Back to resultsClinical Study to Investigate the PK, Efficacy, and Safety of Wilate in Patients With Severe Hemophilia 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 hemophilia A (<1% FVIII:C) according to medical history
- Male patients aged ≥12 years
- Previous treatment with a FVIII concentrate for at least 150 exposure days (EDs)
- Immunocompetence (CD4+ count >200/µL)
- Good documentation of the historical bleeding rate (at least for the 6 months preceding study start)
- Voluntarily given, fully informed written and signed consent obtained by the patient (or parent/legal guardian in case of adolescents) before any study-related procedures are conducted
Whenever possible, the interval between the Screening Visit and the PK or Non-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., exclusion criterion no. 4).
Exclusion Criteria:
- Any coagulation disorders other than hemophilia A
- History of FVIII inhibitor activity (≥0.6 BU) or detectable FVIII inhibitory anti-bodies (≥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 anti-retroviral chemotherapy) such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar drugs
- Treatment with any investigational medicinal product in another interventional clinical study currently or within 4 weeks before enrollment
Sites / Locations
- Specialized Hospital for Active Treatment "Joan Pavel"
- National Haemophilia Centre
- Krakowskie Centrum Medyczne
- Korczowski Bartosz Gabinet Lekarski
- Centrul Medical Unirea -Policlinica Enescu
- Barnaul Branch of RAMS hematology center
- Federal Scientific Hematology Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
All patients
Arm Description
All patients will receive Wilate for prophylactic treatment
Outcomes
Primary Outcome Measures
Total Annualized Bleeding Rate (TABR)
The total number of bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel.
Secondary Outcome Measures
Spontaneous Annualized Bleeding Rate (SABR)
The number of spontaneous bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel.
Efficacy of Wilate in the Treatment of Breakthrough BEs
The proportion of BEs successfully treated with Wilate were documented by the patient (together with the investigator in case of on-site treatments) in the patient diary for all BEs according to a 4-point hemostatic efficacy scale including the four items: 'excellent,' 'good,' moderate,' and 'none', where '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) and 'none' was defined as "No improvement within 12 hours, or worsening of symptoms, requiring more than two injections for complete resolution" (worst outcome). All efficacy ratings assessed as either 'excellent' or 'good' were considered 'successfully treated.'
Wilate Consumption Data (Average Total Normdose of FVIII IU/kg Per Month of Study) for Prophylaxis
The average consumption of Wilate per month of study (IU/kg) for all patients receiving prophylaxis.
Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Norm) of FVIII:C
PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The value of the AUCnorm of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.
Pharmacokinetic (PK) Assessment (in Vivo Half-Life (t1/2)) of FVIII:C
PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The in vivo half-life of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.
Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration [Cmax]) of FVIII:C
PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The maximum plasma concentration of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.
Incremental in Vivo Recovery (IVR) of Wilate Over Time
The rise in FVIII activity in IU/dl per unit dose administered in IU/kg was determined from all patients at baseline, 3 and 6 months, using the 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 an association between ABO blood type and the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay.
Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate
ANOVA was used in an exploratory sense to assess an association between VWF:Ag with the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay.
Safety and Tolerability of Wilate by Monitoring Adverse Events (AEs) Throughout the Study
At each (scheduled or unscheduled) study visit, AEs were documented by the investigator throughout the study.
Immunogenicity of Wilate by Testing for FVIII Inhibitors
FVIII inhibitor activity was determined at each study visit before the injection of Wilate using the modified Bethesda assay (Nijmegen modification).
Virus Safety Measured by the Number of 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. All patients negative at screening were tested again at the study completion visit. The number with Parvovirus B19 seroconversions between BL and end of study was recorded.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02954575
Brief Title
Clinical Study to Investigate the PK, Efficacy, and Safety of Wilate in Patients With Severe Hemophilia A
Official Title
Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Patients With Severe Hemophilia A
Study Type
Interventional
2. Study Status
Record Verification Date
December 2020
Overall Recruitment Status
Completed
Study Start Date
December 2016 (Actual)
Primary Completion Date
March 29, 2018 (Actual)
Study Completion Date
March 29, 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
The purpose of this study is to obtain additional data on the safety and efficacy of Wilate in PTPs with hemophilia A with at least 150 previous exposure days (EDs) to a FVIII concentrate who undergo prophylactic treatment with Wilate for 6 months and at least 50 EDs, thus supplementing the existing database to obtain approval of Wilate for the indication hemophilia A in the USA.
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
57 (Actual)
8. Arms, Groups, and Interventions
Arm Title
All patients
Arm Type
Experimental
Arm Description
All patients will receive Wilate for prophylactic treatment
Intervention Type
Drug
Intervention Name(s)
Wilate
Other Intervention Name(s)
von Willebrand factor / Factor VIII (plasma derived)
Primary Outcome Measure Information:
Title
Total Annualized Bleeding Rate (TABR)
Description
The total number of bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Spontaneous Annualized Bleeding Rate (SABR)
Description
The number of spontaneous bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel.
Time Frame
6 months
Title
Efficacy of Wilate in the Treatment of Breakthrough BEs
Description
The proportion of BEs successfully treated with Wilate were documented by the patient (together with the investigator in case of on-site treatments) in the patient diary for all BEs according to a 4-point hemostatic efficacy scale including the four items: 'excellent,' 'good,' moderate,' and 'none', where '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) and 'none' was defined as "No improvement within 12 hours, or worsening of symptoms, requiring more than two injections for complete resolution" (worst outcome). All efficacy ratings assessed as either 'excellent' or 'good' were considered 'successfully treated.'
Time Frame
6 months
Title
Wilate Consumption Data (Average Total Normdose of FVIII IU/kg Per Month of Study) for Prophylaxis
Description
The average consumption of Wilate per month of study (IU/kg) for all patients receiving prophylaxis.
Time Frame
6 months
Title
Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Norm) of FVIII:C
Description
PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The value of the AUCnorm of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.
Time Frame
Initial PK visit (Day -1) and PK study completion visit (6 months); data collected 1 h prior to injection and 15 min, 1 h, 3 h, 6 h, 9 h, 24 h, 30 h and 48 h after the end of injection
Title
Pharmacokinetic (PK) Assessment (in Vivo Half-Life (t1/2)) of FVIII:C
Description
PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The in vivo half-life of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.
Time Frame
Initial PK assessment (Day -1) and PK study completion visit (6 months); data collected 1 h prior to infusion and 15 min, 1 h, 3 h, 6 h, 9 h, 24 h, 30 h and 48 h after the end of injection
Title
Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration [Cmax]) of FVIII:C
Description
PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The maximum plasma concentration of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.
Time Frame
Initial PK assessment (Day -1) and 6 months
Title
Incremental in Vivo Recovery (IVR) of Wilate Over Time
Description
The rise in FVIII activity in IU/dl per unit dose administered in IU/kg was determined from all patients at baseline, 3 and 6 months, using the OS assay.
Time Frame
Baseline, 3 and 6 months
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 an association between ABO blood type and the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay.
Time Frame
6 months
Title
Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate
Description
ANOVA was used in an exploratory sense to assess an association between VWF:Ag with the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay.
Time Frame
6 months
Title
Safety and Tolerability of Wilate by Monitoring Adverse Events (AEs) Throughout the Study
Description
At each (scheduled or unscheduled) study visit, AEs were documented by the investigator throughout the study.
Time Frame
6 months
Title
Immunogenicity of Wilate by Testing for FVIII Inhibitors
Description
FVIII inhibitor activity was determined at each study visit before the injection of Wilate using the modified Bethesda assay (Nijmegen modification).
Time Frame
6 months
Title
Virus Safety Measured by the Number of 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. All patients negative at screening were tested again at the study completion visit. The number with Parvovirus B19 seroconversions between BL and end of study was recorded.
Time Frame
6 months
Other Pre-specified Outcome Measures:
Title
Efficacy of Wilate in Surgical Prophylaxis
Description
Hemostatic efficacy was assessed at the end of surgery by the surgeon and at end of the postoperative period by the hematologist, using a 4-point hemostatic efficacy scale including the four items: 'excellent' (best possible outcome), 'good', 'moderate' and 'none' (worst outcome). Overall efficacy was assessed by the investigator, taking both the intra and postoperative assessments into account, and using the 'excellent,' 'good,' moderate,' and 'none' scale.
Time Frame
6 months
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Severe hemophilia A (<1% FVIII:C) according to medical history
Male patients aged ≥12 years
Previous treatment with a FVIII concentrate for at least 150 exposure days (EDs)
Immunocompetence (CD4+ count >200/µL)
Good documentation of the historical bleeding rate (at least for the 6 months preceding study start)
Voluntarily given, fully informed written and signed consent obtained by the patient (or parent/legal guardian in case of adolescents) before any study-related procedures are conducted
Whenever possible, the interval between the Screening Visit and the PK or Non-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., exclusion criterion no. 4).
Exclusion Criteria:
Any coagulation disorders other than hemophilia A
History of FVIII inhibitor activity (≥0.6 BU) or detectable FVIII inhibitory anti-bodies (≥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 anti-retroviral chemotherapy) such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar drugs
Treatment with any investigational medicinal product in another interventional clinical study currently or within 4 weeks before enrollment
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
Specialized Hospital for Active Treatment "Joan Pavel"
City
Sofia
Country
Bulgaria
Facility Name
National Haemophilia Centre
City
Budapest
Country
Hungary
Facility Name
Krakowskie Centrum Medyczne
City
Krakow
Country
Poland
Facility Name
Korczowski Bartosz Gabinet Lekarski
City
Rzeszow
Country
Poland
Facility Name
Centrul Medical Unirea -Policlinica Enescu
City
Bucharest
Country
Romania
Facility Name
Barnaul Branch of RAMS hematology center
City
Barnaul
Country
Russian Federation
Facility Name
Federal Scientific Hematology Center
City
Moscow
Country
Russian Federation
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Clinical Study to Investigate the PK, Efficacy, and Safety of Wilate in Patients With Severe Hemophilia A
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