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An Open Label Study to Determine the Safety and Efficacy of Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection in Adolescent and Adult Patients With Hemophilia A.

Primary Purpose

Hemophilia A

Status

Completed

Phase

Phase 3

Locations

China

Study Type

Interventional

Intervention

Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection

About this trial

This is an interventional treatment trial for Hemophilia A focused on measuring Hemophilia A, Efficacy and Safety, Factor VIII-Fc Fusion Protein, Adolescent and Adult Patients, Phase III, Pharmacokinetics

Eligibility Criteria

12 Years - 60 Years (Child, Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

1)Male, aged 12 to 60 years
2)Severe hemophilia A. The activity of the coagulation factor VIII (FVIII:C) < 1%, and previously treated with FVIII concentrate (s) for a minimum of 150 exposure days (EDs) prior to study entry.
3) No history of a positive inhibitor test (< 0.6 BU) or clinical signs of decreased response to FVIII administrations within 2 years before the test or during the screening period. No Family history of inhibitors.
4) Non-immune deficiency, with a certain immune capacity (CD4 > 200/μL)
5) Platelet count > 100,000 platelets/μL.
6) Normal prothrombin time or INR < 1.3.
7) Normal previous results of vWF antigen examination.
8) Negative lupus anticoagulant.
9) the patient has a detailed record of bleeding events for at least 6 months (the subject can be admitted to the on-demand treatment group with spontaneous bleeding ≥3 times within 6 months).
10) Capable of understanding and willing to comply with the conditions of the protocol have read (patient and/or guardian).

Exclusion Criteria:

1) Hypersensitive to any of the excipients of the test materials (e.g. allergic to murine or hamster origin heterologous proteins).
2) History of hypersensitivity or anaphylaxis associated with any FVIII or II immunoglobulin administration.
3) Other coagulation disorder(s) in addition to hemophilia A.
4) Patients with severe heart disease, including myocardial infarction, heart failure (III or higher level).
5) Clinically significant of other systematic diseases: alcoholism, drug abuse, mental disorders and mental retardation.
6) Significant hepatic or renal impairment (ALT and AST > 2×ULN; serum bilirubin level > 3 × upper limit of normal (ULN), BUN > 2×ULN, Cr > 176.8µmol/L).
7) Patients who received any anticoagulant or antiplatelet therapy within one week prior screening or need to receive an anticoagulant or antiplatelet therapy during the period of clinical trials.
8) Patients having major surgery or receiving blood or blood components transfusion within 4 weeks prior screening or having planned major surgery schedule during the study.
9) Patients who previously participated in the other clinical trials within 1 month prior screening.
10) One or more clinically significant tests for Hepatitis B Virus Surface Antigen, Human Immunodeficiency Virus (HIV), Antisyphilitic spirulina (TPHA) and Hepatitis C Virus (HCV) Antibody.
11) Any life-threatening disease or condition which, according to the investigator's judgment, could not benefit from the trial participation.
12) Patient who is considered by the other investigators not suitable for clinical study.

NOTE:Other protocol-defined Inclusion/Exclusion criteria may apply.

Sites / Locations

Anhui Provincial Hospital
Capital Medical University affiliated Beijing Children's Hospital
Chongqing Three Gorges Central Hospital
Fujian Medical University Union Hospital
The First Hospital of Lanzhou University
The Second Affiliated Hospital of Guangzhou Medical University
Nanfang Hospital of Southern Medical University
The Affiliated Hospital of Guizhou Medical University
Henan provincial People's Hospital
Henan Cancer Hospital
Xiangya Hospital of Central South University
The Affiliated Hospital of Xuzhou Medical College
Jiangxi Provincial People's Hospital
Jinan central hospital
The Affiliated Hospital of Qingdao University
The Second Hospital of Shanxi Medical University
Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm 1-on demand treatment

Arm 2- prophylaxis treatment

Arm Description

Part A-Participants will receive on-demand treatment with Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection for 6 months.

Part B-Participants will receive prophylaxis treatment with Recombinant Human Coagulation Factor VIII-Fc fusion for 6 months. 12 Participants of them will receive PK assessment at ED1 and ED35(Participants will be tested for PK assessment at timepoints throughout the study based on exposure days (ED). One ED is equivalent to a 24 hours period in which drug is dosed.)，measured by one-stage assay, they would not be given prophylaxis treatment until the completion of PK blood collection.

Outcomes

Primary Outcome Measures

Part A - score of bleeding symptoms and Vital signs.

Response to treatment with rFVIIIFc for bleeding episodes, using the 4-point bleeding response scale.

Part B- Annualized Bleeding Rates(ABR).

Annualized bleeding rate = (number of bleeding episodes during the efficacy, period/total number of days during the efficacy period)*365.25. The efficacy period begins with the first prophylactic dose of FRSW107 and ends with the last dose (for prophylaxis or a bleed). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. A bleeding episode started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. Any injection to treat the bleeding episode taken more than 72 hours after the preceding one was considered the first injection to treat a new bleeding episode at the same location. Any bleeding at a different location was considered a separate bleeding episode, regardless of time from last injection.

Part B-Number of target joints.

The joint with ≥3 times of spontaneous bleeding in 6 consecutive months is the target joint, while the joint with < 2 times of bleeding in 12 consecutive months is no longer the target joint.

Secondary Outcome Measures

Part A-rFVIIIFc incremental recovery (IR).

Incremental recovery of Factor VIII (FVIII) within 1 hour after end of infusions was determined and mean recovery values were reported.

Part A -Total Dose Required for Resolution of a Bleeding Episode.

The total dose required to resolve a bleeding episode per participant, based on the efficacy period. The efficacy period begins with the first dose and ends with the last dose (for a bleed). For 'Per bleeding episode' values, for each bleeding episode, the total dose is the sum of the doses (IU/kg) administered across all injections given to treat that bleeding episode. For 'Per participant' values, the total dose (IU/kg) used to resolve each bleed is averaged across all bleeding episodes per participant.Quality of life assessment.

Part A -Number of injections required to resolve a bleeding episode.

The number of injections required to resolve a bleeding episode per participant, based on the efficacy period. The efficacy period begins with the first dose and ends with the last dose (for a bleed). All injections given from the initial sign of a bleed, until the last date/time within the bleed window are counted. The resolution of a bleed is defined as no sign of bleeding following injection for the bleed. For 'Per participant' values, the number of injections required to resolve each bleed is averaged across all bleeding episodes per participant.

Part A -Quality of life assessment.

Quality of life assessment by Haemophilia Joint Health Score（HJHS）.

Part B -Number of injections required to resolve a bleeding episode.

The number of injections required to resolve a bleeding episode per participant, based on the efficacy period. The efficacy period begins with the first prophylactic dose and ends with the last dose (for prophylaxis or a bleed). All injections given from the initial sign of a bleed, until the last date/time within the bleed window are counted. The resolution of a bleed is defined as no sign of bleeding following injection for the bleed. For 'Per participant' values, the number of injections required to resolve each bleed is averaged across all bleeding episodes per participant.

Part B -Quality of life assessment.

Quality of life assessment by Haemophilia Joint Health Score(HJHS).

Part B -Number of participants with inhibitor development

Number of participants who developed a positive FVIII inhibitor level (≥0.6 Bethesda unit [BU]) during the study was summarized and classified as participants developing low titer inhibitor (i.e. ≤ 5.0 BU) and participants developing high titer inhibitor (i.e. > 5.0 BU).

Part B - Number of Participants With Incidence of Antibody Formation to CHINESE HAMSTER OVARY (CHO).

A test to analyze the formation of antibodies to CHO.

Part B -Number of All Bleeds.

The annualized number of bleeds experienced by participants.

Part B-Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay

Maximum measured concentration of rFVIIIFc.

Part B-Half-life (t½) as Measured by aPTT Clotting Assay

Time required for the concentration of the drug to reach half of its original value.

Part B-Clearance (CL) as Measured by the aPTT Clotting Assay

The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.

Part B-Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay.

The apparent volume of distribution at steady state. (Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.).

Part B-Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay.

The average time at which the number of absorbed molecules reside in the body, after single-dose administration.

Part B-Time of Cmax (Tmax) as Measured by aPTT Clotting Assay.

Time at which maximum activity (Cmax) is observed.

Part B-Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay.

Area under the plasma concentration time-curve from zero to the last measured concentration.

Full Information

NCT ID

NCT04456387

First Posted

June 22, 2020

Last Updated

August 24, 2023

Sponsor

Zhengzhou Gensciences Inc

1. Study Identification

Unique Protocol Identification Number

NCT04456387

Brief Title

An Open Label Study to Determine the Safety and Efficacy of Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection in Adolescent and Adult Patients With Hemophilia A.

Official Title

An Open-Label, Multicenter Evaluation of the Safety and Efficacy of Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection (FRSW107) in Adolescent and Adult Patients With Hemophilia A.

Study Type

Interventional

2. Study Status

Record Verification Date

October 2020

Overall Recruitment Status

Completed

Study Start Date

October 15, 2020 (Actual)

Primary Completion Date

September 30, 2021 (Actual)

Study Completion Date

September 30, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Zhengzhou Gensciences Inc

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

The primary objectives of the study are to evaluate the efficacy of Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection (FRSW107) in the Prevention and Treatment of Bleeding in patients with hemophilia A. The secondary objectives are to evaluate the efficacy and safety of Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection (FRSW107) in the prevention and treatment of bleeding episodes, to investigate the quality of life in patients who used the FRSW107.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hemophilia A

Keywords

Hemophilia A, Efficacy and Safety, Factor VIII-Fc Fusion Protein, Adolescent and Adult Patients, Phase III, Pharmacokinetics

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

119 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1-on demand treatment

Arm Type

Experimental

Arm Description

Part A-Participants will receive on-demand treatment with Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection for 6 months.

Arm Title

Arm 2- prophylaxis treatment

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection

Intervention Description

Participants received on-demand treatment, doses range from 30 IU/kg to 50 IU/kg, or doses divided on the discretion of the Investigator.

Intervention Type

Drug

Intervention Name(s)

Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection

Intervention Description

Participants received prophylaxis treatment at 50 IU/kg every three days.

Primary Outcome Measure Information:

Title

Part A - score of bleeding symptoms and Vital signs.

Description

Response to treatment with rFVIIIFc for bleeding episodes, using the 4-point bleeding response scale.

Time Frame

For the duration of study participation, 6 months.

Title

Part B- Annualized Bleeding Rates(ABR).

Description

Time Frame

For the duration of study participation, 6 months.

Title

Part B-Number of target joints.

Description

The joint with ≥3 times of spontaneous bleeding in 6 consecutive months is the target joint, while the joint with < 2 times of bleeding in 12 consecutive months is no longer the target joint.

Time Frame

For the duration of study participation, 6 months.

Secondary Outcome Measure Information:

Title

Part A-rFVIIIFc incremental recovery (IR).

Description

Incremental recovery of Factor VIII (FVIII) within 1 hour after end of infusions was determined and mean recovery values were reported.

Time Frame

For the duration of study participation, 6 months.

Title

Part A -Total Dose Required for Resolution of a Bleeding Episode.

Description

Time Frame

For the duration of study participation, 6 months.

Title

Part A -Number of injections required to resolve a bleeding episode.

Description

Time Frame

For the duration of study participation, 6 months.

Title

Part A -Quality of life assessment.

Description

Quality of life assessment by Haemophilia Joint Health Score（HJHS）.

Time Frame

For the duration of study participation, 6 months.

Title

Part B -Number of injections required to resolve a bleeding episode.

Description

Time Frame

For the duration of study participation, 6 months.

Title

Part B -Quality of life assessment.

Description

Quality of life assessment by Haemophilia Joint Health Score(HJHS).

Time Frame

For the duration of study participation, 6 months.

Title

Part B -Number of participants with inhibitor development

Description

Time Frame

6 months and at least 50 exposure days.

Title

Part B - Number of Participants With Incidence of Antibody Formation to CHINESE HAMSTER OVARY (CHO).

Description

A test to analyze the formation of antibodies to CHO.

Time Frame

before and the duration of study participation, 6 months.

Title

Part B -Number of All Bleeds.

Description

The annualized number of bleeds experienced by participants.

Time Frame

before and the duration of study participation, 6 months.

Title

Part B-Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay

Description

Maximum measured concentration of rFVIIIFc.

Time Frame

Samples taken at pre-injection, and post dose up to 96 hours at ED1 and ED35(Participants will be tested for PK assessment at timepoints throughout the study based on exposure days (ED). One ED is equivalent to a 24 hours period in which drug is dosed.).

Title

Part B-Half-life (t½) as Measured by aPTT Clotting Assay

Description

Time required for the concentration of the drug to reach half of its original value.

Time Frame

Title

Part B-Clearance (CL) as Measured by the aPTT Clotting Assay

Description

The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.

Time Frame

Title

Part B-Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay.

Description

Time Frame

Title

Part B-Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay.

Description

The average time at which the number of absorbed molecules reside in the body, after single-dose administration.

Time Frame

Title

Part B-Time of Cmax (Tmax) as Measured by aPTT Clotting Assay.

Description

Time at which maximum activity (Cmax) is observed.

Time Frame

Title

Part B-Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay.

Description

Area under the plasma concentration time-curve from zero to the last measured concentration.

Time Frame

Other Pre-specified Outcome Measures:

Title

Part B-Response to treatment of bleeds.

Description

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.

Time Frame

the duration of study participation, 6 months.

Title

Number of Participants With Adverse Events (AEs) and Serious Adverse Events. (SAEs) as a Measure of Safety and Tolerability

Description

An AE is any untoward medical occurrence that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition.

Time Frame

the duration of study participation, 6 months.

10. Eligibility

Sex

Male

Gender Based

Yes

Gender Eligibility Description

Hemophilia A is an X-chromosome-linked recessive inherited bleeding disorder caused by a deficiency of coagulation factor VIII (FVIII).

Minimum Age & Unit of Time

12 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 1)Male, aged 12 to 60 years 2)Severe hemophilia A. The activity of the coagulation factor VIII (FVIII:C) < 1%, and previously treated with FVIII concentrate (s) for a minimum of 150 exposure days (EDs) prior to study entry. 3) No history of a positive inhibitor test (< 0.6 BU) or clinical signs of decreased response to FVIII administrations within 2 years before the test or during the screening period. No Family history of inhibitors. 4) Non-immune deficiency, with a certain immune capacity (CD4 > 200/μL) 5) Platelet count > 100,000 platelets/μL. 6) Normal prothrombin time or INR < 1.3. 7) Normal previous results of vWF antigen examination. 8) Negative lupus anticoagulant. 9) the patient has a detailed record of bleeding events for at least 6 months (the subject can be admitted to the on-demand treatment group with spontaneous bleeding ≥3 times within 6 months). 10) Capable of understanding and willing to comply with the conditions of the protocol have read (patient and/or guardian). Exclusion Criteria: 1) Hypersensitive to any of the excipients of the test materials (e.g. allergic to murine or hamster origin heterologous proteins). 2) History of hypersensitivity or anaphylaxis associated with any FVIII or II immunoglobulin administration. 3) Other coagulation disorder(s) in addition to hemophilia A. 4) Patients with severe heart disease, including myocardial infarction, heart failure (III or higher level). 5) Clinically significant of other systematic diseases: alcoholism, drug abuse, mental disorders and mental retardation. 6) Significant hepatic or renal impairment (ALT and AST > 2×ULN; serum bilirubin level > 3 × upper limit of normal (ULN), BUN > 2×ULN, Cr > 176.8µmol/L). 7) Patients who received any anticoagulant or antiplatelet therapy within one week prior screening or need to receive an anticoagulant or antiplatelet therapy during the period of clinical trials. 8) Patients having major surgery or receiving blood or blood components transfusion within 4 weeks prior screening or having planned major surgery schedule during the study. 9) Patients who previously participated in the other clinical trials within 1 month prior screening. 10) One or more clinically significant tests for Hepatitis B Virus Surface Antigen, Human Immunodeficiency Virus (HIV), Antisyphilitic spirulina (TPHA) and Hepatitis C Virus (HCV) Antibody. 11) Any life-threatening disease or condition which, according to the investigator's judgment, could not benefit from the trial participation. 12) Patient who is considered by the other investigators not suitable for clinical study. NOTE:Other protocol-defined Inclusion/Exclusion criteria may apply.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Renchi Yang, PhD

Organizational Affiliation

Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College

Official's Role

Principal Investigator

Facility Information:

Facility Name

Anhui Provincial Hospital

City

Hefei

State/Province

Anhui

ZIP/Postal Code

230001

Country

China

Facility Name

Capital Medical University affiliated Beijing Children's Hospital

City

Beijing

State/Province

Beijing

ZIP/Postal Code

100045

Country

China

Facility Name

Chongqing Three Gorges Central Hospital

City

Chongqing

State/Province

Chongqing

ZIP/Postal Code

404000

Country

China

Facility Name

Fujian Medical University Union Hospital

City

Fuzhou

State/Province

Fujian

ZIP/Postal Code

350001

Country

China

Facility Name

The First Hospital of Lanzhou University

City

Lanzhou

State/Province

Gansu

ZIP/Postal Code

730000

Country

China

Facility Name

The Second Affiliated Hospital of Guangzhou Medical University

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510260

Country

China

Facility Name

Nanfang Hospital of Southern Medical University

City

Guangzhou

State/Province

Guangzhou

ZIP/Postal Code

510515

Country

China

Facility Name

The Affiliated Hospital of Guizhou Medical University

City

Guiyang

State/Province

Guizhou

ZIP/Postal Code

550004

Country

China

Facility Name

Henan provincial People's Hospital

City

Zhengzhou

State/Province

Henan

ZIP/Postal Code

450003

Country

China

Facility Name

Henan Cancer Hospital

City

Zhengzhou

State/Province

Henan

ZIP/Postal Code

450008

Country

China

Facility Name

Xiangya Hospital of Central South University

City

Changsha

State/Province

Hunan

ZIP/Postal Code

410013

Country

China

Facility Name

The Affiliated Hospital of Xuzhou Medical College

City

Xuzhou

State/Province

Jiangsu

ZIP/Postal Code

221000

Country

China

Facility Name

Jiangxi Provincial People's Hospital

City

Nanchang

State/Province

Jiangxi

ZIP/Postal Code

330006

Country

China

Facility Name

Jinan central hospital

City

Ji'nan

State/Province

Shandong

ZIP/Postal Code

250013

Country

China

Facility Name

The Affiliated Hospital of Qingdao University

City

QingDao

State/Province

Shandong

ZIP/Postal Code

266000

Country

China

Facility Name

The Second Hospital of Shanxi Medical University

City

Taiyuan

State/Province

Shanxi

ZIP/Postal Code

030001

Country

China

Facility Name

Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College

City

Tianjin

State/Province

Tianjin

ZIP/Postal Code

300020

Country

China

12. IPD Sharing Statement

Learn more about this trial

An Open Label Study to Determine the Safety and Efficacy of Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection in Adolescent and Adult Patients With Hemophilia A.

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