Clinical Trial Results:
This is a combined clinical report for PB-102-F01 study (EudraCT number 2012-004786-40) and its extension study PB-102-F02 (2013-002554-78) of a Phase 1/2, Open-Label, Dose Ranging Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Exploratory Efficacy Parameters of pegunigalsidase alfa (PRX-102) administered by Intravenous Infusion every 2 weeks for a total of 12 Months [divided into 12 weeks (PB-102-F01 study ) followed by 38 weeks (PB-102-F02 study)] to Adult Fabry Patients.
Summary
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EudraCT number |
2013-002554-78 |
Trial protocol |
GB ES |
Global end of trial date |
06 Mar 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Jan 2018
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First version publication date |
03 Jan 2018
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Other versions |
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Summary report(s) |
CSR Synopsis |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
PB-102-F02 / PB-102-F01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01769001 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Protalix Ltd.
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Sponsor organisation address |
2 Snunit St, Carmiel, Israel, 20100
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Public contact |
Rainer Schuckelt, CATO Europe GmbH, 49 2234379440, r.schuckelt@cato-europe.com
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Scientific contact |
Raul Chertkoff, Protalix Ltd., 972 49028100, raul@protalix.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 May 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
06 Mar 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Mar 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the safety, tolerability, pharmacokinetics and exploratory efficacy parameters of pegunigalsidase alfa (PRX-102) in adult Fabry patients who have successfully completed treatment with pegunigalsidase alfa in the core study PB-102-F01, and continued to receive treatment (at the same dose that was initially assigned to each patient) in the PB-102-F02 extension study.
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Protection of trial subjects |
Since this study (F01 and F02) represents the first administration of pegunigalsidase alfa (PRX-102) to humans, the patients were infused sequentially and stepwise in order to evaluate tolerability.
The first 6 patients were given the lowest dose (0.2 mg/kg) for at least 2 infusions each and if well tolerated, the next 6 patients were given the 1 mg/kg dose for at least 2 infusions each, and if well tolerated, the last 6 patients were given the highest dose (2 mg/kg).
Specifically in the 2mg/kg treatment group, patients were provided with premedication as a preventive measure.
Custom tailoring of infusion volume and rate were implemented for patients weighing over 100Kg in the 1mg/kg and 2mg/kg treatment groups.
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Background therapy |
Not Applicable | ||
Evidence for comparator |
Not Applicable | ||
Actual start date of recruitment |
05 Nov 2012
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
5 Years | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 1
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Country: Number of subjects enrolled |
Spain: 2
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Paraguay: 1
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Country: Number of subjects enrolled |
United States: 13
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Worldwide total number of subjects |
18
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EEA total number of subjects |
3
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
17
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment efforts were conducted in North and South America, Europe and Australia for PB-102-F01 (3 months), and all patients who completed this study continued to the PB102-F02 extension study for an additional 9 months, to complete a total of 12 months of treatment. Eighteen patients were eligible for enrollment, and 16 completed the study. | ||||||||||||
Pre-assignment
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Screening details |
Eighteen (18) patients were eligible for enrollment for PB-102-F01 study after meeting all inclusion criteria. The eligible patients who completed PB-102-F01, needed to sign an informed consent for PB-102-F02. | ||||||||||||
Pre-assignment period milestones
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Number of subjects started |
18 | ||||||||||||
Number of subjects completed |
18 | ||||||||||||
Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||
Arms
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Arm title
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Pegunigalsidase alfa | ||||||||||||
Arm description |
Safety analysis was performed on all 18 treated patients, and efficacy analysis was performed on the 16 patients who completed the study and received all infusions. Efficacy was analyzed on all 16 patients (9 males and 7 females), and additionally on phenotypically classic Fabry disease patients (9 males and 1 female). | ||||||||||||
Arm type |
Dose range finding | ||||||||||||
Investigational medicinal product name |
pegunigalsidase alfa
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Investigational medicinal product code |
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Other name |
PRX-102, Alpha-galactosidase-A
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Pharmaceutical forms |
Concentrate and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
All patients who completed study PB-102-F01 (12 weeks) were enrolled into extension study PB-102-F02 to receive one of three pegunigalsidase alfa (PRX-102) doses (0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg), which was the same dose they had received in study PB-102-F01, and continued to receive pegunigalsidase alfa (PRX-102) as an intravenous infusion every 2 weeks for an additional 38 weeks, i.e. for a total of 12 months of treatment.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Efficacy group
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The efficacy population in the study inlcuded 16 patients: 6 patients in the 0.2 mg/kg treatment group, 6 patients in the 1.0 mg/kg after one patient withdrew due to an AE and one patient was discontinued from the study by the investigator, and 4 patients in the 2.0 mg/kg treatment group.
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Subject analysis set title |
Safety group
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The safety population in the study inlcuded 18 patients: 6 patients in the 0.2 mg/kg treatment group, 8 patients in the 1.0 mg/kg (6 completed the study; 1 was discontinued by the investigator and 1 withdrew due to an AE), and 4 patients in the 2.0 mg/kg treatment groups.
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Subject analysis set title |
0.2 mg/kg cohort
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Six patients were enrolled in the 0.2mg/kg treatment group and completed the study (12 months).
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Subject analysis set title |
1 mg/kg cohort
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Eight patients were enrolled in the 1.0 mg/kg treatment group, however only 6 patients completed the study (12 months), after one withdrew due to an AE and one patient was discontinued from the study by the investigator.
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Subject analysis set title |
2 mg/kg cohort
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Four patients were enrolled in the 2.0 mg/kg treatment group and completed the study (12 months).
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Subject analysis set title |
Phenotypically Classic Fabry Patients
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Of the 16 patients who completed the 12 months treatment period, 10 (9 males and 1 female) fit the description of phenotypically classic patients.
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End points reporting groups
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Reporting group title |
Pegunigalsidase alfa
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Reporting group description |
Safety analysis was performed on all 18 treated patients, and efficacy analysis was performed on the 16 patients who completed the study and received all infusions. Efficacy was analyzed on all 16 patients (9 males and 7 females), and additionally on phenotypically classic Fabry disease patients (9 males and 1 female). | ||
Subject analysis set title |
Efficacy group
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The efficacy population in the study inlcuded 16 patients: 6 patients in the 0.2 mg/kg treatment group, 6 patients in the 1.0 mg/kg after one patient withdrew due to an AE and one patient was discontinued from the study by the investigator, and 4 patients in the 2.0 mg/kg treatment group.
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Subject analysis set title |
Safety group
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The safety population in the study inlcuded 18 patients: 6 patients in the 0.2 mg/kg treatment group, 8 patients in the 1.0 mg/kg (6 completed the study; 1 was discontinued by the investigator and 1 withdrew due to an AE), and 4 patients in the 2.0 mg/kg treatment groups.
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Subject analysis set title |
0.2 mg/kg cohort
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Six patients were enrolled in the 0.2mg/kg treatment group and completed the study (12 months).
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Subject analysis set title |
1 mg/kg cohort
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Eight patients were enrolled in the 1.0 mg/kg treatment group, however only 6 patients completed the study (12 months), after one withdrew due to an AE and one patient was discontinued from the study by the investigator.
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Subject analysis set title |
2 mg/kg cohort
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Four patients were enrolled in the 2.0 mg/kg treatment group and completed the study (12 months).
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Subject analysis set title |
Phenotypically Classic Fabry Patients
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Of the 16 patients who completed the 12 months treatment period, 10 (9 males and 1 female) fit the description of phenotypically classic patients.
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End point title |
Safety - Adverse Events (AE) [1] | ||||||||||
End point description |
Reportings of adverse events reported by the patient and from monitoring with clinical laboratory, physical examination and ECG.
For the complete analysis, please refer to the AEs section.
Results represent the number of adverse events that were considered possibly, probably, or definitely related to treatment, experienced by 11/18 patients in the safety group.
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End point type |
Primary
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End point timeframe |
Patients were evaluated for AEs throughout the 12 months, from signing ICF up to 2 months after the last infusion.
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Justification: This is a Phase 1/2 study with no formal statistical analyses required of pre-specified. Results of safety evaluations were summarized and described. |
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No statistical analyses for this end point |
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End point title |
Kidney Function Assessment - eGFR - mean change from baseline | |||||||||||||||
End point description |
Estimated GFR was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
The mean annualized eGFR slope of the phenotypically classic patients (n=9, after excluding one patient from the analysis due to intermittent treatment with doxycycline throughout the year) was 0.01 (±1.37).
The results presented here represent the absolute mean change from baseline (visit 1) to 12 months.
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End point type |
Other pre-specified
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End point timeframe |
Levels of estimated glomerular filtration rate (eGFR) calculated by the CKD-EPI equation, based on measured serum creatinine, were determined on day 1 and weeks 4, 8, 12, 26, 38 and 52, and used to determine the annualized slope of eGFR per patient.
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No statistical analyses for this end point |
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End point title |
Plasma Gb3 levels | |||||||||||||||||||||||||||||||||||
End point description |
Results are presented as mean percent change from baseline (visit 1) to 12 months +/- standard error.
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End point type |
Other pre-specified
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End point timeframe |
Plasma Gb3 concentration (ug/mL) was measured at baseline and every 3 months up to 12 months.
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No statistical analyses for this end point |
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End point title |
Plasma Lyso-Gb3 Levels | |||||||||||||||||||||||||||||||||||
End point description |
Results are presented as mean percent change from baseline (visit 1) to 12 months +/- standard error.
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End point type |
Other pre-specified
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End point timeframe |
Plasma Lyso-Gb3 concentration (ng/mL) was measured at baseline and every 3 months up to 12 months.
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No statistical analyses for this end point |
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End point title |
Kidney Gb3 accumulation – biopsies | |||||||||||||||
End point description |
Kidney biopsy was performed at baseline of study PB-102-F01 and following a total of 6 months treatment with pegunigalsidase alfa (at Month 3 visit of study PB-102-F02). Approximately 300 capillaries were scored in each specimen. The Barisoni Lipid Inclusion Scoring System (BLISS) was used as the quantitative scoring methodology for scoring Gb3 inclusions in kidney peritubular capillary (PTC) biopsy samples.
The final score of each biopsy was the average number of inclusions per capillary.
The scoring system was implemented by 3 pathologists/readers, who were blinded to patient, dose, and duration of treatment.
A decrease in scoring from baseline to 6 Month is considered an indication for clinical improvement.
Results are presented as percent change from baseline (visit 1) to month 6.
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End point type |
Other pre-specified
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End point timeframe |
Two kidney biopsies were performed: the first was at visit 1 in PB-102-F01 study and the second was after a total of 6 months of treatment (i.e., at 3 months into study PB-102-F02).
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No statistical analyses for this end point |
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End point title |
Cardiac Fibrosis per MRI | |||||||||||||||
End point description |
Cardiac MRI was performed to estimate left ventricular mass (LVM), left ventricular mass index (LVMi), ejection fraction (EF) and percentage and mass of the myocardial fibrotic area.
Results represent the number of segments with fibrosis after 1 year of treatment.
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End point type |
Other pre-specified
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End point timeframe |
Cardiac MRI was performed in order to assess myocardial fibrosis at baseline, 6 months and 12 months visit.
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No statistical analyses for this end point |
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End point title |
Cardiac MRI - Ejection Fraction | |||||||||||||||
End point description |
Results are presented as mean percent change from baseline (visit 1) to 12 months.
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End point type |
Other pre-specified
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End point timeframe |
Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
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No statistical analyses for this end point |
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End point title |
Cardiac MRI – LVM | |||||||||||||||
End point description |
Results are presented as mean percent change from baseline (visit 1) to 12 months.
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End point type |
Other pre-specified
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End point timeframe |
Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
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No statistical analyses for this end point |
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End point title |
Cardiac MRI - LVMI | |||||||||||||||
End point description |
Results are presented as mean percent change from baseline (visit 1) to 12 months.
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End point type |
Other pre-specified
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End point timeframe |
Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics – AUC | ||||||||||||||||||||
End point description |
PK parameters were derived from the plasma concentration versus time profiles.
Pegunigalsidase alfa PK parameters and profile indicate dose dependency: the PK results for all three dose levels demonstrated that mean values for AUC0-∞ (the area under the plasma concentration curve from 0 hours to infinity) increased with increasing dose on Day 1 and at Months 3, 6, and 12.
The enzyme was found to be available throughout the 2-week infusion intervals with a plasma half-life of approximately 80 hours.
Results reported represent the values following a single dosing of the study drug.
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End point type |
Other pre-specified
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End point 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.
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics - Terminal Half Life | ||||||||||||||||||||
End point description |
PK parameters were derived from the plasma concentration versus time profiles.
t1/2 = half life.
The PK results for all three dose levels demonstrated that the enzyme was found to be available throughout the 2-week intervals with a plasma half-life of approximately 80 hours.
Results reported represent the values following a single dosing of the study drug.
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End point type |
Other pre-specified
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End point 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.
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics - Clearance of Drug (Cl) | ||||||||||||||||||||
End point 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 values following a single dosing of the study drug.
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End point type |
Other pre-specified
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End point 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.
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics - Volume of Distribution (Vz) | ||||||||||||||||||||
End point 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 values following a single dosing of the study drug.
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End point type |
Other pre-specified
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End point 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.
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics – Cmax | ||||||||||||||||||||
End point 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 values following a single dosing of the study drug.
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End point type |
Other pre-specified
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End point 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.
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No statistical analyses for this end point |
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End point title |
Safety - Anti-Drug Antibodies | |||||||||||||||||||||||||
End point description |
Low incidence of treatment induced ADA (3 of 16) with reversible and transient effect on PK was observed.
Three (3) patients developed treatment-induced IgG antibodies to pegunigalsidase alfa (PRX-102).
Two (2) patients from the 0.2 mg/kg treatment group had titers as high as 4633 and 2198, respectively, and both were positive for neutralizing antibodies.
One (1) patient from the 1.0 mg/kg treatment group had a titer as high as 237. This patient was negative for neutralizing antibodies.
ADA response was transient and tolerization was observed.
Results reported represent the number of patients who were ADA positive per group.
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End point type |
Other pre-specified
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End point 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.
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
AEs were collected from the start of treatment throughout the 12 months of the study, including a follow up at the end of the study.
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Adverse event reporting additional description |
Any laboratory abnormality assessed as clinically significant by the investigator was recorded as an adverse event.
A specific analysis was performed for events that occured during and up to 2h post infusion.
Total AEs - 223; 169 not treatment related, 54 treatment related.
Reported are the infusion related AEs.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
All patients
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Reporting group description |
All patients who received at least a single partial treatment are included in this reporting group analysis. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |