A Study of Adynovate in Previously Treated Chinese Teenagers and Adults With Severe Hemophilia A

Study Overview
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Brief Summary
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The main aim of the study is to determine how well Adynovate works to decrease bleeding in previously treated Chinese men and boys with severe hemophilia A when given prophylactically. Participants will be treated with Adynovate twice a week for 26 weeks or until participants have received 50 days of treatment with Adynovate (whichever takes longer). Participants will need to visit their study clinic several times during their participation.

Official Title
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A Phase 3, Prospective, Multicenter, Open-label Study of Efficacy, Safety, and Pharmacokinetics of PEGylated Recombinant Factor VIII (ADYNOVATE) Administered for Prophylaxis and Treatment of Bleeding in Chinese Previously Treated Patients With Severe Hemophilia A (FVIII <1%)

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: Adynovate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant and/or legally authorized representative must voluntarily sign a written informed consent form (ICF) after all relevant aspects of the study have been explained and discussed with the Participant. For the participants less than (<) 18 years old, participants will give assent AND their parents/legally authorized representative should sign the ICF accordingly. Participant and/or legally authorized representative understands and is willing and able to comply with all requirements of the study protocol. Participant should be ethnic Chinese. Participant is 12 to 65 years of age at screening and male. Participant has severe hemophilia A (FVIII clotting activity <1 percent [%]) as confirmed by the central laboratory at screening after a washout period of at least 72 to 96 hours. The last on-demand or prophylactic treatment received is within 3 months before screening. Participant has documented previous treatment with plasma-derived FVIII concentrates or recombinant FVIII for greater than (>) 150 EDs. Participant is human immunodeficiency virus (HIV)-negative, or HIV-positive with stable disease and CD4+ count greater than or equal to (>=) 200 cells per cubic millimeter (/mm^3). Participant is hepatitis C virus (HCV) negative by antibody testing (if positive, additional polymerase chain reaction testing will be performed to confirm), as confirmed at screening; or HCV-positive with chronic stable hepatitis, as assessed by the investigator. Exclusion Criteria: Participant has detectable FVIII inhibitory antibodies (>=0.6 Bethesda units [BU] per milliliter [/mL] using the Nijmegen modification of the Bethesda assay) as confirmed by the central laboratory at screening. Participant has a confirmed history of FVIII inhibitory antibodies (>=0.6 BU using the Nijmegen modification of the Bethesda assay or >=0.6 BU using the Bethesda assay) at any time prior to screening. Participant has a known hypersensitivity to Adynovate or ADVATE or any of the components of the study drugs, such as mouse or hamster proteins, or other FVIII products. Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (example, qualitative platelet defect or von Willebrand's disease). Participant has severe hepatic dysfunction (example, >=5 times the upper limit of normal [ULN] for alanine aminotransferase [ALT] or aspartate aminotransferase [AST], a recent or persistent international normalized ratio [INR] >1.5, as confirmed by the local laboratory at screening). Participant has severe renal impairment (serum creatinine >1.5 times the ULN) as confirmed by the local laboratory at screening. Participant is planned or likely to undergo major surgery during the study period. Participant has current or recent (<30 days) use of other PEGylated drugs before study participation or scheduled use of such drugs during study participation. Participant has received emicizumab therapy within 6 months of screening. Participant is currently receiving, or scheduled to receive during the study, an immunomodulating drug (example, systemic corticosteroid agent at a dose equivalent to hydrocortisone >10 milligram per day [mg/day], or alpha-interferon) other than antiretroviral chemotherapy. Participant has participated in another clinical study involving the use of an investigational product (IP) other than Adynovate or an investigational device within 30 days before the screening visit or is scheduled to participate in another clinical study involving an IP or investigational device during this study. Participant has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance. Participant, in the opinion of the investigator, is unable or unwilling to comply with the study protocol.

Ages Eligible for Study
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Minimum Age: 12 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adynovate 45±5 IU/kg<br>Participants will receive prophylactic treatment with Adynovate (45 [±5] international units per kilogram [IU/kg]), infusion, intravenously, twice-weekly, over a period of 26 weeks or at least 50 EDs, whichever occurs last. | Biological: Adynovate<br>* Adynovate will be injected intravenously using an appropriately sized syringe as a bolus infusion over a period of less than or equal to (<=) 5 minutes (maximum infusion rate, 10 milliliters per minute [mL/min]).<br>* Other names: Antihemophilic Factor (recombinant) PEGylated, Rurioctocog Alfa Pegol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Annualized Bleeding Rates (ABR) | Total ABR for all bleeding episodes, spontaneous or traumatic, recorded in the participant's electronic diary and/or recorded in the physician/nurse/study site notes will be reported. | Baseline up to Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ABR Based on Bleeding Site and Cause |  | Baseline up to Week 26 | 
| Number of Adynovate Infusions per Week During the Prophylactic Treatment Period |  | Baseline up to Week 26 | 
| Number of Adynovate Infusions per Month During the Prophylactic Treatment Period |  | Baseline up to Week 26 | 
| Weight-adjusted Consumption of Adynovate per Week During the Prophylactic Treatment Period |  | Baseline up to Week 26 | 
| Weight-adjusted Consumption of Adynovate per Month During the Prophylactic Treatment Period |  | Baseline up to Week 26 | 
| Percentage of Participants With Zero Bleeding Episodes During the Study |  | Baseline up to Week 26 | 
| Time Intervals Between Bleeding Episodes |  | Baseline up to Week 26 | 
| Overall Hemostatic Efficacy Rating at Bleed Resolution for Treatment of Breakthrough Bleeding Episodes |  | Baseline up to Week 26 | 
| Number of Adynovate Infusions per Bleeding Episode |  | Baseline up to Week 26 | 
| Weight-adjusted Consumption of Adynovate per Bleeding Episode |  | Baseline up to Week 26 | 
| Number of Minor Surgeries With Hemostatic Efficacy Response Based on Global Hemostatic Efficacy Assessment (GHEA) Score as Assessed by the Operating Surgeon/Investigator | GHEA score consists of 3 individual rating scales: (1) Intra-operative Efficacy Assessment Scale, (2) Post-operative Efficacy Assessment Scale, and (3) Peri-operative Efficacy Assessment Scale. Each rating scale is based on 4 points scale ranging from: 3 (Excellent), 2 (Good), 1 (Fair), and 0 (None). Total score ranged from 0 to 9, where scores evaluates as: excellent (7 to 9), good (5 to 7), fair (3 to 4), and none (0 to 2). The scores of 3 individual ratings scales will be added together to form a GHEA score. For a GHEA score of 7 to be rated excellent with no individual assessment scores less than (<) 2 and at least 1 assessment score equal to (=) 3; otherwise a score of 7 will be rated good. | Baseline up to Week 26 | 
| Volume of Actual and Predicted Intra-operative and Post-operative Blood Loss After the Surgery as Assessed by the Operating Surgeon/Investigator |  | Post-operative: Day 1 and at discharge Week 26 | 
| Number of Participants who Require Perioperative Transfusion of Blood, Red blood Cells, Platelets, and Other Blood Products |  | Baseline up to Week 26 | 
| Daily Intra-Operative and Post-Operative Weight-Adjusted Consumption Dose of Adynovate |  | Baseline up to Week 26 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs will include TEAEs by severity, TEAEs by causality, thromboembolic events, hypersensitivity reactions, any clinically significant changes in vital signs and clinical laboratory parameters. | Screening up to Week 26 | 
| Number of Participants With Confirmed Inhibitory Antibodies to Factor VIII (FVIII), Binding Antibodies to Adynovate and Chinese Hamster Ovary (CHO) Protein |  | Screening up to Week 26 | 
| FVIII Activity Level in Plasma Assessed by a 1-stage Clotting Assay |  | Baseline and Week 20: 0-96 hours post-infusion | 
| Incremental Recovery Over Time During Adynovate Prophylactic Treatment |  | Baseline up to Week 26 | 
| Pre-dose Level of FVIII Activity and Antigen and von Willebrand Factor (VWF) Antigen in Plasma |  | Baseline up to Week 26: Within 30 minutes pre-infusion | 
| Clearance (CL) for FVIII Activity Following an Initial Single Dose and Steady-state Dose of Adynovate |  | Baseline and Week 20: 0-96 hours post-infusion | 
| Volume of Distribution (V) for FVIII Activity Following an Initial Single Dose and Steady-state Dose of Adynovate |  | Baseline and Week 20: 0-96 hours post-infusion | 
| Area Under the Concentration Versus Time Curve From 0 to 96 Hours (AUC0-96) for FVIII Activity Following an Initial Single Dose and Steady-state Dose of Adynovate |  | Baseline and Week 20: 0-96 hours post-infusion | 
| Maximum Concentration (Cmax) for FVIII Activity Following an Initial Single Dose and Steady-state Dose of Adynovate |  | Baseline and Week 20: 0-96 hours post-infusion | 
| Pre-dose Concentration (Cpredose) for FVIII Activity Following an Initial Single Dose and Steady-state Dose of Adynovate |  | Baseline and Week 20: Within 30 minutes pre-infusion | 
| Terminal Phase Elimination Half-life (T1/2) for FVIII Activity Following an Initial Single Dose and Steady-state Dose of Adynovate |  | Baseline and Week 20: 0-96 hours post-infusion |