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Clinical Study to Investigate the PK, Efficacy, and Safety of Wilate in Patients With Severe Hemophilia A

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ClinicalTrials.gov Identifier: NCT02954575
Recruitment Status : Completed
First Posted : November 3, 2016
Results First Posted : December 3, 2019
Last Update Posted : January 19, 2021
Sponsor:
Information provided by (Responsible Party):
Octapharma

Tracking Information
First Submitted Date  ICMJE October 27, 2016
First Posted Date  ICMJE November 3, 2016
Results First Submitted Date  ICMJE March 20, 2019
Results First Posted Date  ICMJE December 3, 2019
Last Update Posted Date January 19, 2021
Actual Study Start Date  ICMJE December 2016
Actual Primary Completion Date March 29, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 13, 2019)
Total Annualized Bleeding Rate (TABR) [ Time Frame: 6 months ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 1, 2016)
Reduction of total annualized bleeding rate [ Time Frame: 6 months ]
50% reduction of the total annualized bleeding rate (TABR) observed in the GENA-01 study, with a total of 58.1 BEs per patient per year.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 13, 2019)
  • Spontaneous Annualized Bleeding Rate (SABR) [ Time Frame: 6 months ]
    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 [ Time Frame: 6 months ]
    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 [ Time Frame: 6 months ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ Time Frame: Initial PK assessment (Day -1) and 6 months ]
    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 [ Time Frame: Baseline, 3 and 6 months ]
    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) [ Time Frame: 6 months ]
    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 [ Time Frame: 6 months ]
    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 [ Time Frame: 6 months ]
    At each (scheduled or unscheduled) study visit, AEs were documented by the investigator throughout the study.
  • Immunogenicity of Wilate by Testing for FVIII Inhibitors [ Time Frame: 6 months ]
    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 [ Time Frame: 6 months ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 1, 2016)
  • Spontaneous Annualized Bleeding Rate (SABR) [ Time Frame: 6 months ]
  • Efficacy of Wilate in the treatment of breakthrough BEs based on the proportion of BEs successfully treated with Wilate [ Time Frame: 6 months ]
  • Efficacy of Wilate in surgical prophylaxis assessed by surgeon and hematologist using predefined assessment criteria [ Time Frame: 6 months ]
  • Wilate consumption data (FVIII IU/kg per week per patient) for prophylaxis [ Time Frame: 6 months ]
  • PK assessment (Area under of curve) of FVIII:C using the one-stage (OS) assays and actual IMP potencies [ Time Frame: 6 months ]
  • PK assessment (In vivo half life) of FVIII:C using the one-stage (OS) assays and actual IMP potencies [ Time Frame: 6 months ]
  • PK assessment (Maximum plasma concentration (Cmax))) of FVIII:C using the one-stage (OS) assays and actual IMP potencies [ Time Frame: 6 months ]
  • Incremental IVR of Wilate over time (at baseline, and at 3 and 6 months of treatment) [ Time Frame: 6 months ]
  • Association between ABO 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 to be measured by the number of incidence of parvovirus B19 seroconversions between baseline and end of study [ Time Frame: 6 months ]
Current Other Pre-specified Outcome Measures
 (submitted: November 13, 2019)
Efficacy of Wilate in Surgical Prophylaxis [ Time Frame: 6 months ]
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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Clinical Study to Investigate the PK, Efficacy, and Safety of Wilate in Patients With Severe Hemophilia A
Official Title  ICMJE Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Patients With Severe Hemophilia A
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Severe Hemophilia A
Intervention  ICMJE Drug: Wilate
Other Name: von Willebrand factor / Factor VIII (plasma derived)
Study Arms  ICMJE Experimental: All patients
All patients will receive Wilate for prophylactic treatment
Intervention: Drug: Wilate
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 13, 2019)
57
Original Estimated Enrollment  ICMJE
 (submitted: November 1, 2016)
55
Actual Study Completion Date  ICMJE March 29, 2018
Actual Primary Completion Date March 29, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Severe hemophilia A (<1% FVIII:C) according to medical history
  2. Male patients aged ≥12 years
  3. Previous treatment with a FVIII concentrate for at least 150 exposure days (EDs)
  4. Immunocompetence (CD4+ count >200/µL)
  5. Good documentation of the historical bleeding rate (at least for the 6 months preceding study start)
  6. 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:

  1. Any coagulation disorders other than hemophilia A
  2. 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
  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 anti-retroviral chemotherapy) such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar drugs
  5. Treatment with any investigational medicinal product in another interventional clinical study currently or within 4 weeks before enrollment
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Bulgaria,   Hungary,   Poland,   Romania,   Russian Federation
Removed Location Countries Serbia,   Ukraine
 
Administrative Information
NCT Number  ICMJE NCT02954575
Other Study ID Numbers  ICMJE WIL-27
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  ICMJE
Plan to Share IPD: No
Responsible Party Octapharma
Study Sponsor  ICMJE Octapharma
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Cristina Solomon, MD Octapharma
PRS Account Octapharma
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP