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

• ClinicalTrials.gov Identifier: NCT04211480
• Recruitment Status: Active, not recruiting
• First Posted: December 26, 2019
• Last Update Posted: October 12, 2022
• Sponsor: Bioray Laboratories
• Collaborators: Xiangya Hospital of Central South University; PLA 923 Hospital
• Information provided by (Responsible Party): Bioray Laboratories

Tracking Information

• First Submitted Date: December 23, 2019
• First Posted Date: December 26, 2019
• Last Update Posted Date: October 12, 2022
• Actual Study Start Date: April 1, 2020
• Estimated Primary Completion Date: October 15, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 26, 2022)

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

• Original Primary Outcome Measures (submitted: December 24, 2019): Incidence and Severity of Adverse Events as a Measure of Safety and Tolerability Adverse events assessed according to NCI-CTCAE v4.03 criteria [ Time Frame: up to 6 months post transplant ]

Current Secondary Outcome Measures (submitted: March 26, 2022)

Efficacy evaluation of γ-globin reactivated autologous hematopoietic stem cells [ Time Frame: up to 24 months post transplant ]

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.

Original Secondary Outcome Measures (submitted: December 24, 2019)

efficacy of β-globin restored autologous hematopoietic stem cells [ Time Frame: 12 months post transplant ]

Independence on blood transfusion post transplant; Or, The amount of red cell transfusion in a year post transplant reduced 50% than that of the last year.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy Evaluation of γ-globin Reactivated Autologous Hematopoietic Stem Cells
• Official Title: 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
• Brief Summary: 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.
• 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
• Study Phase: Not Applicable
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: β Thalassemia Major

Intervention

Biological: γ-globin reactivated autologous hematopoietic stem cells

gene edited autologous hematopoietic stem cells with γ-globin expression

Study Arms

Experimental: γ-globin reactivated autologous hematopoietic stem cells

each subject will accept one dose of γ-globin reactivated autologous hematopoietic stem cells

Intervention: Biological: γ-globin reactivated autologous hematopoietic stem cells

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: October 9, 2022): 6
• Original Estimated Enrollment (submitted: December 24, 2019): 12
• Estimated Study Completion Date: December 1, 2023
• Estimated Primary Completion Date: October 15, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 5 Years to 15 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT04211480
• Other Study ID Numbers: 2019-BRL-00CH1
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol
• Time Frame: IPD sharing will begin at 6 months and end at 36 months following article publication.
• 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.

• Current Responsible Party: Bioray Laboratories
• Original Responsible Party: Same as current
• Current Study Sponsor: Bioray Laboratories
• Original Study Sponsor: Same as current

Collaborators

• Xiangya Hospital of Central South University
• PLA 923 Hospital

Investigators

• Principal Investigator: Bin Fu, Prof.; Xiangya Hospital Central University

• PRS Account: Bioray Laboratories
• Verification Date: October 2022