BAY81-8973 Pediatric Safety and Efficacy Trial

Phase 3

Completed

• Conditions: Haemophilia A
• Interventions: Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973)

• Registration Number: NCT01311648
• Lead Sponsor: Bayer

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 available

Study Timeline

• Study First Submitted: 2011-02-18
• Study First Submitted QC: 2011-03-08
• Study First Posted: 2011-03-09
• Study Start: 2011-06-09
• Primary Completion: 2019-09-09
• Results First Submitted: 2020-09-01
• Results First Submitted QC: 2020-10-09
• Study Completion: 2020-10-27
• Results First Posted: 2020-11-03
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-16
• Last Update Posted: 2023-12-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 94

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PUPs/MTPs 0-<6 years	Recombinant Factor VIII (Kovaltry, BAY81-8973)	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 at least 50 EDs or until inhibitor development in main study - Part B. Participants having reached at least 50 EDs in main study - Part B were offered participation in an open label extension study and received BAY81-8973 25-50 IU/kg at least 2x/week for at least 100 cumulative EDs (main study - Part B and extension study); participants who developed an inhibitor in main study - Part B were offered participation in open label extension study and received Immune Tolerance Induction (ITI) treatment with BAY81-8973 until successful eradication of the inhibitor, or until failure, for approximately 18 months.
PTPs 0-12 years	Recombinant Factor VIII (Kovaltry, BAY81-8973)	Previously treated patients (PTPs) aged below 12 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (EDs) in main study - Part A. Participants having reached at least 50 EDs in main study - Part A were offered participation in an open label extension study (optional). Participants who transitioned from main study - Part A to the extension study received BAY81-8973, 25-50 IU/kg at least 2x/week for at least 100 cumulative EDs (main study - Part A and extension study).

Primary Outcome Measures

Name	Time	Method
Annualized Number of Total Bleeds Within 48 h	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 \[EDs\]; Part B: at least 50 EDs or until inhibitor development) was summarized and reported. Total bleeds: sum of spontaneous bleeds, trauma bleeds (only treated bleeds were classified as spontaneous or trauma), untreated bleeds and 'other' bleeds ('other' bleeds were infusions with reason given as 'other').

Secondary Outcome Measures

Name	Time	Method
Half-life (t1/2) of BAY81-8973 in Plasma	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.
Annualized Number of Total Bleeds During Prophylaxis Treatment	Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 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 (only treated bleeds were classified as spontaneous or trauma), untreated bleeds and 'other' bleeds ('other' bleeds were infusions with reason given as 'other').
Number of Participants With Inhibitor Development in Main Study	Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months)	Number of participants with confirmed positive FVIII inhibitor titer (≥ 0.6 Bethesda unit \[BU/mL\]) during the main study was summarized and classified as participants developing low titer inhibitor (i.e. ≥ 0.6 to ≤ 5.0 BU/mL) and participants developing high titer inhibitor (i.e. \> 5.0 BU/mL).
Factor VIII Recovery Values	Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months)	Incremental recovery of Factor VIII (FVIII) at 20-30 min after end of infusions was determined and mean recovery values were reported.
Number of Infusions Per Bleed	Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 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	Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 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.
Hemostatic Control During Major and Minor Surgeries	Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 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 New Inhibitor Development in Extension Study	From start of extension study to at least 100 cumulative exposure days (EDs) (median 421 EDs; median 3.8 years)	Number of participants who had not developed an inhibitor during the main study but developed an inhibitor (confirmed positive FVIII inhibitor titer \[≥ 0.6 BU/mL\]) during the extension study was summarized and classified as participants developing low titer inhibitor (i.e. ≥ 0.6 to ≤ 5.0 BU/mL) and participants developing high titer inhibitor (i.e. \> 5.0 BU/mL).
Consumption of Factor VIII in All Infusions	Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 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	Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 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	Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 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.