BAY81-8973 Pediatric Safety and Efficacy Trial

• ClinicalTrials.gov Identifier: NCT01311648
• Recruitment Status: Completed
• First Posted: March 9, 2011
• Results First Posted: November 3, 2020
• Last Update Posted: November 23, 2020
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: February 18, 2011
• First Posted Date: March 9, 2011
• Results First Submitted Date: September 1, 2020
• Results First Posted Date: November 3, 2020
• Last Update Posted Date: November 23, 2020
• Actual Study Start Date: June 9, 2011
• Actual Primary Completion Date: September 9, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 9, 2020)

• Annualized Number of Total Bleeds Within 48 h [ Time Frame: Within 48 hours post infusion ]
  Annualized number (mean +/- standard deviation) of total bleeds that occurred within 48 hours after all prophylaxis infusions [Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days (approximately 8 months)] was summarized and reported. Total bleeds: sum of spontaneous bleeds, trauma bleeds, untreated bleeds and 'other' bleeds ('other' bleeds were infusions with reason given as 'other').
• Annualized Number of Total Bleeds Within 48 h [ Time Frame: Within 48 hours post infusion ]
  Annualized number (median [inter-quartile range (Q1-Q3)]) of total bleeds that occurred within 48 hours after all prophylaxis infusions [Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days (approximately 8 months)] was summarized and reported. Total bleeds: sum of spontaneous bleeds, trauma bleeds, untreated bleeds and 'other' bleeds ('other' bleeds were infusions with reason given as 'other').

Original Primary Outcome Measures (submitted: March 8, 2011)

• Annualized number of bleeds within 48 hours (h) after a prophylaxis injection [ Time Frame: 6 months ]
• Number of infusions for the treatment of a bleed [ Time Frame: 6 months ]

Current Secondary Outcome Measures (submitted: October 9, 2020)

• Annualized Number of Total Bleeds During Prophylaxis Treatment [ Time Frame: Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days (approximately 8 months) ]
  Annualized number (mean +/- standard deviation) of total bleeds that occurred during prophylaxis treatment was summarized and reported. Total bleeds: sum of spontaneous bleeds, trauma bleeds, untreated bleeds and 'other' bleeds ('other' bleeds were infusions with reason given as 'other').
• Annualized Number of Total Bleeds During Prophylaxis Treatment [ Time Frame: Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days (approximately 8 months) ]
  Annualized number (median [inter-quartile range (Q1-Q3)]) of total bleeds that occurred during prophylaxis treatment was summarized and reported. Total bleeds: sum of spontaneous bleeds, trauma bleeds, untreated bleeds and 'other' bleeds ('other' bleeds were infusions with reason given as 'other').
• Hemostatic Control During Major and Minor Surgeries [ Time Frame: Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days (approximately 8 months) ]
  For participants who underwent major or minor surgeries during the study, hemostasis during the surgeries was assessed as excellent, good, moderate or poor. Number of surgeries per assessment was summarized and reported.
• Number of Participants With Inhibitor Development [ Time Frame: Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days (approximately 8 months) ]
  Number of participants with confirmed positive FVIII inhibitor titer (≥0.6 Bethesda unit [BU]) during the study was summarized and classified as participants developing low titer inhibitor (i.e. ≥0.6 to ≤ 5.0 BU) and participants developing high titer inhibitor (i.e. > 5.0 BU).
• Factor VIII Recovery Values [ Time Frame: Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days (approximately 8 months) ]
  Incremental recovery of Factor VIII (FVIII) at 20-30 min after end of infusions was determined and mean recovery values were reported.
• Consumption of Factor VIII in All Infusions [ Time Frame: Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days (approximately 8 months) ]
  Factor VIII (FVIII) usage/consumption was summarized for all infusions. Consumption per participant's body weight per year was calculated and reported.
• Consumption of FVIII in Infusions for Prophylaxis [ Time Frame: Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days (approximately 8 months) ]
  Factor VIII (FVIII) usage/consumption was summarized for prophylaxis infusions. Consumption per participant's body weight per year was calculated and reported.
• Consumption of FVIII in Infusions for the Treatment of Bleeds [ Time Frame: Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days (approximately 8 months) ]
  Factor VIII (FVIII) usage/consumption was summarized for infusions used to treat breakthrough bleeds. Consumption per participant's body weight per year was calculated and reported.
• Number of Infusions Per Bleed [ Time Frame: Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days (approximately 8 months) ]
  The number of infusions used to treat a bleed was defined as the first infusion to treat the bleed plus all follow-up infusions to treat the same bleed, if any. The mean value of number of infusions for each bleed was calculated and reported.
• Response to Treatment of Bleeds [ Time Frame: Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days (approximately 8 months) ]
  Participants or caregivers were asked to assess the response to treatment of bleeds as excellent, good, moderate or poor. Percentage of bleeds per assessment was summarized and reported.
• Half-life (t1/2) of BAY81-8973 in Plasma [ Time Frame: Pre-infusion and until 24 hours post infusion ]
  Half-life (t1/2) of BAY81-8973 in plasma was measured. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. Occurrence of "±" in relation with coefficient of variation is auto-generated by the database.

Original Secondary Outcome Measures (submitted: March 8, 2011)

• Incidence of inhibitory antibody [ Time Frame: 6 months ]
• Total annualized consumption of FVIII per subject [ Time Frame: 6 months ]

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

Descriptive Information

• Brief Title: BAY81-8973 Pediatric Safety and Efficacy Trial
• Official Title: A Multicenter Phase III Uncontrolled Open-label Trial to Evaluate Safety and Efficacy of BAY81-8973 in Children With Severe Hemophilia A Under Prophylaxis Therapy

Brief Summary

The primary objective was to evaluate the safety and efficacy of the treatment with BAY81-8973 for prophylaxis and treatment of breakthrough bleeds in children with severe hemophilia A.

The secondary objectives were

• To assess the safety and efficacy of BAY81-8973 during surgeries.
• To assess incremental recovery of BAY81-8973.
• To assess pharmacokinetic (PK) parameters in a subset of children (Previously treated patients [PTPs] and previously untreated patients [PUPs] / minimally treated patients [MTPs] - participation in PK sampling was voluntary and required consent).

• 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: Haemophilia A

Intervention

• Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973)
  25-50 IU/kg at least 2x/week
• Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973)
  15-50 IU/kg at least 1x/week

Study Arms

• Experimental: Part A: PTPs 0-<6 years
  Previously treated patients (PTPs) aged below 6 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED)
  Intervention: Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973)
• Experimental: Part A: PTPs 6-12 years
  Previously treated patients (PTPs) aged 6 to 12 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED)
  Intervention: Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973)
• Experimental: Part B: PUPs/MTPs 0-<6 years
  Previously untreated patients (PUPs) or minimally treated patients (MTPs, patients who had no more than 3 exposure days [EDs] with any FVIII product) received BAY81-8973 15-50 IU/kg at least 1x/week for 50 EDs
  Intervention: Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973)

Publications *

• Oldenburg J, Windyga J, Hampton K, Lalezari S, Tseneklidou-Stoeter D, Beckmann H, Maas Enriquez M. Safety and efficacy of BAY 81-8973 for surgery in previously treated patients with haemophilia A: results of the LEOPOLD clinical trial programme. Haemophilia. 2016 May;22(3):349-53. doi: 10.1111/hae.12839. Epub 2016 Mar 1.
• Ljung R, Kenet G, Mancuso ME, Kaleva V, Rusen L, Tseneklidou-Stoeter D, Michaels LA, Shah A, Hong W, Maas Enriquez M; investigators of the LEOPOLD Kids Trial. BAY 81-8973 safety and efficacy for prophylaxis and treatment of bleeds in previously treated children with severe haemophilia A: results of the LEOPOLD Kids Trial. Haemophilia. 2016 May;22(3):354-60. doi: 10.1111/hae.12866. Epub 2015 Dec 9.
• Keating GM. BAY 81-8973 (Octocog Alfa; Kovaltry(®)): A Review in Haemophilia A. BioDrugs. 2016 Oct;30(5):453-459. Review.
• Shah A, Delesen H, Garger S, Lalezari S. Pharmacokinetic properties of BAY 81-8973, a full-length recombinant factor VIII. Haemophilia. 2015 Nov;21(6):766-71. doi: 10.1111/hae.12691. Epub 2015 May 8.
• Maas Enriquez M, Thrift J, Garger S, Katterle Y. BAY 81-8973, a full-length recombinant factor VIII: Human heat shock protein 70 improves the manufacturing process without affecting clinical safety. Protein Expr Purif. 2016 Nov;127:111-115. doi: 10.1016/j.pep.2016.07.009. Epub 2016 Jul 18. Review.
• Garmann D, McLeay S, Shah A, Vis P, Maas Enriquez M, Ploeger BA. Population pharmacokinetic characterization of BAY 81-8973, a full-length recombinant factor VIII: lessons learned - importance of including samples with factor VIII levels below the quantitation limit. Haemophilia. 2017 Jul;23(4):528-537. doi: 10.1111/hae.13192. Epub 2017 Feb 20.
• Mahlangu JN, Ahuja SP, Windyga J, Church N, Shah A, Schwartz L. BAY 81-8973, a full-length recombinant factor VIII for the treatment of hemophilia A: product review. Ther Adv Hematol. 2018 Jul;9(7):191-205. doi: 10.1177/2040620718777903. Epub 2018 Jun 12. Review.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 4, 2019): 94
• Original Estimated Enrollment (submitted: March 8, 2011): 51
• Actual Study Completion Date: October 27, 2020
• Actual Primary Completion Date: September 9, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male
• PTPs (previously treated patients): aged <= 12 years
• PUPs (previously untreated patients) / MTPs (minimally treated patients): aged < 6 years
• Severe hemophilia A defined as < 1% FVIII concentration (FVIII:C)
• PTPs: >= 50 exposure days (EDs) with any FVIII concentrate, no current evidence of inhibitory antibody, and no history of FVIII inhibitor formation
• PUPs: no prior exposure to any FVIII product
• MTPs: having no more than 3 EDs with any FVIII product, no current evidence of inhibitory antibody and no history of FVIII inhibitor formation

Exclusion Criteria:

• With another bleeding disorder that is different from Hemophilia A
• With thrombocytopenia (platelet count < 100 000/mm^3)
• Creatinine > 2x upper limit of normal or Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) > 5x upper limit of normal
• Without a negative inhibitor testing at screening (except for PUPs)
• Receiving chemotherapy, immune modulatory drugs, has received another investigational FVIII product within the last month, or received another experimental drug within the last 3 months
• Requires any pre-medication to tolerate FVIII treatment
• Known hypersensitivity to active substance, mouse, or hamster protein

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: up to 12 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Bulgaria, Canada, Denmark, Hungary, Ireland, Israel, Italy, Latvia, Lithuania, Mexico, Norway, Poland, Romania, Russian Federation, Spain, United States
• Removed Location Countries: Austria, Greece, Serbia, Sweden, United Kingdom

Administrative Information

• NCT Number: NCT01311648
• Other Study ID Numbers: 13400; 2010-021781-29 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

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: Not Provided
• Responsible Party: Bayer
• Study Sponsor: Bayer
• Collaborators: Not Provided

Investigators

• Study Director: Bayer Study Director; Bayer

• PRS Account: Bayer
• Verification Date: November 2020