BAY81-8973 Pediatric Safety and Efficacy Trial

NCT01311648 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 134002010-021781-29
• Study Type: interventional
• Target: 94
• Locations: 17 countries
• Sites: 43

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).

Conditions

Haemophilia A

Keywords

Recombinant factor VIII; Pediatric use

Outcome Measures

Primary Outcomes (2)

• Annualized Number of Total Bleeds Within 48 h

  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').

  Within 48 hours post infusion

• Annualized Number of Total Bleeds Within 48 h

  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').

  Within 48 hours post infusion

Secondary Outcomes (12)

• 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 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)

• 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)

• 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 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)

Study Arms (2)

PTPs 0-12 years

EXPERIMENTAL

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)

PUPs/MTPs 0-<6 years

EXPERIMENTAL

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)

Interventions

Recombinant Factor VIII (Kovaltry, BAY81-8973) BIOLOGICAL

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.

PTPs 0-12 years

Eligibility Criteria

• Age: 0 Years - 12 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Bayer: lead

Study Sites (43)

Unknown Facility

New Orleans, Louisiana, 70112, United States

Location

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Cincinnati, Ohio, 45229, United States

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Cleveland, Ohio, 44106, United States

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Columbus, Ohio, 43205-2696, United States

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Bahía Blanca, Buenos Aires, B8001HXM, Argentina

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Plovdiv, 4002, Bulgaria

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Varna, 9010, Bulgaria

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Edmonton, Alberta, T6G 2C8, Canada

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Hamilton, Ontario, L8N 3Z5, Canada

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Toronto, Ontario, M5G 1X8, Canada

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Århus N, 8200, Denmark

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Budapest, 1089, Hungary

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Debrecen, 4032, Hungary

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Mohács, 7700, Hungary

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Crumlin, Dublin, 12, Ireland

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Ramat Gan, 5262000, Israel

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Bari, Apulia, 70126, Italy

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Rome, Lazio, 00165, Italy

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Milan, Lombardy, 20122, Italy

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Catania, Sicily, 95123, Italy

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Padua, Veneto, 35128, Italy

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Riga, LV-1004, Latvia

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Vilnius, 08406, Lithuania

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Guadalajara, Jalisco, 44280, Mexico

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San Juan del Río, Querétaro, 76800, Mexico

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Oaxaca City, 68000, Mexico

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Oslo, Norway

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Lodz, 91-738, Poland

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Warsaw, 00-576, Poland

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Wroclaw, 50-368, Poland

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Bucharest, 011026, Romania

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Bucharest, 022328, Romania

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Cluj-Napoca, 400177, Romania

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Timișoara, 300011, Romania

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Kazan', 139445, Russia

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Kirov, 610027, Russia

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Volgograd, 400138, Russia

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Esplugues de Llobregat, Barcelona, 8950, Spain

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A Coruña, 15006, Spain

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Alicante, 03010, Spain

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Cáceres, 10003, Spain

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Madrid, 28046, Spain

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Valencia, 46026, Spain

Location

Related Publications (11)

• 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.

  PMID: 26931631 RESULT

• 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.

  PMID: 26663410 RESULT

• 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.

  PMID: 27577234 RESULT

• 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.

  PMID: 25952661 RESULT

• 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.

  PMID: 27436242 RESULT

• 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.

  PMID: 28220555 RESULT

• 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.

  PMID: 30013766 RESULT

• 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.

  PMID: 32197139 RESULT

• Kenet G, Moulton T, Wicklund BM, Ahuja SP, Escobar M, Mahlangu J. Switching from Sucrose-Formulated rFVIII to Octocog Alfa (BAY 81-8973) Prophylaxis Improves Bleed Outcomes in the LEOPOLD Clinical Trials. J Blood Med. 2023 Jun 7;14:379-388. doi: 10.2147/JBM.S405624. eCollection 2023.

  PMID: 37309365 RESULT

• Ljung R, Chan AKC, Glosli H, Afonja O, Becker B, Tseneklidou-Stoeter D, Mancuso ME, Saulyte-Trakymiene S, Kenet G. BAY 81-8973 Efficacy and Safety in Previously Untreated and Minimally Treated Children with Severe Hemophilia A: The LEOPOLD Kids Trial. Thromb Haemost. 2023 Jan;123(1):27-39. doi: 10.1055/s-0042-1757876. Epub 2023 Jan 10.

  PMID: 36626898 RESULT

• Ljung R, Chan AKC, Ahuja SP, Mancuso ME, Marquez JFC, Volk F, Blanchette V, Kerlin BA, Trakymiene SS, Glosli H, Kenet G. BAY 81-8973 Demonstrates Long-Term Safety and Efficacy in Children With Severe Haemophilia A: Results From the LEOPOLD Kids Extension Study. Eur J Haematol. 2025 Mar;114(3):556-565. doi: 10.1111/ejh.14362. Epub 2024 Dec 12.

  PMID: 39667975 DERIVED

Related Links

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MeSH Terms

Conditions

Hemophilia A

Interventions

Factor VIII; F8 protein, human

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Limitations and Caveats

Due to the small number of participants per reporting group, all presented summary measures (e.g. mean and proportion) have to be evaluated with caution. If displayed standard deviation should be taken into account. The participant who had a low titer inhibitor detected after 549 EDs during the extension study was considered to have a false positive result due to cross reactivity with IgG anticardiolipin antibodies.

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: Bayer

clinical-trials-contact@bayer.com

1-888-8422937

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 18, 2011
• First Posted: March 9, 2011
• Study Start: June 9, 2011
• Primary Completion: September 9, 2019
• Study Completion: October 27, 2020
• Last Updated: December 5, 2023
• Results First Posted: November 3, 2020

Record last verified: 2023-11

Locations

BU (2); IE (1); HU (3); ME (3); RU (3); DK (1); CA (3); US (4); LA (1); RO (4); PL (3); AR (1); LI (1); IT (5); ES (6); IL (1); NO (1)