Gene Therapy for Chinese Hemophilia A (HA)

Clinical Exploration of Clinical Exploration Adeno-associated Virus Vector Expression of Human Coagulation Factor VIII Gene Therapy for Hemophilia A

IHBDH-GTHA-2020 is an open- label, non- randomized study to evaluate the safety, tolerability and kinetics of a single intravenous infusion of GS001 in hemophilia A subjects with <1 IU/dl residual FVIII levels.

Study Overview

• Status: Recruiting
• Conditions: Hemophilia A; Gene Therapy
• Intervention / Treatment: Genetic: Injection of GS001

Detailed Description

IHBDH-GTHA-2020 is a open- label, non- randomized study to evaluate the safety, tolerability and kinetics of GS001 in hemophilia A subjects with residual FVIII levels<1 IU/dl. The first patient will receive a single intravenous infusion of GS001 at a dose level of 2 x 10^12 vg/kg body weight. After three weeks of follow-up for the first patient post infusion of GS001, the dose of GS001 can be adjusted for the other two patients based on the activity level of FVIII:C and safety assessment. Following completion of the first 3 patients received GS001 infusion at 2 x 10^12 vg/kg dose level , the following 3 patients will continue to be enrolled to this dose group if there isn't any unexpected safety risk based on the assessments of FVIII expression and safety profile. The safety data and the activity level of FVIII:C from the first 6 subjects at 2 x 10^12 vg/kg dose level will undergo review by an independent DMC prior to dosing the first subject in the next dose level, DMC may recommend dose escalation to 6 x 10^12 vg/kg body weight or other recommended dose levels.

If the DMC recommends dose escalation to 6 x 10 ^12 vg/kg body weight or other recommended doses, at least 10 weeks of safety data and the activity level of FVIII:C post GS001 infusion from the first 3 subjects in this given dose level will undergo review by an independent DMC prior to dosing the following subjects. Based on the data from the first 3 subjects, DMC may recommend the dose adjustments for subsequent enrolled subjects, and expand the number of subject enrolled. Based on the safety, preliminary efficacy and vector kinetics profile of single intravenous infusions of GS001 at different dose levels in severe hemophilia A patients with endogenous factor FVIII activity levels ≤ 1% in this study, and based on the benefit-risk assessment of the subjects, the dose level to be administered for future larger clinical trial in patients with severe hemophilia A will be determined.

After all enrolled subjects have been followed for at least 12 weeks after intravenous infusion GS001, periodic analysis will be performed. Primary analysis of safety and efficacy will be performed 52 (± 2) weeks after intravenous infusion GS001, and all subjects will receive 52 (± 2) weeks of comprehensive safety and efficacy assessments. After completing the 52 (± 2) week visit (end-of-study visit), subjects will continue to be followed in this study for up to an additional 4 years for long-term safety and efficacy assessment to evaluate the long-term safety and efficacy of GS001 treatment.

A total of 12 to 15 subjects are expected to be enrolled in this study. Subjects will provide informed consent and then undergo screening assessments up to 4-8 weeks prior administration of GS001. All subjects will undergo 260 weeks (5 years) safety observation.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Wei Liu, MD; Phone Number: +82223909240; Email: liuwei1@ihcams.ac.cn
• Study Contact Backup: Name: Lei Zhang, MD; Phone Number: +82223909240; Email: zhanglei1@ihcams.ac.cn

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300020
      • Recruiting
      • Chinese Academy of Medical Science and Blood Disease Hospital
      • Contact: Shuo Chen, MD; Phone Number: +862223909240; Email: zhanglei1@ihcams.ac.cn
      • Contact: Jun L Liu, MD; Phone Number: +862223909095; Email: gcp@ihcams.ac.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Be able to understand the purpose and risks of the study and provide informed consent according to national and local privacy laws;
2. Male subjects and ≥ 18 years of age;
3. Have hemophilia A with ≤1 IU/dL (≤1%) endogenous FVIII activity levels at the time of screening. If the screening result is >1% due to previous treatment with FVIII product, then it may be confirmed by documented historical evidence from a certified clinical laboratory demonstrating ≤1% FVIII activity levels ;
4. No history of hypersensitivity or anaphylaxis associated with FVIII product administration;
5. Have no measurable FVII inhibitor as assessed by laboratory two times that were at least one week apart; or documented no prior history of FVIII inhibitor after 150 EDs and no clinical signs or symptoms of decreased response to FVIII infusion ;
6. Have acceptable laboratory values sampled at screening and repeated prior to Day 0; A. Hemoglobin ≥ 11 g/dL; B. Platelets ≥ 100 x 10^9/L; C. AST, ALT, alkaline phosphatase ≤ 1.25 upper limit of normal (ULN); D. Bilirubin ≤ 1.25 ULN; E. Creatinine ≤ 2 mg/dL.
7. Agree to use reliable barrier contraception until the end of the 52 weeks observation period, and three consecutive semen samples are negative for vector sequences after GS001 infusion.

Exclusion Criteria:

1. Have Hepatitis B, hepatitis C or HBsAg, HCVAb, HBV-DNA, HCV-RNA are positive and have clinical significance. Both natural clearers and those who have cleared HCV on antiviral therapy are deemed eligible;
2. Currently Receiving antiviral therapy for hepatitis B and C;
3. Have history of chronic infections or other chronic diseases that may pose a risk to the study participation;
4. Have participated in a previous gene therapy research trial within the last 52 weeks or in a clinical study with an investigational drug within the past 30 days;
5. The subject has any concurrent diseases that cannot tolerate treatments of prednisone or prednisolone as judged by the investigator;
6. History of arterial or venous thromboembolic events (e.g., deep vein thrombosis, non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolism);
7. Known inherited or acquired thrombophilia, including conditions associated with increased risk of thromboembolism, such as atrial fibrillation;
8. Major surgery planned in 1 year period following the infusion with GS001;
9. Hypersensitivity to the study vector;
10. Have clinically major diseases or any other unspecified conditions that, in the opinion of the Investigator, makes the subject unsuitable for participating in the study;
11. Patients who are unable or unwilling to comply with the schedule of visits and study assessments described in the clinical protocol;
12. Evidence of other bleeding disorders not associated with hemophilia A.

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: Treatment group; Arm of GS001	Genetic: Injection of GS001; Patients will be enrolled sequentially every 3 weeks or more between cohorts. Dose escalation may occur after a single patient has been safely dosed if the resulting FVIII activity at Week 3 is < 5 IU/dL.The dose levels are as follows: 2×10^12 vg/kg; 6×10^12vg/kg or other recommended doses; 2×10^13 vg/kg or other recommended doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment- related adverse events	Number of patients experiencing treatment-related adverse events.	From screening through up to the end of study (about 5 years).
Percentage of subjects in each dose group with newly occurred clinically significant abnormalities in physical examination compared to the baseline.	The number of subjects in each dose group with clinically significant changes in physical examination compared to the baseline.	From the start of study treatment (Day 1) through up to the end of study (about 5 years).
Changes of Weighted Mean of vital signs (systolic blood pressure [SBP] and diastolic blood pressure [DBP], pulse rate, temperature, respiratory rate) from baseline at each assessment time point for each dose group	The vital signs (SBP, DBP, pulse rate, temperature, respiratory rate) of the subjects were measured. The maximum, minimum, and mean observed values of vital signs (SBP, DBP, pulse rate, temperature, respiratory rate) from the dosing (Day 1) to the end of the study were calculated for each subject.	From the start of study treatment (Day 1) through up to the end of study (about 5 years).
Changes of Mean Alkaline Phosphatase (ALP), Alanine Amino Transferase (ALT), Aspartate Amio Transferase (AST) from baseline at each assessment time point for each dose group	Blood samples of subjects were collected for the evaluation of liver function throughout this study. All of these parameters are measured to help assess the condition of the liver. For ALP, AST and ALT, the percentage of subjects with the worst post-treatment results in each dose group will be summarized as follows: > 1.0 x ULN ≤ 1.5x ULN; > 1.5 x ULN ≤ 3.0 x ULN; > 3.0 x ULN ≤ 5.0 x ULN; > 5.0 x ULN	From the start of study treatment (Day 1) through up to the end of study (about 5 years).
Immune response to AAV capsid proteins	Changes in the expression levels of neutralizing and binding antibodies of AAV.	From screening period through up to 5 years.
Immune response to FVIII transgene	The changes of FVIII inhibitor and antibody levels	From screening period through up to 5 years.
Viral vector shedding of GS001	The vector shedding in serum, PMBC, saliva, urine, semen and feces will be monitored	From date of infusion until the date of 3 consecutive documented negative results, assessed up to 1 year.
Thrombosis risk assessment	For any individual who reaches >150% vector-derived FVIII: C activity levels following the infusion of GS001, laboratory parameters of thrombotic potential will be assessed.	From the start of study treatment (Day 1) through up to the end of study (about 5 years).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vector- derived FVIII:C and FVIII antigen levels	Vector- derived FVIII:C and FVIII antigen levels will be measured after dosing.	From pre-dose phase through up to 1 years post-dose
FVIII usage within 1 year after GS001 infusion	Number of FVIII replacement therapies and total utilization of exogenous FVIII (IU/kg) replacement therapy.	From week 3 to week 52 post GS001 infusion.
Number of bleeding events requiring exogenous FVIII replacement therapy within 1 year after GS001 infusion	Number of bleeding events (Spontaneous and Traumatic) requiring exogenous FVIII replacement therapy	Week 3 to Week 52 post GS001 Infusion
Number of bleeding events within 1 year after GS001 infusion	Number of bleeding events (spontaneous or traumatic) including untreated bleeding events	Week 3 to Week 52 post GS001 infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long-term FVIII: C activity Level	FVIII: C activity Level at Year 2 (Week 104), Year 3 (Week 156), Year 4 (Week 208), Year 5 (Week 260) post GS001 Infusion	From year 2 to year 5 post GS001 infusion.
Annualized number of bleeding episodesrequiring exogenous FVIII replacement therapy during long-term follow up.	Annualized number of bleeding episodes requiring exogenous FVIII replacement therapy during every one-year period from Years 2 to Year 5 (week 53 to week 260) post GS001 infusion	From year 2 to year 5 post GS001 infusion.
Total utilization of FVIII replacement therapy (IU/kg) per year for long-term follow up.	Total utilization of FVIII replacement therapy (IU/kg) per year from Years 2 to Year 5 (week 53 to week 260) post GS001 infusion	From year 2 to year 5 post GS001 infusion.
Annualized number of bleeding episodes (spontaneous and traumatic) per year for long-term follow up.	Annualized number of bleeding episodes (spontaneous and traumatic) per year including untreated bleeding episodes per year from Years 2 to Year 5 (week 53 to week 260) post GS001 infusion.	From year 2 to year 5 post GS001 infusion.
Target joints	Number of Target joints, International Hemophilia Prevention and Treatment Collaborative Group (IPSG) MRI score, changes in joint health score changes	From date of GS001 infusion until the end of study (about 5 years).
Level of Activity and hemophilia activities list	Changes in Level of Activity and hemophilia activities list	From date of GS001 infusion until the end of study (about 5 years).
Health-related quality of life	Health-related quality of life evaluated by EQ-5D, pain assessment	From date of GS001 infusion until the end of study (about 5 years).
Health economics evaluation	Health economic parameters include, but are not limited to, the following:number of hospitalizations, number of hospitalization days, number of emergency room visits, number of unscheduled visits, number of days off school or work.	From date of GS001 infusion until the end of study (about 5 years).

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China
• Investigators: Principal Investigator: lei zhang, MD, Chinese Academy of Medical Science and Blood Disease Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2021
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): July 31, 2028

Study Registration Dates

• First Submitted: January 25, 2021
• First Submitted That Met QC Criteria: January 27, 2021
• First Posted (Actual): January 28, 2021

Study Record Updates

• Last Update Posted (Actual): August 1, 2025
• Last Update Submitted That Met QC Criteria: July 31, 2025
• Last Verified: January 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
• Other Study ID Numbers: IIT2020030

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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