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

Study Overview
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Brief Summary
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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.

Official Title
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A Post Approval Commitment Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of KOVALTRY in Chinese Children, Adolescents /Adults With Severe Hemophilia A

Conditions
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Hemophilia A

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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: PTPs <12 years of age<br>Previously treated severe hemophilia A patients (PTPs) <12 years of age | Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 1<br>* 25 to 50 IU of Kovaltry per kg body weight given via intravenous (IV) infusion twice weekly, three times weekly, or every other day according to individual requirements for 6 months. The dose decisions are at the discretion of the investigator.<br>|
| Experimental: Part A: PTPs ≥12 to 65 years of age<br>Previously treated severe hemophilia A patients (PTPs) ≥12 to 65 years of age | Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 2<br>* 12 year-old: 25 to 50 IU of Kovaltry per kg body weight given via intravenous (IV) infusion twice weekly, three times weekly, or every other day for 6 months. >12 year-old: 20 to 40 IU of Kovaltry per kg of body weight given via intravenous (IV) infusion two or three times per week for 6 months. The dose decisions are at the discretion of the investigator.<br>|
| Experimental: Part B: PUPs/MTPs <6 years of age<br>Previously untreated/minimally treated severe hemophilia A patients (PUPs/MTPs) <6 years of age | Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 3<br>* 15 to 50 IU of Kovaltry per kg body weight (minimum dose: 250 IU) given via intravenous (IV) infusions at least once a week. The dose decisions are at the discretion of the investigator.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized bleeding rate of all bleeding episodes during prophylaxis treatment | Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment in previously treated patients (PTPs). | Part A: up to 6 months | 
| Annualized bleeding rate within 48 hours of previous prophylaxis infusion | Annualized bleeding rate (ABR) of bleeding episodes within 48 hours of previous prophylaxis infusion in previously untreated/minimally treated patients (PUPs/MTPs). | Part B: up to 48 hours post-infusion for at least 50 exposure days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized bleeding rate of treated bleeding episodes | Annualized bleeding rate (ABR) of bleeding episodes treated with BAY81-8973 during prophylaxis treatment. | Part A: up to 6 months; Part B: up to at least 50 exposure days | 
| Annualized bleeding rate of target joint bleeding episodes | Annualized bleeding rate (ABR) of target joint bleeding episodes during prophylaxis treatment. | Part A: up to 6 months; Part B: up to at least 50 exposure days | 
| Annualized bleeding rate within 48 hours of previous prophylaxis infusion | Annualized bleeding rate (ABR) of bleeding episodes within 48 hours of previous prophylaxis infusion. | Part A: up to 48 hours post-infusion for 6 months | 
| Annualized bleeding rate of all bleeding episodes during prophylaxis treatment | Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment in previously untreated/minimally treated patients (PUPs/MTPs). | Part B: up to at least 50 exposure days | 
| Assessment of response to treatment of bleeds | Participants or caregivers assessment to Kovaltry treatment on ISTH 4 point response scale for response to treatment of bleed [excellent, good, moderate or poor]. | Part A: up to 6 months; Part B: up to at least 50 exposure days | 
| Number of surgeries based on physician's assessment of adequacy of hemostasis in minor surgery | Physician's assessment of participant's hemostatic response to Kovaltry treatment on the ISTH 4 point response scale for adequacy of hemostasis for surgical procedures [excellent, good, moderate or poor]. | Part A: up to 6 months; Part B: up to at least 50 exposure days | 
| Number of participants without bleeding episodes | Number of participants who report no bleeding event during prophylaxis. | Part A: up to 6 months; Part B: up to at least 50 exposure days | 
| Number of infusions per bleeding episode | Number of infusions of BAY81-8973 needed to achieve hemostasis for a bleeding episode. | Part A: up to 6 months; Part B: up to at least 50 exposure days | 
| Factor VIII usage | BAY81-8973 consumption during the study. | Part A: up to 6 months; Part B: up to at least 50 exposure days | 
| Factor VIII inhibitor development by the Nijmegen Bethesda assay | Number of participants with positive Factor VIII (FVIII) inhibitor test (≥0.6 Bethesda unit [BU]). | Part A: up to 6 months; Part B: up to at least 50 exposure days | 
| In-vivo recovery | In-vivo recovery (or incremental recovery) is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight. | Part A: baseline, Month 2 and Month 6; Part B: baseline and end of study | 
| Maximum concentration (Cmax) of Kovaltry in plasma | Cmax: Maximum observed drug concentration following an infusion of 50 IU/kg. | Part A: pre-infusion and up to 30 minutes post-infusion | 
| Area under the plasma concentration versus time curve (AUC) from zero to infinity after single (first) dose | AUC: The total area under the plasma concentration versus time curve following an infusion of 50 IU/kg. | Part A: pre-infusion and up to 48 hours post-infusion | 
| Half-life (t1/2) of Kovaltry in plasma | t1/2: Terminal half-life is the time the plasma concentration during terminal phase is halved following an infusion of 50 IU/kg. | Part A: pre-infusion and up to 48 hours post-infusion | 
| Treatment-emergent adverse events |  | Part A: up to 6 months; Part B: up to at least 50 exposure days |