Clinical Trial Results:
Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Pediatric Patients with Severe Hemophilia A
Summary
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EudraCT number |
2017-001531-40 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
02 Nov 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Nov 2020
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First version publication date |
30 Nov 2020
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Other versions |
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 |
WIL-30
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Octapharma AG
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Sponsor organisation address |
Seidenstrasse 2, Lachen, Switzerland, CH-8853
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Public contact |
VP, Clinical R&D Haematology, Octapharma AG, +41 554512189, cristina.solomon@octapharma.com
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Scientific contact |
VP, Clinical R&D Haematology, Octapharma AG, +41 554512189, cristina.solomon@octapharma.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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
16 Oct 2019
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Nov 2018
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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 |
The primary objective of this study is to determine the FVIII:C pharmacokinetics (PK) for Wilate in previously treated patients (PTP) with severe hemophilia A aged 1 to <12 years.
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Protection of trial subjects |
This trial was conducted in accordance to the principles of ICH- GCP, ensuring that the rights, safety and well-being of patients are protected and in consistency with the Declaration of Helsinki and national regulatory requirements. Inclusion and exclusion criteria were carefully defined in order to protect subjects from contraindications, interactions with other medication and risk factors associated with the investigational medicinal product. Throughout the study safety was assessed, such as of monitoring of AEs, SAEs and concomitant medications.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Nov 2017
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Long term follow-up planned |
No
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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 |
Russian Federation: 3
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Country: Number of subjects enrolled |
Ukraine: 7
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Worldwide total number of subjects |
10
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EEA total number of subjects |
0
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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) |
10
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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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 |
- | ||||||||||
Pre-assignment
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Screening details |
Male patients with documented diagnosis of Severe Haemophilia A were screened according to predefined in- and exclusion criteria. | ||||||||||
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 |
Not applicable
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Blinding used |
Not blinded | ||||||||||
Arms
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Arm title
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Wilate | ||||||||||
Arm description |
The dosage and frequency of Wilate treatment during the study was determined by the individual patient’s clinical situation. Dose (and duration) of treatment for breakthrough BEs was dependent on the location and extent of bleeding and on the clinical condition of the patient.Two patients underwent surgeries treated with Wilate. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Wilate
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Investigational medicinal product code |
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Other name |
HUMAN COAGULATION FACTOR VIII, VON WILLEBRAND FACTOR COMPLEX
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Pharmaceutical forms |
Powder and solvent for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
The dosage and frequency of Wilate treatment during the study was determined by the individual patient’s clinical situation. In the 2-day PK Assessment Phase performed before the start of the Prophylactic Treatment, Wilate was administered to all patients as a single dose of 50 ± 5 IU kg BW. In the Prophylactic Treatment Phase, Wilate was to be administered every 2 to 3 days at a dose of 20–40 IU/kg Wilate/kg BW for 6 months (+2 weeks) and at least 50 EDs. In case of unacceptably frequent spontaneous breakthrough BEs the dose of Wilate was to be increased by approximately 5 IU/kg.
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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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End points reporting groups
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Reporting group title |
Wilate
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Reporting group description |
The dosage and frequency of Wilate treatment during the study was determined by the individual patient’s clinical situation. Dose (and duration) of treatment for breakthrough BEs was dependent on the location and extent of bleeding and on the clinical condition of the patient.Two patients underwent surgeries treated with Wilate. | ||
Subject analysis set title |
SAF Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety (SAF) set included all patients who received at least one infusion of IMP
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Subject analysis set title |
PK Set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The PK set includes all patients for whom a valid Wilate PK profile was obtained.
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Subject analysis set title |
PP Set
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The PP set, i.e., a subset of the FAS, excludes patients with major protocol deviations that may have an impact on the evaluation of the efficacy outcome parameters.
Of the patients in the PP population, only 8 patients had evaluable bleeding events. Five of these patients were aged 1-<6 years, and 3 aged 6-<12 years.
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Subject analysis set title |
SURG Set
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The surgery (SURG) set is a subset of the FAS, containing all patients who underwent a surgical procedure treated with Wilate during their Prophylactic Treatment Phase.
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Subject analysis set title |
PK Set 1-<6 years
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
patients in PK Set aged 1-<6 years
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Subject analysis set title |
PK Set 6-<12 years
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
patients in PK Set aged 6-<12 years
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Subject analysis set title |
FAS Set 1 to <6 years
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
FAS Set 1 to <6 years
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Subject analysis set title |
FAS Set 6 to <12 years
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
FAS Set 6 to <12 years
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Subject analysis set title |
FAS Set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The full analysis set (FAS) defined according to the intention-to-treat (ITT) principle will include all enrolled subjects who received at least one infusion of IMP (after the initial PK
visit).
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Subject analysis set title |
PP Set 1-<6 years
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
All patients in the PP population aged 1-<6 years.
Of the patients in the PP population, only 8 patients had evaluable bleeding events. Five of these patients were aged 1-<6 years, and 3 aged 6-<12 years
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Subject analysis set title |
PP Set 6-<12 Years
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
All patients in the PP population aged 6-<12 years.
Of the patients in the PP population, only 8 patients had evaluable bleeding events. Five of these patients were aged 1-<6 years, and 3 aged 6-<12 years
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End point title |
Pharmacokinetic (PK) Assessment (Area Under the Curve (AUC) of FVIII:C [1] | ||||||||||||||||
End point description |
PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate AUC is hours (h) x international units (IU)/decilitre (dL).
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End point type |
Primary
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End point timeframe |
0h, 0.25h, 1h, 6h, 24h and 48 h after the end of injection
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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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Normalised (AUCNorm)) of FVIII:C for Wilate [2] | ||||||||||||||||
End point description |
PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The mean area under the curve normalised for the administered dose (AUCnorm) was calculated for Wilate. The units of measure used were AUC divided by dose.
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End point type |
Primary
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End point timeframe |
0h, 0.25h, 1h, 6h, 24h and 48 h after end of injection
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Notes [2] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration) for FVIII:C [3] | ||||||||||||||||
End point description |
PK assessments of FVIII:C were determined using the one-stage (OS) assays. The maximum plasma concentration of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study. Units of measure for maximum plasma concentration are international units (IU)/ decilitre (dL)
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End point type |
Primary
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End point timeframe |
0h, 0.25h, 1h, 6h, 24h and 48 h after the end of injection
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Notes [3] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetic (PK) Assessment (Half-life (h)) of FVIII:C [4] | ||||||||||||||||
End point description |
PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate half-life is hours.
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End point type |
Primary
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End point timeframe |
0h, 0.25h, 1h, 6h, 24h and 48 h after the end of injection
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Notes [4] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided. |
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No statistical analyses for this end point |
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End point title |
harmacokinetic (PK) Assessment (Time to Reach Maximum Plasma Concentration (Tmax)) of FVIII:C [5] | ||||||||||||||||
End point description |
PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate Tmax is hours (h).
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End point type |
Primary
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End point timeframe |
48 h after the end of injection
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Notes [5] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetic (PK) Assessment (Mean Residence Time (MRT)) of FVIII:C [6] | ||||||||||||||||
End point description |
PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate MRT is hours.
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End point type |
Primary
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End point timeframe |
48 h after the end of injection
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Notes [6] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetic (PK) Assessment (Volume of Distribution (Vd)) of FVIII:C [7] | ||||||||||||||||
End point description |
PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate Vd is decilitre (dL)/ kilograms (kg).
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End point type |
Primary
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End point timeframe |
0h, 0.25h, 1h, 6h, 24h and 48 h after the end of injection
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Notes [7] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetic (PK) Assessment (Clearance) of FVIII:C [8] | ||||||||||||||||
End point description |
PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate clearance are decilitre (dL)/ hours (h)/ kilograms (kg).
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End point type |
Primary
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End point timeframe |
0h, 0.25h, 1h, 6h, 24h and 48 h after the end of injection
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Notes [8] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided. |
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No statistical analyses for this end point |
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End point title |
Incremental In Vivo Recovery (IVR) of FVIII:C [9] | ||||||||||||||||
End point description |
The incremental IVR was determined from all patients at baseline was determined using the one-stage (OS) assay (standardised to 50 IU/kg).
The units of measure to calculate IVR is kilograms (kg) / deciliter (dL).
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End point type |
Primary
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End point timeframe |
48 h after the end of injection
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Notes [9] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided. |
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No statistical analyses for this end point |
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End point title |
Efficacy of prophylactic treatment with Wilate based on Total Annualized Bleeding Rate (TABR) | ||||||||||||||||
End point description |
The total number of bleeding events (BEs) in the time period between the first dose of IMP and the study completion visit, divided by the duration (in years) between the first dose of IMP and the study completion visit. Surgery periods, and BEs occurring within these periods, will be excluded from the calculation of TABR.
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End point type |
Secondary
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End point timeframe |
6 months
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No statistical analyses for this end point |
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End point title |
Efficacy of prophylactic treatment with Wilate based on Spontaneous Annualized Bleeding Rate (SABR) | ||||||||||||||||
End point description |
The SABR was calculated in analogy to the TABR. The total number of spontaneous bleeding events (BEs) in the time period between the first dose of IMP and the study completion visit, divided by the duration (in years) between the first dose of IMP and the study completion visit. Surgery periods, and BEs occurring within these periods, will be excluded from the calculation of the SABR.
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End point type |
Secondary
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End point timeframe |
6 months
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No statistical analyses for this end point |
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End point title |
Efficacy of Wilate in the Treatment of Breakthrough Bleeding Events (BEs) | ||||||||||||||||||||||||||||||||||||
End point description |
The proportion of BEs successfully treated with Wilate was assessed by the patient (together with the investigator in case of on-site treatment) in a patient diary. The treatment efficacy for all BEs was assessed using a pre-defined four-point scale: 'excellent', 'good', 'moderate', 'none'. 'Excellent' was defined as "Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection" (best outcome); 'good 'was defined as "definite pain relief and/or improvement in signs of bleeding within approximately 8-12 hours after an injection, requiring up to 2 injections for complete resolution". All efficacy ratings assessed as either 'excellent' or 'good' were considered 'successfully treated'. 'Moderate' was defined as "probable or slight beneficial effect within approximately 12 hours after the first injection" and 'none' defined as "no improvement within 12 hours, or worsening of symptoms".
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End point type |
Secondary
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End point timeframe |
6 months
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No statistical analyses for this end point |
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End point title |
Wilate Consumption Data: Average Dose of Wilate Per Week of Study | ||||||||||||||||
End point description |
The average consumption of Wilate per week of the study (IU/kg) for all patients receiving prophylaxis.
The analysis was performed in the full analysis (FAS) population (total: n=10). The FAS comprised 5 patients were aged 1-<6 years and 5 were aged 6-<12 years.
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End point type |
Secondary
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End point timeframe |
6 months
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No statistical analyses for this end point |
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End point title |
Incremental in Vivo Recovery (IVR) of Wilate Over Time | ||||||||||||||||||||||||||||
End point description |
The rise in FVIII:C activity in IU/dl per unit dose administered in IU/kg was determined for all patients at baseline, 3 and 6 months, using the one-stage (OS) assay. (Standardised to 50
IU/kg).
The analysis was performed in the full analysis (FAS) population (total: n=10). The FAS comprised 5 patients were aged 1-<6 years and 5 were aged 6-<12 years.
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End point type |
Secondary
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End point timeframe |
Baseline, and 3 and 6 months of treatment
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No statistical analyses for this end point |
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End point title |
Association Between ABO Blood Type and the FVIII:C Half-life of Wilate (OS Assay) | ||||||||||||||||||||||||
End point description |
Analysis of variance (ANOVA) was used in an exploratory sense to assess a possible association between the ABO blood type and the FVIII:C half-life of Wilate. This was analysed by calculating the mean square in a one-stage (OS) assay.
The analysis was performed for the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-<6 years and 5 aged 6-<12 years.
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End point type |
Secondary
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End point timeframe |
6 months
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No statistical analyses for this end point |
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End point title |
Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate | ||||||||||||||||||||||||
End point description |
Analysis of variance (ANOVA) was used in an exploratory sense to assess a possible association between VWF:Ag with the FVIII:C half-life of Wilate. This was analysed by calculating the mean square in a one-stage (OS) assay.
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End point type |
Secondary
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End point timeframe |
6 months
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No statistical analyses for this end point |
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End point title |
Immunogenicity of Wilate: Number of Participants With FVIII Inhibitor Activity at 6 Months | ||||||||
End point description |
FVIII inhibitor activity was determined at each study visit: screening, PK, Day 14 visit, Day 30 visit, 3 Months visit and 6 Months visit before injection (estimated along with 95% Pearson-Clopper CIs)
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End point type |
Secondary
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End point timeframe |
6 months
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No statistical analyses for this end point |
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End point title |
Virus Safety Measured by the Number With Parvovirus B19 Seroconversions Between Baseline (BL) and End of Study | ||||||||
End point description |
Virus safety was evaluated by taking a plasma sample for parvovirus B19 antibody testing before the first injection of Wilate at the PK visit. All patients negative at screening were tested again at the Study Completion visit. The number of Parvovirus B19 seroconversions between BL and end of study was recorded
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End point type |
Secondary
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End point timeframe |
6 month
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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 |
Throughout the Study
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
Safety Population (SAF)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||
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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 |