Safety and Efficacy Evaluation of γ-globin Reactivated Autologous Hematopoietic Stem Cells

an Open Label Trial of Evaluation of the Safety and Efficacy of Treatment With γ-globin Reactivated Autologous Hematopoietic Stem Cells in Subjects With β-thalassemia Major

This is a non-randomized, open label, single-dose, phase 1/2 study in up to 12 participants with β-thalassemia major.This study aims to evaluate the safety and efficacy of the treatment with γ-globin reactivated autologous hematopoietic stem cells in subjects with β-thalassemia major.

Study Overview

• Status: Completed
• Conditions: β Thalassemia Major
• Intervention / Treatment: Biological: γ-globin reactivated autologous hematopoietic stem cells

Detailed Description

γ-globin reactivated autologous hematopoietic stem cells will be manufactured using Crispr/Cas9 gene editing system. Subject participation for this study will be 1 year. Subjects who enroll in this study will be asked to participate in a subsequent long-term follow up study that will monitor the safety and efficacy of the treatment they receive for up to 15 years post-transplant.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200241
      • Shanghai Bioray Laboratories Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 15 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Fully understand and voluntarily sign informed consent. 5-15years old. At least one legal guardian and/or Subjects to sign informed consent.
• Clinically diagnosed as β-thalassemia major, phenotypes including β0β0, β+β0,βEβ0 genotype.
• Subjects with no affection with EBV, HIV, CMV, TP, HAV, HBV and HCV.
• Subjects body condition eligible for autologous stem cell transplant.

Exclusion Criteria:

• Subjects acceptable for allogeneic hematopoietic stem cell transplantation and have an available fully matched related donor.
• Active bacterial, viral, or fungal infection.
• Treated with erythropoietin prior 3 months.
• Immediate family member with any known hematological tumor.
• Subjects with severe psychiatric disorders to be unable to cooperate.
• Recently diagnosed as malaria.
• History of complex autoimmune disease.
• Persistent aspartate transaminase (AST), alanine transaminase (ALT), or total bilirubin value >3 X the upper limit of normal (ULN).
• Subjects with severe heart, lung and kidney diseases.
• With serious iron overload, serum ferritin>5000mg/ml.
• Any other condition that would render the subject ineligible for HSCT, as determined by the attending transplant physician or Investigator.
• Subjects who are receiving treatment from another clinical study, or have received another gene therapy.
• Subjects or guardians had resisted the guidance of the attending doctor.
• Subjects whom the investigators do not consider appropriate for participating in this clinical study.

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: γ-globin reactivated autologous hematopoietic stem cells; each subject will accept one dose of γ-globin reactivated autologous hematopoietic stem cells	Biological: γ-globin reactivated autologous hematopoietic stem cells; gene edited autologous hematopoietic stem cells with γ-globin expression

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety evaluation of γ-globin reactivated autologous hematopoietic stem cells	Proportion of subjects with engraftment; Overall survival.	up to 24 months post transplant
Incidence and severity of adverse events as a measure of safety and tolerability. Adverse events assessed according to NCI-CTCAE v5.0 criteria	Incidence of AEs and SAEs post transplant	up to 24 months post transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy evaluation of γ-globin reactivated autologous hematopoietic stem cells	Proportion of subjects achieving transfusion independence for at least 6 months (TI6); Proportion of subjects achieving TI12; Proportion of alleles with intended genetic modification in bone marrow cells; Change in total hemoglobin concentration; Change from baseline in annualized frequency and volume of packed RBC transfusions.	up to 24 months post transplant

Collaborators and Investigators

• Sponsor: Bioray Laboratories
• Collaborators: Xiangya Hospital of Central South University; The 923rd Hospital of Joint Logistics Support Force of People's Liberation Army
• Investigators: Principal Investigator: Bin Fu, Prof., Xiangya Hospital Central University

Publications and helpful links

General Publications

• Brusson M, Miccio A. Genome editing approaches to beta-hemoglobinopathies. Prog Mol Biol Transl Sci. 2021;182:153-183. doi: 10.1016/bs.pmbts.2021.01.025. Epub 2021 Mar 1.
• Fu B, Liao J, Chen S, Li W, Wang Q, Hu J, Yang F, Hsiao S, Jiang Y, Wang L, Chen F, Zhang Y, Wang X, Li D, Liu M, Wu Y. CRISPR-Cas9-mediated gene editing of the BCL11A enhancer for pediatric beta0/beta0 transfusion-dependent beta-thalassemia. Nat Med. 2022 Aug;28(8):1573-1580. doi: 10.1038/s41591-022-01906-z. Epub 2022 Aug 4.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2020
• Primary Completion (Actual): October 15, 2023
• Study Completion (Actual): November 27, 2023

Study Registration Dates

• First Submitted: December 23, 2019
• First Submitted That Met QC Criteria: December 24, 2019
• First Posted (Actual): December 26, 2019

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 4, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Thalassemia; beta-Thalassemia
• Other Study ID Numbers: 2019-BRL-00CH1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data (IPD) that underlie the results reported in published article will be shared, after deidentification (text, tables,figures and appendices). Other available documents include study protocol.
• IPD Sharing Time Frame: IPD sharing will begin at 6 months and end at 36 months following article publication.
• IPD Sharing Access Criteria: IPD will be shared with investigators for individual data meta-analysis, after their proposed use of the data has been approved by an independent review committee. Proposals should be directed to yxwu@bio.ecnu.edu.cn and fu.bin@csu.edu.cn. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No