Clinical trial NCT01311648: BAY81-8973 Pediatric Safety and Efficacy Trial
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Haemophilia A
Keywords: Recombinant factor VIII
Pediatric use
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2011-03-09
Enrollment: 94
Sex: MALE
Minimum age (years): 0
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).


Eligibility 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

Primary outcomes:
measure: Annualized Number of Total Bleeds Within 48 h
timeFrame: Within 48 hours post infusion
measure: Annualized Number of Total Bleeds Within 48 h
timeFrame: Within 48 hours post infusion
Secondary outcomes:
measure: Annualized Number of Total Bleeds During Prophylaxis Treatment
timeFrame: 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)
measure: Annualized Number of Total Bleeds During Prophylaxis Treatment
timeFrame: 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)
measure: Hemostatic Control During Major and Minor Surgeries
timeFrame: 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)
measure: Number of Participants With Inhibitor Development in Main Study
timeFrame: 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)
measure: Number of Participants With New Inhibitor Development in Extension Study
timeFrame: From start of extension study to at least 100 cumulative exposure days (EDs) (median 421 EDs; median 3.8 years)
measure: Factor VIII Recovery Values
timeFrame: 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)
measure: Consumption of Factor VIII in All Infusions
timeFrame: 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)
measure: Consumption of FVIII in Infusions for Prophylaxis
timeFrame: 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)
measure: Consumption of FVIII in Infusions for the Treatment of Bleeds
timeFrame: 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)
measure: Number of Infusions Per Bleed
timeFrame: 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)
measure: Response to Treatment of Bleeds
timeFrame: 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)
measure: Half-life (t1/2) of BAY81-8973 in Plasma
timeFrame: Pre-infusion and until 24 hours post infusion
Other outcomes:
Locations:
city: New Orleans
country: United States
state: Louisiana
city: Cincinnati
country: United States
state: Ohio
city: Cleveland
country: United States
state: Ohio
city: Columbus
country: United States
state: Ohio
city: Bahía Blanca
country: Argentina
state: Buenos Aires
city: Plovdiv
country: Bulgaria
city: Varna
country: Bulgaria
city: Edmonton
country: Canada
state: Alberta
city: Hamilton
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Århus N
country: Denmark
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Mohacs
country: Hungary
city: Crumlin
country: Ireland
state: Dublin
city: Ramat Gan
country: Israel
city: Roma
country: Italy
state: Lazio
city: Milano
country: Italy
state: Lombardia
city: Bari
country: Italy
state: Puglia
city: Catania
country: Italy
state: Sicilia
city: Padova
country: Italy
state: Veneto
city: Riga
country: Latvia
city: Vilnius
country: Lithuania
city: Guadalajara
country: Mexico
state: Jalisco
city: San Juan del Río
country: Mexico
state: Querétaro
city: Oaxaca
country: Mexico
city: Oslo
country: Norway
city: Lodz
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Bucharest
country: Romania
city: Bucharest
country: Romania
city: Cluj-Napoca
country: Romania
city: Timisoara
country: Romania
city: Kazan
country: Russian Federation
city: Kirov
country: Russian Federation
city: Volgograd
country: Russian Federation
city: Esplugues de LLobregat
country: Spain
state: Barcelona
city: A Coruña
country: Spain
city: Alicante
country: Spain
city: Cáceres
country: Spain
city: Madrid
country: Spain
city: Valencia
country: Spain
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.