Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Paediatric Patients With Severe Haemophilia A

• ClinicalTrials.gov Identifier: NCT03376516
• Recruitment Status: Completed
• First Posted: December 18, 2017
• Results First Posted: December 24, 2019
• Last Update Posted: January 19, 2021
• Sponsor: Octapharma
• Information provided by (Responsible Party): Octapharma

Tracking Information

• First Submitted Date: December 13, 2017
• First Posted Date: December 18, 2017
• Results First Submitted Date: October 23, 2019
• Results First Posted Date: December 24, 2019
• Last Update Posted Date: January 19, 2021
• Actual Study Start Date: November 22, 2017
• Actual Primary Completion Date: November 3, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 6, 2019)

• Pharmacokinetic (PK) Assessment (Area Under the Curve (AUC)) of FVIII:C [ Time Frame: 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate ]
  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 [ Time Frame: 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of 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 [ Time Frame: 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate ]
  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 [ Time Frame: 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate ]
  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 [ Time Frame: 48 h following a single dose of Wilate ]
  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 [ Time Frame: 48 h following a single dose of Wilate ]
  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 [ Time Frame: 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate ]
  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 [ Time Frame: 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate ]
  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 [ Time Frame: 48 h following a single dose of Wilate ]
  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)

Original Primary Outcome Measures (submitted: December 13, 2017)

• Area under the curve (AUC) [ Time Frame: 48 h following a single dose of Wilate ]
  Determined using the chromogenic (CHR) and one-stage (OS) assays and actual IMP potencies
• FVIII:C area under the curve of FVIII:C normalised for the administered dose (AUCnorm) [ Time Frame: 48 h following a single dose of Wilate ]
  Determined using the chromogenic (CHR) and one-stage (OS) assays and actual IMP potencies
• FVIII:C in vivo half-life [ Time Frame: 48 h following a single dose of Wilate ]
  Determined using the chromogenic (CHR) and one-stage (OS) assays and actual IMP potencies
• FVIII:C maximum plasma concentration (Cmax) [ Time Frame: 48 h following a single dose of Wilate ]
  Determined using the chromogenic (CHR) and one-stage (OS) assays and actual IMP potencies
• FVIII:C time to reach maximum plasma concentration (Tmax) [ Time Frame: 48 h following a single dose of Wilate ]
  Determined using the chromogenic (CHR) and one-stage (OS) assays and actual IMP potencies
• Mean residence time (MRT) [ Time Frame: 48 h following a single dose of Wilate ]
  Determined using the chromogenic (CHR) and one-stage (OS) assays and actual IMP potencies
• FVIII:C volume of distribution (Vd) [ Time Frame: 48 h following a single dose of Wilate ]
  Determined using the chromogenic (CHR) and one-stage (OS) assays and actual IMP potencies
• FVIII:C clearance (CL) [ Time Frame: 48 h following a single dose of Wilate ]
  Determined using the chromogenic (CHR) and one-stage (OS) assays and actual IMP potencies
• FVIII:C incremental in vivo recovery (IVR) [ Time Frame: 48 h following a single dose of Wilate ]
  Calculated from FVIII:C plasma levels measured before injection and peak levels obtained in the 15-min post-injection sample using actual IMP potencies

Current Secondary Outcome Measures (submitted: December 6, 2019)

• Total Annualized Bleeding Rate (TABR) [ Time Frame: 6 months ]
  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) [ Time Frame: 6 months ]
  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) [ Time Frame: 6 months ]
  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 [ Time Frame: 6 months ]
  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 [ Time Frame: Baseline, and 3 and 6 months of treatment ]
  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) [ Time Frame: 6 months ]
  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 [ Time Frame: 6 months ]
  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 [ Time Frame: 6 months ]
  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 [ Time Frame: 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 [ Time Frame: 6 months ]
  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

Original Secondary Outcome Measures (submitted: December 13, 2017)

• Total annualised bleeding rate (TABR) [ Time Frame: 6 months ]
  Calculated as the total number of BEs in the time period between first dose of IMP and the Study Completion Visit, divided by the duration (in years) between 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 annualised bleeding rate (SABR) [ Time Frame: 6 months ]
  Calculated in analogy with the total annualised bleeding rate
• Efficacy of Wilate in the treatment of breakthrough BEs based on the proportion of BEs successfully treated with Wilate [ Time Frame: 6 months ]
  At the end of a BE, treatment efficacy will be assessed by the patient (together with the Investigator in case of on-site treatment) using predefined four-point scale: 'excellent', 'good', 'moderate', 'none'. All efficacy ratings assessed as either 'excellent' or 'good' will be considered 'successfully treated.'
• Consumption of Wilate for prophylaxis [ Time Frame: 6 months ]
  Calculated as FVIII IU/kg per week per patient
• FVIII:C incremental in vivo recovery (IVR) of Wilate over time [ Time Frame: Baseline, and 3 and 6 months of treatment ]
  Calculated from FVIII:C plasma levels measured before injection and peak levels obtained in the 15-min post-injection sample using actual IMP potencies
• Association between AB0 blood type and the FVIII:C half-life of Wilate [ Time Frame: 6 months ]
• Association between VWF:Ag concentration and the FVIII:C half-life of Wilate [ Time Frame: 6 months ]
• Safety and tolerability of Wilate by monitoring adverse events (AEs) throughout the study [ Time Frame: 6 months ]
• Immunogenicity of Wilate by testing for FVIII inhibitors [ Time Frame: 6 months ]
• Virus safety in terms of parvovirus B19 [ Time Frame: 6 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Severe Hemophilia A

Intervention

Drug: Wilate

von Willebrand factor / Factor VIII (plasma derived)

Study Arms

Experimental: All patients

All patients will receive Wilate for prophylactic treatment. Patients will also receive Wilate for treatment of breakthrough bleeding events as required

Intervention: Drug: Wilate

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 6, 2019): 11
• Original Estimated Enrollment (submitted: December 13, 2017): 10
• Actual Study Completion Date: November 3, 2018
• Actual Primary Completion Date: November 3, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Severe haemophilia A (<1% FVIII:C) according to medical history
2. Male patients aged 1 to <12 years
3. Previous treatment with a FVIII concentrate for at least 50 exposure days (EDs)
4. Immunocompetence (CD4+ count >200/μL)
5. 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:

1. Any coagulation disorders other than haemophilia A
2. 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
3. Severe liver or kidney diseases (alanine aminotransferase [ALAT] and aspartate transaminase [ASAT] levels >5 times of upper limit of normal, creatinine >120 μmol/L)
4. 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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 1 Year to 11 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Russian Federation, Ukraine

Administrative Information

• NCT Number: NCT03376516
• Other Study ID Numbers: WIL-30
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Octapharma
• Original Responsible Party: Same as current
• Current Study Sponsor: Octapharma
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Cristina Solomon, MD; Octapharma

• PRS Account: Octapharma
• Verification Date: December 2020