Back to resultsPharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Paediatric Patients With Severe Haemophilia A
Primary Purpose
Severe Hemophilia A
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Wilate
Sponsored by
About this trial
This is an interventional treatment trial for Severe Hemophilia A
Eligibility Criteria
Inclusion Criteria:
- Severe haemophilia A (<1% FVIII:C) according to medical history
- Male patients aged 1 to <12 years
- Previous treatment with a FVIII concentrate for at least 50 exposure days (EDs)
- Immunocompetence (CD4+ count >200/μL)
- Voluntarily given, fully informed written and signed consent obtained by the patient's parent(s) or legal guardian and, depending on the children's developmental stage and intellectual capacity, informed assent by the patients before any study-related procedures are performed
The interval between the Screening Visit and the PK Visit should not exceed 30 days. If the 30-day interval is exceeded, determination of the CD4+ count is to be repeated and must be >200/μL for patients to be enrolled (i.e., inclusion criterion no. 4).
Exclusion Criteria:
- Any coagulation disorders other than haemophilia A
- History of FVIII inhibitor activity (≥0.6 BU) or detectable FVIII inhibitory antibodies (≥0.6 BU using the Nijmegen modification of the Bethesda assay) at screening, as determined by the central laboratory
- Severe liver or kidney diseases (alanine aminotransferase [ALAT] and aspartate transaminase [ASAT] levels >5 times of upper limit of normal, creatinine >120 μmol/L)
- Patients receiving or scheduled to receive immunomodulating drugs (other than antiretroviral chemotherapy), such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar drugs
Sites / Locations
- Kirov SSC Hematology and Transfusiology
- "National Children's Specialized Clinic "OKHMATDYT"
- "Western Ukrainian Specialized Children's Medical Center"
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
All patients
Arm Description
All patients will receive Wilate for prophylactic treatment. Patients will also receive Wilate for treatment of breakthrough bleeding events as required
Outcomes
Primary Outcome Measures
Pharmacokinetic (PK) Assessment (Area Under the Curve (AUC)) of FVIII:C
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).
Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Normalised (AUCNorm)) of FVIII:C for Wilate
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.
Pharmacokinetic (PK) Assessment (Half-life (h)) of FVIII:C
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.
Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration) for FVIII:C
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)
Pharmacokinetic (PK) Assessment (Time to Reach Maximum Plasma Concentration (Tmax)) of FVIII:C
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).
Pharmacokinetic (PK) Assessment (Mean Residence Time (MRT)) of FVIII:C
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.
Pharmacokinetic (PK) Assessment (Volume of Distribution (Vd)) of FVIII:C
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).
Pharmacokinetic (PK) Assessment (Clearance) of FVIII:C
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).
Incremental In Vivo Recovery (IVR) of FVIII:C
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)
Secondary Outcome Measures
Total Annualized Bleeding Rate (TABR)
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.
Spontaneous Annualized Bleeding Rate (SABR)
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.
Efficacy of Wilate in the Treatment of Breakthrough Bleeding Events (BEs)
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".
Wilate Consumption Data: Average Dose of Wilate Per Week of Study
The average consumption of Wilate per week of the study (IU/kg) for all patients receiving prophylaxis
Incremental in Vivo Recovery (IVR) of Wilate Over Time
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.
Association Between ABO Blood Type and the FVIII:C Half-life of Wilate (OS Assay)
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.
Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate
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.
Safety and Tolerability of Wilate by Monitoring The Number of Adverse Events (AEs) Throughout the Study
At each visit (whether scheduled or unscheduled) , AEs will be documented by the investigator throughout the study. In addition, the investigator will check the patient diaries for any documented event.
Immunogenicity of Wilate: Number of Participants With FVIII Inhibitor Activity at 6 Months
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.
Virus Safety Measured by the Number With Parvovirus B19 Seroconversions Between Baseline (BL) and End of Study
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03376516
Brief Title
Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Paediatric Patients With Severe Haemophilia A
Official Title
Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Paediatric Patients With Severe Haemophilia A
Study Type
Interventional
2. Study Status
Record Verification Date
December 2020
Overall Recruitment Status
Completed
Study Start Date
November 22, 2017 (Actual)
Primary Completion Date
November 3, 2018 (Actual)
Study Completion Date
November 3, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Octapharma
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
A prospective, non-controlled, international, multi-centre phase 3 study to investigate the pharmacokinetics, efficacy, safety, and immunogenicity of Wilate in previously treated children with severe haemophilia A
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Hemophilia A
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
11 (Actual)
8. Arms, Groups, and Interventions
Arm Title
All patients
Arm Type
Experimental
Arm Description
All patients will receive Wilate for prophylactic treatment. Patients will also receive Wilate for treatment of breakthrough bleeding events as required
Intervention Type
Drug
Intervention Name(s)
Wilate
Intervention Description
von Willebrand factor / Factor VIII (plasma derived)
Primary Outcome Measure Information:
Title
Pharmacokinetic (PK) Assessment (Area Under the Curve (AUC)) of FVIII:C
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).
Time Frame
0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate
Title
Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Normalised (AUCNorm)) of FVIII:C for Wilate
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.
Time Frame
0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate
Title
Pharmacokinetic (PK) Assessment (Half-life (h)) of FVIII:C
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.
Time Frame
0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate
Title
Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration) for FVIII:C
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)
Time Frame
0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate
Title
Pharmacokinetic (PK) Assessment (Time to Reach Maximum Plasma Concentration (Tmax)) of FVIII:C
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).
Time Frame
48 h following a single dose of Wilate
Title
Pharmacokinetic (PK) Assessment (Mean Residence Time (MRT)) of FVIII:C
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.
Time Frame
48 h following a single dose of Wilate
Title
Pharmacokinetic (PK) Assessment (Volume of Distribution (Vd)) of FVIII:C
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).
Time Frame
0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate
Title
Pharmacokinetic (PK) Assessment (Clearance) of FVIII:C
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).
Time Frame
0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate
Title
Incremental In Vivo Recovery (IVR) of FVIII:C
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)
Time Frame
48 h following a single dose of Wilate
Secondary Outcome Measure Information:
Title
Total Annualized Bleeding Rate (TABR)
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.
Time Frame
6 months
Title
Spontaneous Annualized Bleeding Rate (SABR)
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.
Time Frame
6 months
Title
Efficacy of Wilate in the Treatment of Breakthrough Bleeding Events (BEs)
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".
Time Frame
6 months
Title
Wilate Consumption Data: Average Dose of Wilate Per Week of Study
Description
The average consumption of Wilate per week of the study (IU/kg) for all patients receiving prophylaxis
Time Frame
6 months
Title
Incremental in Vivo Recovery (IVR) of Wilate Over Time
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.
Time Frame
Baseline, and 3 and 6 months of treatment
Title
Association Between ABO Blood Type and the FVIII:C Half-life of Wilate (OS Assay)
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.
Time Frame
6 months
Title
Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate
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.
Time Frame
6 months
Title
Safety and Tolerability of Wilate by Monitoring The Number of Adverse Events (AEs) Throughout the Study
Description
At each visit (whether scheduled or unscheduled) , AEs will be documented by the investigator throughout the study. In addition, the investigator will check the patient diaries for any documented event.
Time Frame
6 months
Title
Immunogenicity of Wilate: Number of Participants With FVIII Inhibitor Activity at 6 Months
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.
Time Frame
6 months
Title
Virus Safety Measured by the Number With Parvovirus B19 Seroconversions Between Baseline (BL) and End of Study
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
Time Frame
6 months
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
11 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Severe haemophilia A (<1% FVIII:C) according to medical history
Male patients aged 1 to <12 years
Previous treatment with a FVIII concentrate for at least 50 exposure days (EDs)
Immunocompetence (CD4+ count >200/μL)
Voluntarily given, fully informed written and signed consent obtained by the patient's parent(s) or legal guardian and, depending on the children's developmental stage and intellectual capacity, informed assent by the patients before any study-related procedures are performed
The interval between the Screening Visit and the PK Visit should not exceed 30 days. If the 30-day interval is exceeded, determination of the CD4+ count is to be repeated and must be >200/μL for patients to be enrolled (i.e., inclusion criterion no. 4).
Exclusion Criteria:
Any coagulation disorders other than haemophilia A
History of FVIII inhibitor activity (≥0.6 BU) or detectable FVIII inhibitory antibodies (≥0.6 BU using the Nijmegen modification of the Bethesda assay) at screening, as determined by the central laboratory
Severe liver or kidney diseases (alanine aminotransferase [ALAT] and aspartate transaminase [ASAT] levels >5 times of upper limit of normal, creatinine >120 μmol/L)
Patients receiving or scheduled to receive immunomodulating drugs (other than antiretroviral chemotherapy), such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar drugs
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Cristina Solomon, MD
Organizational Affiliation
Octapharma
Official's Role
Study Director
Facility Information:
Facility Name
Kirov SSC Hematology and Transfusiology
City
Kirov
Country
Russian Federation
Facility Name
"National Children's Specialized Clinic "OKHMATDYT"
City
Kyiv
Country
Ukraine
Facility Name
"Western Ukrainian Specialized Children's Medical Center"
City
Lviv
Country
Ukraine
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Paediatric Patients With Severe Haemophilia A
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