BAY81-8973 Pediatric Safety and Efficacy Trial

NCT ID: NCT01311648

Last Updated: 2023-12-05

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

94 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-06-09

Study Completion Date

2020-10-27

Brief Summary

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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

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Conditions

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Haemophilia A

Keywords

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Recombinant factor VIII Pediatric use

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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).

Group Type EXPERIMENTAL

Recombinant Factor VIII (Kovaltry, BAY81-8973)

Intervention Type 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.

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.

Group Type EXPERIMENTAL

Recombinant Factor VIII (Kovaltry, BAY81-8973)

Intervention Type BIOLOGICAL

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

Interventions

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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.

Intervention Type 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

Intervention Type BIOLOGICAL

Eligibility Criteria

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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
Minimum Eligible Age

0 Years

Maximum Eligible Age

12 Years

Eligible Sex

MALE

Accepts Healthy Volunteers

No

Sponsors

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Bayer

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Bayer Study Director

Role: STUDY_DIRECTOR

Bayer

Locations

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New Orleans, Louisiana, United States

Site Status

Cincinnati, Ohio, United States

Site Status

Cleveland, Ohio, United States

Site Status

Columbus, Ohio, United States

Site Status

Bahía Blanca, Buenos Aires, Argentina

Site Status

Plovdiv, , Bulgaria

Site Status

Varna, , Bulgaria

Site Status

Edmonton, Alberta, Canada

Site Status

Hamilton, Ontario, Canada

Site Status

Toronto, Ontario, Canada

Site Status

Århus N, , Denmark

Site Status

Budapest, , Hungary

Site Status

Debrecen, , Hungary

Site Status

Mohács, , Hungary

Site Status

Crumlin, Dublin, Ireland

Site Status

Ramat Gan, , Israel

Site Status

Bari, Apulia, Italy

Site Status

Rome, Lazio, Italy

Site Status

Milan, Lombardy, Italy

Site Status

Catania, Sicily, Italy

Site Status

Padua, Veneto, Italy

Site Status

Riga, , Latvia

Site Status

Vilnius, , Lithuania

Site Status

Guadalajara, Jalisco, Mexico

Site Status

San Juan del Río, Querétaro, Mexico

Site Status

Oaxaca City, , Mexico

Site Status

Oslo, , Norway

Site Status

Lodz, , Poland

Site Status

Warsaw, , Poland

Site Status

Wroclaw, , Poland

Site Status

Bucharest, , Romania

Site Status

Bucharest, , Romania

Site Status

Cluj-Napoca, , Romania

Site Status

Timișoara, , Romania

Site Status

Kazan', , Russia

Site Status

Kirov, , Russia

Site Status

Volgograd, , Russia

Site Status

Esplugues de Llobregat, Barcelona, Spain

Site Status

A Coruña, , Spain

Site Status

Alicante, , Spain

Site Status

Cáceres, , Spain

Site Status

Madrid, , Spain

Site Status

Valencia, , Spain

Site Status

Countries

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Austria Greece Serbia Sweden United Kingdom United States Argentina Bulgaria Canada Denmark Hungary Ireland Israel Italy Latvia Lithuania Mexico Norway Poland Romania Russia Spain

References

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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.

Reference Type RESULT
PMID: 26931631 (View on PubMed)

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.

Reference Type RESULT
PMID: 26663410 (View on PubMed)

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.

Reference Type RESULT
PMID: 27577234 (View on PubMed)

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.

Reference Type RESULT
PMID: 25952661 (View on PubMed)

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.

Reference Type RESULT
PMID: 27436242 (View on PubMed)

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.

Reference Type RESULT
PMID: 28220555 (View on PubMed)

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.

Reference Type RESULT
PMID: 30013766 (View on PubMed)

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.

Reference Type RESULT
PMID: 32197139 (View on PubMed)

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.

Reference Type RESULT
PMID: 37309365 (View on PubMed)

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.

Reference Type RESULT
PMID: 36626898 (View on PubMed)

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.

Reference Type DERIVED
PMID: 39667975 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

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http://www.clinicaltrialsregister.eu/

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https://clinicaltrials.bayer.com/

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Other Identifiers

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2010-021781-29

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

13400

Identifier Type: -

Identifier Source: org_study_id