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 17, 2021
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Study Description

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

Study Design

• Study Type: Interventional (Clinical Trial)
• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• Ages Eligible for Study: 0 Years 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

Contacts and Locations

Locations

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

• 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

More Information

Additional Information:

Click here to find information about studies related to Bayer Healthcare products conducted in Europe 

Click here to find results for studies related to Bayer products 

Publications of Results:

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(R)): A Review in Haemophilia A. BioDrugs. 2016 Oct;30(5):453-459. doi: 10.1007/s40259-016-0191-4.

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.

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.

Kenet G, Ljung R, Rusen L, Kerlin BA, Blanchette V, Saulyte Trakymiene S, Uscatescu V, Beckmann H, Tseneklidou-Stoeter D, Church N. Continued benefit demonstrated with BAY 81-8973 prophylaxis in previously treated children with severe haemophilia A: Interim analysis from the LEOPOLD Kids extension study. Thromb Res. 2020 May;189:96-101. doi: 10.1016/j.thromres.2020.03.005. Epub 2020 Mar 9.

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

• 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:

Hemophilia A; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Factor VIII; Coagulants