A Post Approval Commitment Study to Gain More Information on How Safe and Effective KOVALTRY is in Chinese Children, Adolescents /Adults With Severe Hemophilia A

Phase 4

Completed

Conditions: Hemophilia A

Interventions: Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 2
Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 1
Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 3

Registration Number: NCT04565236

Lead Sponsor: Bayer

Brief Summary: The goal of this study is to gather more information on safety and efficacy of Kovaltry for the prevention and treatment of bleeds in Chinese children, adolescents/adults with severe hemophilia A. In addition, pharmacokinetic parameters of Kovaltry will be assessed in a subset of patients.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 45

Inclusion Criteria

Part A (PTPs):

Chinese participants with severe hemophilia A (defined as Factor VIII (FVIII): C < 1% with one- stage clotting assay documented at the time of screening)
Currently receiving on-demand or any type of prophylaxis treatment regimen with any FVIII product
For participants < 12 years of age, ≥ 50 exposure days (ED); for participants ≥ 12 to 65 years of age, ≥ 150 ED with any FVIII product
No current evidence of inhibitor
No history of FVIII inhibitor formation
Signed informed consent

Part B (PUPs/MTPs):

Participants must be <6 years of age at the time of their parent or legal representative's signature of informed consent on the participant's behalf
Chinese participants with severe hemophilia A (defined as Factor VIII (FVIII): C < 1% with one- stage clotting assay documented at the time of screening)
PUPs must have no previous exposure to any FVIII product. MTPs must have no more than 1 ED with any purified FVIII concentrate or 3 exposures with FFP or cryoprecipitate.
MTPs must have no current evidence of inhibitor antibody as measured by the Nijmegen-modified Bethesda assay (<0.6 BU/mL) in 2 consecutive samples and must have absence of clinical signs or symptoms of decreased response to FVIII administration. Testing for the 2 negative samples must be performed by the central laboratory at least 1 week but not more than 2 weeks apart. Participants may not receive FVIII product within 72 hours prior to the collection of samples for inhibitor testing.
PUPs and MTPs must observe a 6-month washout period if they have received subcutaneous factor substitution therapy (emicizumab).
PUPs may be included if they will receive their first FVIII dose with KOVALTRY for treatment of first bleed and agree to start prophylaxis as part of their care. MTPs may be included if they agree to start prophylaxis as part of their care.

Exclusion Criteria

Part A (PTPs):

Any other bleeding disease that is different from hemophilia A (e.g. von Willebrand disease, hemophilia B)
Platelet count < 100 000/mm^3
Impaired renal function (serum creatinine > 2.0 mg/dL) or active liver disease (alanine aminotransferase/aspartate aminotransferase [ALT/AST] > 5x ULN)
Human immunodeficiency virus (HIV) positive with an absolute CD4 lymphocyte cell count < 250 cells/μL
Known hypersensitivity to the active substance, mouse or hamster protein
Receiving chemotherapy, immune modulatory drugs other than anti-retroviral chemotherapy, or chronic use of oral or intravenous (IV) corticosteroids (> 14 days) within the last 3 months.
Requiring any pre-medication to tolerate FVIII infusions (e.g. antihistamines)
Currently participating in another investigational drug study, or having previously participated in a clinical study involving an investigational drug within 30 days of signing informed consent or participated in completed interventional clinical studies with BAY81-8973 (Kovaltry)
Planned major surgery, defined as surgery with respiratory assistance and/or general anesthesia

Part B (PUPs/MTPs):

Any other bleeding disease that is different from hemophilia A (e.g. von Willebrand disease, hemophilia B)
Platelet count < 100 000/mm^3
Impaired renal function (serum creatinine >2× upper limit of normal [ULN]) or active liver disease (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >5× ULN) based on screening laboratory assessments
MTPs with history of FVIII inhibitor formation
Known hypersensitivity to the active substance, mouse or hamster protein
First treatment with KOVALTRY for high risk bleeding situations (e.g., surgery, intracranial bleed) or requiring intensive or prolonged treatment
Receiving chemotherapy, immune modulatory drugs other than anti-retroviral chemotherapy, or chronic use of oral or intravenous (IV) corticosteroids (> 14 days) within the last 3 months.
Requiring any pre-medication to tolerate FVIII infusions (e.g. antihistamines)
Currently participating in another investigational drug study, or having previously participated in a clinical study involving an investigational drug within 30 days of signing informed consent or participated in completed interventional clinical studies with BAY 81-8973 (Kovaltry)
Planned major surgery, defined as surgery with respiratory assistance and/or general anesthesia
Unable to tolerate volume of blood draws required for study participation

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Part A: PTPs ≥12 to 65 years of age	Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 2	Previously treated severe hemophilia A patients (PTPs) ≥12 to 65 years of age
Part A: PTPs <12 years of age	Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 1	Previously treated severe hemophilia A patients (PTPs) \<12 years of age
Part B: PUPs/MTPs <6 years of age	Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 3	Previously untreated/minimally treated severe hemophilia A patients (PUPs/MTPs) \<6 years of age

Primary Outcome Measures

Name	Time	Method
Annualized Bleeding Rate (ABR) of All Bleeding Episodes During Prophylaxis Treatment in Part A	Up to 6 months	Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred during the prophylaxis treatment period is reported for previously treated patients (PTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery.
Annualized Bleeding Rate (ABR) of All Bleeding Episodes Within 48 Hours of Previous Prophylaxis Infusion in Part B	Up to 48 hours post-infusion during 6 months	Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred within 48 hours of previous prophylaxis infusion is reported for previously untreated/minimally treated patients (PUPs/MTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery.

Secondary Outcome Measures

Name	Time	Method
Annualized Bleeding Rate (ABR) of All Bleeding Episodes Within 48 Hours of Previous Prophylaxis Infusion in Part A	Up to 48 hours post-infusion during 6 months	Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred within 48 hours of previous prophylaxis infusion is reported for previously treated patients (PTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery.
Annualized Bleeding Rate (ABR) of All Bleeding Episodes During Prophylaxis Treatment in Part B	Up to 51 exposure days	Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred during the prophylaxis treatment period is reported for previously untreated/minimally treated patients (PUPs/MTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery.
Number of Infusions Per Bleeding Episode	Part A: up to 6 months; Part B: up to 51 exposure days	The mean value of number of infusions for the treatment of one bleed to achieve hemostasis is reported.
Number of Surgeries Per Physician's Assessment of Adequacy of Hemostasis in Minor Surgery	Part A: up to 6 months; Part B: up to 51 exposure days	For participants who underwent minor surgeries during the study, investigators were ask to assess the adequacy of hemostasis during the surgeries as excellent, good, moderate or poor. Number of surgeries per assessment is reported.
FVIII In-vivo Recovery in Part B	At baseline, Visit 6 (ED 20), unscheduled visit and final visit, up to 51 exposure days	Incremental recovery of Factor VIII (FVIII) was determined by collecting blood samples pre-infusion and 15-30 minutes after the end of the infusion. Mean recovery values at different time points are reported.
Factor VIII Inhibitor Development by the Nijmegen Bethesda Assay	Part A: up to 6 months; Part B: up to 51 exposure days	Number of participants who developed a positive Factor VIII (FVIII) inhibitor level (≥0.6 Bethesda unit \[BU/mL\]) during the study is reported.
Number of Participants With Treatment-emergent Adverse Events	Part A: up to 6 months; Part B: up to 51 exposure days	An adverse event (AE) was any untoward medical occurrence in a participant, associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly/birth defect; another medical important serious event as judged by the investigator. AEs or SAEs were considered to be treatment emergent (TEAEs or TESAEs) if they started after the first KOVALTRY infusion and up to 3 days after the last dose.
FVIII In-vivo Recovery in Part A	At baseline, Month 2 and final visit, up to 6 months	Incremental recovery of Factor VIII (FVIII) was determined by collecting blood samples pre-infusion and 15-30 minutes after the end of the infusion. Mean recovery values at different time points are reported.
Maximum Observed Concentration of FVIII in Plasma (Cmax) in Part A	at baseline for PTPs < 12 Years and at baseline and final visit (month 6) for PTPs >= 12 Years	For the assessment, participants were administered a dose of 50 IU/kg KOVALTRY. Participants must have no signs or symptoms of an acute bleeding episode. For participants below 12 years, the evaluation was only performed once at baseline. For adolescents/adult participants 12 years or older, the evaluation was performed twice at baseline and at final visit.
Area Under the Plasma Concentration of FVIII Versus Time Curve From Zero to Infinity (AUC) in Part A	at baseline for PTPs < 12 Years and at baseline and final visit (month 6) for PTPs >= 12 Years	For the assessment, participants were administered a dose of 50 IU/kg KOVALTRY. Participants must have no signs or symptoms of an acute bleeding episode. For participants below 12 years, the evaluation was only performed once at baseline. For adolescents/adult participants 12 years or older, the evaluation was performed twice at baseline and at final visit.
Half-life (t1/2) of FVIII in Plasma in Part A	at baseline for PTPs < 12 Years and at baseline and final visit (month 6) for PTPs >= 12 Years	For the assessment, participants were administered a dose of 50 IU/kg KOVALTRY. Participants must have no signs or symptoms of an acute bleeding episode. For participants below 12 years, the evaluation was only performed once at baseline. For adolescents/adult participants 12 years or older, the evaluation was performed twice at baseline and at final visit.

Trial Locations

Locations (10): The Children's Hospital Zhejiang University School of Med
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Hangzhou, Hangzhou Province, China
Beijing Children's Hospital, Capital Medical University
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Beijing, Beijing, China
Shijiazhuang General Hospital
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Shijiazhuang, Hebei, China
NJ Drum Tower Hospital, the Affil Hos of NJ Univ Med School
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Nanjing, Jiangsu, China
1st Affiliated hospital of Soochow University
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Suzhou, Jiangsu, China
Jiangxi Provincial People's Hospital
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Nanchang, Jiangxi, China
Children's Hospital of Shanxi
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Taiyuan, Shanxi, China
Chengdu Women & Children's Central Hospital
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Chengdu, Sichuan, China
Peking Union Medical College Hospital CAMS
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Beijing, China
Childrens Hospital of Shanghai
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Shanghai, China