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

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

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

Condition or disease Intervention/treatment Phase
Severe Hemophilia A Drug: Wilate Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Paediatric Patients With Severe Haemophilia A
Actual Study Start Date : November 22, 2017
Actual Primary Completion Date : November 3, 2018
Actual Study Completion Date : November 3, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

Arm Intervention/treatment
Experimental: All patients
All patients will receive Wilate for prophylactic treatment. Patients will also receive Wilate for treatment of breakthrough bleeding events as required
Drug: Wilate
von Willebrand factor / Factor VIII (plasma derived)




Primary Outcome Measures :
  1. 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).

  2. 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.


  3. 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.

  4. 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)


  5. 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).

  6. 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.

  7. 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).

  8. 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).

  9. 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)



Secondary Outcome Measures :
  1. 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.


  2. 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.


  3. 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".

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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



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Ages Eligible for Study:   1 Year to 11 Years   (Child)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03376516


Locations
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Russian Federation
Kirov SSC Hematology and Transfusiology
Kirov, Russian Federation
Ukraine
"National Children's Specialized Clinic "OKHMATDYT"
Kyiv, Ukraine
"Western Ukrainian Specialized Children's Medical Center"
Lviv, Ukraine
Sponsors and Collaborators
Octapharma
Investigators
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Study Director: Cristina Solomon, MD Octapharma
  Study Documents (Full-Text)

Documents provided by Octapharma:
Study Protocol  [PDF] June 19, 2017
Statistical Analysis Plan  [PDF] July 8, 2019

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Responsible Party: Octapharma
ClinicalTrials.gov Identifier: NCT03376516    
Other Study ID Numbers: WIL-30
First Posted: December 18, 2017    Key Record Dates
Results First Posted: December 24, 2019
Last Update Posted: December 24, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn