Haemophilia APhase 3NCT01311648
BAY81-8973 Pediatric Safety and Efficacy Trial
A Phase 3 study testing Recombinant Factor VIII (Kovaltry, BAY81-8973) in people with Haemophilia A, run by Bayer at 43 sites in 17 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 0 to 12 years, men only
- Conditions the study is for
- Haemophilia A
- What is being tested?
- Recombinant Factor VIII (Kovaltry, BAY81-8973)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 94 participants
- Where
- 43 sitesin 17 countries
- Study dates
- 9 Jun 2011to 27 Oct 2020
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 0 to 12 years
- Men only
- No healthy volunteers
- Child
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
43 sites in 17 countries.
43 sites in 17 countries
Spain6 sites
Study site
A Coruña, 15006
Study site
Alicante, 03010
Study site
Cáceres, 10003
Study site
Esplugues de Llobregat, Barcelona, 8950
Study site
Madrid, 28046
Study site
Valencia, 46026
Italy5 sites
Study site
Bari, Apulia, 70126
Study site
Catania, Sicily, 95123
Study site
Milan, Lombardy, 20122
Study site
Padova, Veneto, 35128
Study site
Rome, Lazio, 00165
United States4 sites
Study site
Cincinnati, Ohio, 45229
Study site
Cleveland, Ohio, 44106
Study site
Columbus, Ohio, 43205-2696
Study site
New Orleans, Louisiana, 70112
Romania4 sites
Study site
Bucharest, 011026
Study site
Bucharest, 022328
Study site
Cluj-Napoca, 400177
Study site
Timișoara, 300011
Canada3 sites
Study site
Edmonton, Alberta, T6G 2C8
Study site
Hamilton, Ontario, L8N 3Z5
Study site
Toronto, Ontario, M5G 1X8
Hungary3 sites
Study site
Budapest, 1089
Study site
Debrecen, 4032
Study site
Mohács, 7700
Mexico3 sites
Study site
Guadalajara, Jalisco, 44280
Study site
Oaxaca City, 68000
Study site
San Juan del Río, Querétaro, 76800
Poland3 sites
Study site
Lodz, 91-738
Study site
Warsaw, 00-576
Study site
Wroclaw, 50-368
Russia3 sites
Study site
Kazan', 139445
Study site
Kirov, 610027
Study site
Volgograd, 400138
About this study
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
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
- Being tested
- Recombinant Factor VIII (Kovaltry, BAY81-8973)
- Keywords
- Recombinant factor VIII, Pediatric use
- Medical subject headings
- Hemophilia A
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
Recombinant Factor VIII (Kovaltry, BAY81-8973)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
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: 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. Receives: Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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').
Measured: 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').
Measured: Within 48 hours post infusion
Secondary outcomes (12)
Annualized Number of Total Bleeds During Prophylaxis Treatment
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').
Measured: 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
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').
Measured: 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
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.
Measured: 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
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).
Measured: 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
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).
Measured: From start of extension study to at least 100 cumulative exposure days (EDs) (median 421 EDs; median 3.8 years)
Factor VIII Recovery Values
Incremental recovery of Factor VIII (FVIII) at 20-30 min after end of infusions was determined and mean recovery values were reported.
Measured: 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)
Consumption of Factor VIII in All Infusions
Factor VIII (FVIII) usage/consumption was summarized for all infusions. Consumption per participant's body weight per year was calculated and reported.
Measured: 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)
Consumption of FVIII in Infusions for Prophylaxis
Factor VIII (FVIII) usage/consumption was summarized for prophylaxis infusions. Consumption per participant's body weight per year was calculated and reported.
Measured: 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)
Consumption of FVIII in Infusions for the Treatment of Bleeds
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.
Measured: 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 Infusions Per Bleed
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.
Measured: 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)
Response to Treatment of Bleeds
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.
Measured: 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)
Half-life (t1/2) of BAY81-8973 in Plasma
Half-life (t1/2) of BAY81-8973 in plasma was measured. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Measured: Pre-infusion and until 24 hours post infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Mar 2011 (estimated)
- Study start9 Jun 2011
- Primary completion9 Sep 2019
- Study completion27 Oct 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Haemophilia AStudies of the same condition, open and under way.
- More trials run by BayerThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 94 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bayer
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Bayer Study Director, Study director, Bayer
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01311648
- Sponsor's protocol ID
- 13400
- Other IDs
- 2010-021781-29
- Status last verified
- Nov 2023
- First submitted
- 18 Feb 2011
- Last updated
- 5 Dec 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
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.
PubMed 26931631Ljung 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.
PubMed 26663410Keating 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.
PubMed 27577234Shah 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.
PubMed 25952661Maas 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.
PubMed 27436242Garmann 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.
PubMed 28220555Mahlangu 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.
PubMed 30013766Kenet 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.
PubMed 32197139Kenet 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.
PubMed 37309365Ljung 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.
PubMed 36626898Ljung 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.
PubMed 39667975