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

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%)

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.

Study Overview

• Status: Completed
• Conditions: Hemophilia A
• Intervention / Treatment: Biological: Adynovate

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
  • Beijing, China
    • Beijing Children's Hospital, Capital Medical University
  • Changsha, China
    • Xiangya Hospital of Central South University
  • Fuzhou, China
    • Fujian Medical University Union Hospital
  • Guangzhou, China
    • Nanfang Hospital Southern Medical University
  • Hefei, China
    • Anhui Province Hospital
  • Jinan, China
    • Jinan Central Hospital
  • Shenzhen, China
    • Shenzhen Second People's Hospital
  • Suzhou, China
    • The First Affiliated Hospital of Soochow University
  • Tianjin, China
    • Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences
  • Wuhan, China
    • Union Hospital Tongji Medical College Huazhong University of Science and Technology
  • Wuhan, China
    • Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.
2. Participant and/or legally authorized representative understands and is willing and able to comply with all requirements of the study protocol.
3. Participant should be ethnic Chinese.
4. Participant is 12 to 65 years of age at screening and male.
5. 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.
6. The last on-demand or prophylactic treatment received is within 3 months before screening.
7. Participant has documented previous treatment with plasma-derived FVIII concentrates or recombinant FVIII for greater than (>) 150 EDs.
8. 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).
9. 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:

1. 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.
2. 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.
3. 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.
4. Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (example, qualitative platelet defect or von Willebrand's disease).
5. 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).
6. Participant has severe renal impairment (serum creatinine >1.5 times the ULN) as confirmed by the local laboratory at screening.
7. Participant is planned or likely to undergo major surgery during the study period.
8. Participant has current or recent (<30 days) use of other PEGylated drugs before study participation or scheduled use of such drugs during study participation.
9. Participant has received emicizumab therapy within 6 months of screening.
10. 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.
11. 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.
12. 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.
13. Participant, in the opinion of the investigator, is unable or unwilling to comply with the study protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adynovate 45±5 IU/kg; Participants received prophylactic treatment with Adynovate (45 [±5] IU/kg), infusion, IV, twice weekly, for at least 50 EDs, or approximately 28 weeks.	Biological: Adynovate; Adynovate was 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]).; Other Names: Antihemophilic Factor (recombinant) PEGylated, Rurioctocog Alfa Pegol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Annualized Bleeding Rates (ABR)	Total ABR was defined as the number of treated and non-treated bleeding episodes (BEs) that occurred during the treatment period, calculated as, ABR= number of unique bleeds during treatment period/(length of treatment period [days]/365.25). Total ABR for all BEs, spontaneous or traumatic, recorded in the participant's electronic diary and/or recorded in the physician/nurse/study site notes were reported.	Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
ABR Based on Bleeding Site	ABR= number of unique bleeds during treatment period/(length of treatment period [days]/365.25). ABR for BEs based on bleeding site: joint or non-joint, recorded in the participant's electronic diary and/or recorded in the physician/nurse/study site notes were reported.	Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
ABR Based on Bleeding Cause	ABR= number of unique bleeds during treatment period/(length of treatment period [days]/365.25). ABR for BEs based on bleeding cause: spontaneous/unknown or injury, recorded in the participant's electronic diary and/or recorded in the physician/nurse/study site notes were reported.	Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Number of Adynovate Infusions Per Week During the Prophylactic Treatment Period		Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Number of Adynovate Infusions Per Month During the Prophylactic Treatment Period		Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Weight-adjusted Consumption of Adynovate Per Week During the Prophylactic Treatment Period	Weight-adjusted consumption (IU/kg) was derived as the total units infused (IU) divided by the last available body weight (kg) prior to the infusion.	Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Weight-adjusted Consumption of Adynovate Per Month During the Prophylactic Treatment Period	Weight-adjusted consumption (IU/kg) was derived as the total units infused (IU) divided by the last available body weight (kg) prior to the infusion.	Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Percentage of Participants With Zero Bleeding Episodes During the Study	Percentages were rounded off to the nearest single decimal place.	Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Average Time Interval Between Bleeding Episodes (BEs)	Average time interval between bleeding episodes (days)= Length of treatment period (days)/ Number of unique bleeds during treatment period. Average time interval was computed for participants with more than 1 unique BEs.	Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Number of Bleeding Events in Each Category of Hemostatic Efficacy Rating at Resolution of Breakthrough Bleeding Episode	Hemostatic efficacy for treatment of BEs was rated on 4-point Likert scale as: excellent=full relief of pain and cessation of objective signs of bleeding after a single infusion, no additional infusion is required for the control of bleeding and administration of further infusion to maintain hemostasis would not affect the scoring; good=definite pain relief and/or improvement in signs of bleeding after a single infusion, possibly requires more than 2 infusions for complete resolution and administration of further infusion to maintain hemostasis would not affect the scoring; fair=probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion, required multiple infusions for complete resolution; none=no improvement of signs or symptoms or conditions worsen. Missing indicates the number of unique bleeding episodes without any overall hemostatic efficacy rating at resolution of breakthrough bleeding episode.	Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Number of Adynovate Infusions Per Bleeding Episode		Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Weight-adjusted Consumption of Adynovate Per Bleeding Episode	Weight-adjusted consumption (IU/kg) was derived as the total units infused (IU) divided by the last available body weight (kg) prior to the infusion.	Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Number of Minor Surgeries With Hemostatic Efficacy Based on Global Hemostatic Efficacy Assessment (GHEA) Score as Assessed by the Operating Surgeon/Investigator	GHEA score consisted 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). The scores of 3 individual ratings scales were added together to form a GHEA score. Total score ranged from 0 to 9, where scores evaluate as: excellent (7 to 9), good (5 to 7), fair (3 to 4), and none (0 to 2). For a GHEA score of 7 to be rated "excellent" no individual assessment scores could be less than (<) 2 and at least 1 assessment score had to be equal to (=) 3; otherwise a score of 7 was rated "good".	Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Number of Participants Who Required Perioperative Transfusion of Blood, Red Blood Cells, Platelets, and Other Blood Products		Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Daily Intra-Operative and Post-Operative Weight-Adjusted Consumption Dose of Adynovate		Baseline through study completion or ≥50 EDs whichever occurred last (approximately 28 weeks)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Treatment-emergent Adverse Events (Serious TEAEs)	An adverse event (AE): any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to medicinal product. TEAE: any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and within 30 days of the last administration of study drug. Serious TEAEs: any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is a medically important.	Up to approximately 28 weeks
Number of Participants With Confirmed Inhibitory Antibodies to Factor VIII (FVIII), Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies to Adynovate and Chinese Hamster Ovary (CHO) Protein		Up to approximately 28 weeks
FVIII Activity Level in Plasma Assessed by a 1-stage Clotting Assay	As per planned analysis, data for this outcome measure was collected and reported for initial pharmacokinetic (PK) assessment and second PK assessment. The initial PK assessment was performed prior to the baseline visit at Day -1. The second PK assessment was performed during the Week 20 visit. FVIII activity level reported was corrected for pre-infusion measurement.	Day -1 and Week 20: pre-infusion, post-infusion at multiple time-points up to 96 hours
Incremental Recovery Over Time During Adynovate Prophylactic Treatment	Incremental recovery (IR) was calculated as IR (international units per deciliter)/(international units per kilogram [(IU/dL)/(IU/kg)] = [PostFVIII (IU/dL)-PreFVIII (IU/dL)]/Weight Adjusted Dose (IU/kg).	Baseline, Week 6, and Study Completion (approximately Week 28)
Pre-dose Level of FVIII Activity in Plasma		Baseline, Weeks 2, 6, 12, and Study Completion (approximately Week 28): Within 30 minutes pre-infusion
Pre-dose Level of FVIII Antigen in Plasma	IU/mL stands for international units per milliliter.	Baseline, Weeks 2, 6, 12, 20, and Study Completion (approximately Week 28): Within 30 minutes pre-infusion
Pre-dose Level of Von Willebrand Factor (VWF) Antigen in Plasma		Baseline, Weeks 2, 6, 12, 20, and Study Completion (approximately Week 28): Within 30 minutes pre-infusion
Clearance (CL) for FVIII Activity Following an Initial Single Dose and Steady-state Dose of Adynovate	Clearance reported was calculated based on pre-infusion corrected concentration data. As per planned analysis, data for this outcome measure was collected and reported for initial PK assessment and second PK assessment. The initial PK assessment was performed prior to the baseline visit at Day -1. The second PK assessment was performed during the Week 20 visit. [(dL/h)/kg] stands for deciliters per hour per kilogram.	Day -1 and Week 20: pre-infusion, post-infusion at multiple timepoints up to 96 hours
Volume of Distribution for FVIII Activity Following an Initial Single Dose and Steady-state Dose of Adynovate	Volume of distribution was calculated based on pre-infusion corrected concentration data. As per planned analysis, data for this outcome measure was collected and reported for initial PK assessment and second PK assessment. The initial PK assessment was performed prior to the baseline visit at Day -1. The second PK assessment was performed during the Week 20 visit.	Day -1 and Week 20: pre-infusion, post-infusion at multiple timepoints up to 96 hours
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	AUC0-96 was calculated based on pre-infusion corrected concentration data. As per planned analysis, data for this outcome measure was collected and reported for initial PK assessment and second PK assessment. The initial PK assessment was performed prior to the baseline visit at Day -1. The second PK assessment was performed during the Week 20 visit. h*IU/dL stands for hour*international units per deciliter.	Day -1 and Week 20: pre-infusion, post-infusion at multiple timepoints up to 96 hours
Maximum Concentration (Cmax) for FVIII Activity Following an Initial Single Dose and Steady-state Dose of Adynovate	Cmax was calculated based on pre-infusion corrected concentration data. As per planned analysis, data for this outcome measure was collected and reported for initial PK assessment and second PK assessment. The initial PK assessment was performed prior to the baseline visit at Day -1. The second PK assessment was performed during the Week 20 visit.	Day -1 and Week 20: pre-infusion, post-infusion at multiple timepoints up to 96 hours
Pre-dose Concentration (Cpredose) for FVIII Activity Following an Initial Single Dose and Steady-state Dose of Adynovate	Cpredose was calculated based on pre-infusion corrected concentration data. As per planned analysis, data for this outcome measure was collected and reported for initial PK assessment and second PK assessment. The initial PK assessment was performed prior to the baseline visit at Day -1. The second PK assessment was performed during the Week 20 visit.	Day -1 and Week 20: pre-infusion, post-infusion at multiple timepoints up to 96 hours
Terminal Phase Elimination Half-life (T1/2) for FVIII Activity Following an Initial Single Dose and Steady-state Dose of Adynovate	T1/2 was calculated based on pre-infusion corrected concentration data. As per planned analysis, data for this outcome measure was collected and reported for initial PK assessment and second PK assessment. The initial PK assessment was performed prior to the baseline visit at Day -1. The second PK assessment was performed during the Week 20 visit.	Day -1 and Week 20: pre-infusion, post-infusion at multiple timepoints up to 96 hours

Collaborators and Investigators

• Sponsor: Takeda
• Investigators: Study Director: Medical Director, Takeda

Publications and helpful links

Helpful Links

• To obtain more information on the study, click here/on this link

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2023
• Primary Completion (Actual): September 5, 2024
• Study Completion (Actual): September 5, 2024

Study Registration Dates

• First Submitted: January 23, 2023
• First Submitted That Met QC Criteria: January 23, 2023
• First Posted (Actual): January 31, 2023

Study Record Updates

• Last Update Posted (Actual): May 1, 2025
• Last Update Submitted That Met QC Criteria: April 15, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Blood Coagulation Disorders; Hemorrhagic Disorders; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemophilia A; Coagulants; BAX 855; Factor VIII
• Other Study ID Numbers: TAK-660-3001; 2023-000502-26 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No