinal Symptoms Questionnaire - Frequency of Diarrhea [ Time Frame: The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits. ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01678898


Locations
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United States, California
UC Davis Medical Center, MIND Institute Department of Pediatrics, Section of Genetics
Sacramento, California, United States, 95817
United States, Georgia
Department of Human Genetics, Emory University School of Medicine
Atlanta, Georgia, United States, 30322
United States, Iowa
University of Iowa Health Clinics
Iowa City, Iowa, United States, 52242
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Maryland
Johns Hopkins University School of Medicine
Baltimore, Maryland, United States, 21205
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15224
United States, Texas
Research Baylor Institute of Metabolic Disease
Dallas, Texas, United States, 75226
United States, Virginia
O & O Alpan LLC
Fairfax, Virginia, United States, 22030
Australia
Royal Melbourne Hospital
Victoria Park, Australia, 3050
Paraguay
Hematology and Clinical Research Private Institute
Asuncion, Paraguay
Serbia
Clinical Center of Serbia
Belgrade, Serbia
Spain
Hospital de Dia Quiron Zaragoza
Zaragoza, Spain, 50012
United Kingdom
The Royal Free Hospital
London, United Kingdom, NW3 2QG
Sponsors and Collaborators
Protalix
Investigators
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Study Director: Einat Almon, PhD Protalix
Publications of Results:
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Responsible Party: Protalix
ClinicalTrials.gov Identifier: NCT01678898    
Obsolete Identifiers: NCT01769001
Other Study ID Numbers: PB-102-F01 & PB-102-F02
First Posted: September 5, 2012    Key Record Dates
Results First Posted: January 27, 2020
Last Update Posted: January 27, 2020
Last Verified: January 2020
Keywords provided by Protalix:
Fabry disease
Alpha galactosidase deficiency
Metabolic storage disease
Additional relevant MeSH terms:
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Fabry Disease
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Cerebral Small Vessel Diseases
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Sphingolipidoses
Metabolism, Inborn Errors
Lipidoses
Lipid Metabolism, Inborn Errors