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BAY81-8973 Pediatric Safety and Efficacy Trial

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ClinicalTrials.gov Identifier: NCT01311648
Recruitment Status : Completed
First Posted : March 9, 2011
Results First Posted : November 3, 2020
Last Update Posted : November 17, 2021
Sponsor:
Information provided by (Responsible Party):
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).

Condition or disease Intervention/treatment Phase
Haemophilia A Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Phase 3

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Study Type : Interventional
Actual Enrollment : 94 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 9, 2011
Actual Primary Completion Date : September 9, 2019
Actual Study Completion Date : October 27, 2020


Arm Intervention/treatment
Experimental: PTPs 0-12 years
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).
Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973)
Main study: 25-50 IU/kg at least 2x/week for 6 months and at least 50 EDs, IV infusion; Extension study: 25-50 IU/kg at least 2x/week for at least 100 cumulative EDs (main study - Part A and extension study), IV infusion. Exposure day (ED): An ED is a unit of time (1 day) in which replacement treatment of Hemophilia is given to a patient.

Experimental: 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 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.
Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973)
Main study: 15-50 IU/kg at least 1x/week for at least 50 EDs or until inhibitor development, IV infusion; Extension study: For participants having reached at least 50 EDs in main study - Part B: 25-50 IU/kg at least 2x/week for at least 100 cumulative EDs (main study - Part B and extension study), IV infusion. For participants who developed an inhibitor in main study - Part B: up to 200 IU/kg per day or 100 IU/kg twice a day at the discretion of the investigator and coordinating investigator until successful eradication of the inhibitor, or until failure, for up to18 months (treatment beyond 18 months required an agreement with the sponsor and coordinating investigator), IV infusion




Primary Outcome Measures :
  1. 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 [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').

  2. 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 [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 :
  1. Annualized Number of Total Bleeds During Prophylaxis Treatment [ Time Frame: 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 (mean +/- standard deviation) 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').

  2. Annualized Number of Total Bleeds During Prophylaxis Treatment [ Time Frame: 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').

  3. Hemostatic Control During Major and Minor Surgeries [ Time Frame: 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.

  4. Number of Participants With Inhibitor Development in Main Study [ Time Frame: 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).

  5. Number of Participants With New Inhibitor Development in Extension Study [ Time Frame: 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).

  6. Factor VIII Recovery Values [ Time Frame: 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.

  7. Consumption of Factor VIII in All Infusions [ Time Frame: 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.

  8. Consumption of FVIII in Infusions for Prophylaxis [ Time Frame: 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.

  9. Consumption of FVIII in Infusions for the Treatment of Bleeds [ Time Frame: 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.

  10. Number of Infusions Per Bleed [ Time Frame: 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.

  11. Response to Treatment of Bleeds [ Time Frame: 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.

  12. 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.



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Ages Eligible for Study:   up to 12 Years   (Child)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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

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): NCT01311648


Locations
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United States, Louisiana
New Orleans, Louisiana, United States, 70112
United States, Ohio
Cincinnati, Ohio, United States, 45229
Cleveland, Ohio, United States, 44106
Columbus, Ohio, United States, 43205-2696
Argentina
Bahía Blanca, Buenos Aires, Argentina, B8001HXM
Bulgaria
Plovdiv, Bulgaria, 4002
Varna, Bulgaria, 9010
Canada, Alberta
Edmonton, Alberta, Canada, T6G 2C8
Canada, Ontario
Hamilton, Ontario, Canada, L8N 3Z5
Toronto, Ontario, Canada, M5G 1X8
Denmark
Århus N, Denmark, 8200
Hungary
Budapest, Hungary, 1089
Debrecen, Hungary, 4032
Mohacs, Hungary, 7700
Ireland
Crumlin, Dublin, Ireland, 12
Israel
Ramat Gan, Israel, 5262000
Italy
Roma, Lazio, Italy, 00165
Milano, Lombardia, Italy, 20122
Bari, Puglia, Italy, 70126
Catania, Sicilia, Italy, 95123
Padova, Veneto, Italy, 35128
Latvia
Riga, Latvia, LV-1004
Lithuania
Vilnius, Lithuania, 08406
Mexico
Guadalajara, Jalisco, Mexico, 44280
San Juan del Río, Querétaro, Mexico, 76800
Oaxaca, Mexico, 68000
Norway
Oslo, Norway
Poland
Lodz, Poland, 91-738
Warszawa, Poland, 00-576
Wroclaw, Poland, 50-368
Romania
Bucharest, Romania, 011026
Bucharest, Romania, 022328
Cluj-Napoca, Romania, 400177
Timisoara, Romania, 300011
Russian Federation
Kazan, Russian Federation, 139445
Kirov, Russian Federation, 610027
Volgograd, Russian Federation, 400138
Spain
Esplugues de LLobregat, Barcelona, Spain, 08950
A Coruña, Spain, 15006
Alicante, Spain, 03010
Cáceres, Spain, 10003
Madrid, Spain, 28046
Valencia, Spain, 46026
Sponsors and Collaborators
Bayer
Investigators
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Study Director: Bayer Study Director Bayer
  Study Documents (Full-Text)

Documents provided by Bayer:
Study Protocol  [PDF] February 1, 2019
Statistical Analysis Plan  [PDF] January 28, 2020

Additional Information:
Publications of Results:

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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01311648    
Other Study ID Numbers: 13400
2010-021781-29 ( EudraCT Number )
First Posted: March 9, 2011    Key Record Dates
Results First Posted: November 3, 2020
Last Update Posted: November 17, 2021
Last Verified: November 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Recombinant factor VIII
Pediatric use
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
Factor VIII
Coagulants