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Safety and Efficacy Evaluation of Autologous CRISPR-Cas12b Edited Hematopoietic Stem Cells

Primary Purpose

Thalassemia, Beta, Thalassemia Major

Status
Recruiting
Phase
Not Applicable
Locations
China
Study Type
Interventional
Intervention
VGB-Ex01
Sponsored by
Institute of Hematology & Blood Diseases Hospital, China
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Thalassemia, Beta

Eligibility Criteria

3 Years - 35 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Age 3-35 years old (inclusive), male or female; The subject and/or his/her legally recognized representative/parent/guardian fully understands the study and all information related to the study and has signed the informed consent form; Clinical diagnosis of transfusion-dependent β-thalassemia (TDT) with a blood transfusion record within 2 years (inclusive) prior to screening showing a history of ≥ 10 units (U)/kg/year (or ≥ 100 mL/kg/year) or ≥ 8 times/year of suspended RBC transfusions in at least 1 consecutive 12-month period; Karnofsky score (for subjects aged ≥ 16 years) or Lansky score (for subjects aged < 16 years) of ≥ 80; Subjects in stable disease state who are eligible for hematopoietic stem cell transplantation as per investigator's judgment; Access to diagnosis and treatment records issued by medical professional institutions within 2 years prior to screening, including the records of blood transfusions, hematology, serum chemistry, and other examinations; Willing and able to comply with study procedures, with good compliance, and willing to receive and complete the follow-up study with a duration of at least 2 years; Subjects of childbearing potential (including female subjects of childbearing potential and male subjects whose partners are of childbearing potential) must use effective contraception within 12 months of treatment. Exclusion Criteria: Diagnosis of associated α-thalassemia: > 1 alpha chain deletion or alpha gene functional defect; Have available HLA-fully matched donors and acceptable for allogeneic hematopoietic stem cell transplantation; Irregular antibody or platelet antibody positive; Prior allogeneic bone marrow transplantation or gene therapy; Subjects with clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator at screening, including but not limited to those with positive etiology of human immunodeficiency virus (HIV-1/2), human cytomegalovirus (HCMV-DNA), Epstein-Barr virus (EBV-DNA), or Treponema pallidum antibody (TP-Ab), or with previous hepatitis B or C infection; Subjects with an injury of major organs Contraindications for hematopoietic stem cell collection and poor collection efficiency judged by the investigator; Contraindications to the clinical investigational product and its excipients, G-CSF (hematopoietic stem cell mobilization), plerixafor (hematopoietic stem cell mobilization), busulfan (myeloablation), and other drugs; Participation within 3 months prior to screening or current participation in another interventional clinical study; History or family history of malignancy or myeloproliferative disorder; History of uncontrollable epilepsy, mental disorder, or other psychiatric disorders; Abuse of psychoactive substance, drug, or alcohol within 6 months prior to enrollment; Pregnant or breastfeeding females; Other diseases or reasons that interfere with study procedures; Any other conditions that the investigator deems unsuitable for the subject's participation in the study.

Sites / Locations

  • Regenerative Medicine CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

VGB-Ex01

Arm Description

Each subject will accept one dose of VGB-Ex01.

Outcomes

Primary Outcome Measures

Incidence of adverse events and serious adverse events
An adverse event is any untoward medical occurrence in a clinical investigation/participant administered a product; the event will not need to have a causal relationship with the treatment. A serious adverse event is any untoward medical occurrence at any dose that resulted in death; life threatening;require inpatient hospitalization or prolongation of existing hospitalization; result in persistent or significant disability/incapacity; result in congenital anomaly/birth defect.
Number of subjects with neutrophil implantation ≤ 42 days
Neutrophil implantation was defined as 3 consecutive days with 3 tests for ANC≥500/μL.

Secondary Outcome Measures

Number of subjects transfusion independence (TI) for at least 6 months after transfusion
TI defined as Hb≥9g/dL without red blood cell infusion
Number of subjects transfusion independence (TI) for at least 12 months after transfusion
TI defined as Hb≥9g/dL without red blood cell infusion
Fetal hemoglobin (HbF) concentration
Changes in HbF concentration from baseline after transfusion
Total hemoglobin (Hb) concentration
Changes in Hb concentration compared with baseline after transfusion
The proportion of circulating red blood cells
Changes in the proportion of circulating red blood cells expressing fetal hemoglobin compared to baseline

Full Information

First Posted
September 11, 2023
Last Updated
October 16, 2023
Sponsor
Institute of Hematology & Blood Diseases Hospital, China
Collaborators
Shanghai Vitalgen BioPharma Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT06041620
Brief Title
Safety and Efficacy Evaluation of Autologous CRISPR-Cas12b Edited Hematopoietic Stem Cells
Official Title
A Study to Evaluate the Efficacy and Safety of Autologous CRISPR-Cas12b Edited Hematopoietic Stem Cells in Transfusion-dependent β Thalassemia Patients
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 31, 2023 (Actual)
Primary Completion Date
December 31, 2025 (Anticipated)
Study Completion Date
June 30, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Institute of Hematology & Blood Diseases Hospital, China
Collaborators
Shanghai Vitalgen BioPharma Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a single-arm, open, single-injection exploratory clinical study with two transfusion-dependent β thalassemia (β-TDT) participants planned to enroll.
Detailed Description
Through CRISPR-Cas 12b editing tool with independent intellectual property rights of Chinese Academy of Sciences, HBG1/2 promoter was edited to reactivate gamma-globin and induce fetal hemoglobin (HbF) expression. This leads to a subsequent reduction in ineffective red blood cell production (due to a reduction in the uncompounded alpha-globin chain) and improved red blood cell survival (due to reduced hemolysis), ultimately improving the sequelae of anemia and reducing the need for transfusion. Safety and efficacy will be evaluated continuously throughout the study, follow-up was up to 24 months. After the end of this trial, participants who received the infusion of autologous CRISPR-Cas12b edited hematopoietic stem cells (VGB-Ex01) will be invited to participate in the long-term follow-up study to complete the 15-year follow-up plan.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
VGB-Ex01
Arm Type
Experimental
Arm Description
Each subject will accept one dose of VGB-Ex01.
Intervention Type
Biological
Intervention Name(s)
VGB-Ex01
Intervention Description
CRISPR-Cas12b editing hematopoietic stem cells
Primary Outcome Measure Information:
Title
Incidence of adverse events and serious adverse events
Description
An adverse event is any untoward medical occurrence in a clinical investigation/participant administered a product; the event will not need to have a causal relationship with the treatment. A serious adverse event is any untoward medical occurrence at any dose that resulted in death; life threatening;require inpatient hospitalization or prolongation of existing hospitalization; result in persistent or significant disability/incapacity; result in congenital anomaly/birth defect.
Time Frame
Baseline up to 24 months
Title
Number of subjects with neutrophil implantation ≤ 42 days
Description
Neutrophil implantation was defined as 3 consecutive days with 3 tests for ANC≥500/μL.
Time Frame
Baseline up to 42 days
Secondary Outcome Measure Information:
Title
Number of subjects transfusion independence (TI) for at least 6 months after transfusion
Description
TI defined as Hb≥9g/dL without red blood cell infusion
Time Frame
Baseline up to 6 months
Title
Number of subjects transfusion independence (TI) for at least 12 months after transfusion
Description
TI defined as Hb≥9g/dL without red blood cell infusion
Time Frame
Baseline up to 12 months
Title
Fetal hemoglobin (HbF) concentration
Description
Changes in HbF concentration from baseline after transfusion
Time Frame
Baseline up to 24 months
Title
Total hemoglobin (Hb) concentration
Description
Changes in Hb concentration compared with baseline after transfusion
Time Frame
Baseline up to 24 months
Title
The proportion of circulating red blood cells
Description
Changes in the proportion of circulating red blood cells expressing fetal hemoglobin compared to baseline
Time Frame
Baseline up to 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 3-35 years old (inclusive), male or female; The subject and/or his/her legally recognized representative/parent/guardian fully understands the study and all information related to the study and has signed the informed consent form; Clinical diagnosis of transfusion-dependent β-thalassemia (TDT) with a blood transfusion record within 2 years (inclusive) prior to screening showing a history of ≥ 10 units (U)/kg/year (or ≥ 100 mL/kg/year) or ≥ 8 times/year of suspended RBC transfusions in at least 1 consecutive 12-month period; Karnofsky score (for subjects aged ≥ 16 years) or Lansky score (for subjects aged < 16 years) of ≥ 80; Subjects in stable disease state who are eligible for hematopoietic stem cell transplantation as per investigator's judgment; Access to diagnosis and treatment records issued by medical professional institutions within 2 years prior to screening, including the records of blood transfusions, hematology, serum chemistry, and other examinations; Willing and able to comply with study procedures, with good compliance, and willing to receive and complete the follow-up study with a duration of at least 2 years; Subjects of childbearing potential (including female subjects of childbearing potential and male subjects whose partners are of childbearing potential) must use effective contraception within 12 months of treatment. Exclusion Criteria: Diagnosis of associated α-thalassemia: > 1 alpha chain deletion or alpha gene functional defect; Have available HLA-fully matched donors and acceptable for allogeneic hematopoietic stem cell transplantation; Irregular antibody or platelet antibody positive; Prior allogeneic bone marrow transplantation or gene therapy; Subjects with clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator at screening, including but not limited to those with positive etiology of human immunodeficiency virus (HIV-1/2), human cytomegalovirus (HCMV-DNA), Epstein-Barr virus (EBV-DNA), or Treponema pallidum antibody (TP-Ab), or with previous hepatitis B or C infection; Subjects with an injury of major organs Contraindications for hematopoietic stem cell collection and poor collection efficiency judged by the investigator; Contraindications to the clinical investigational product and its excipients, G-CSF (hematopoietic stem cell mobilization), plerixafor (hematopoietic stem cell mobilization), busulfan (myeloablation), and other drugs; Participation within 3 months prior to screening or current participation in another interventional clinical study; History or family history of malignancy or myeloproliferative disorder; History of uncontrollable epilepsy, mental disorder, or other psychiatric disorders; Abuse of psychoactive substance, drug, or alcohol within 6 months prior to enrollment; Pregnant or breastfeeding females; Other diseases or reasons that interfere with study procedures; Any other conditions that the investigator deems unsuitable for the subject's participation in the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jun Shi, PhD
Phone
13752253515
Email
shijun@ihcams.ac.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jun Shi, PhD
Organizational Affiliation
Institute of Hematology & Blood Diseases Hospital, China
Official's Role
Principal Investigator
Facility Information:
Facility Name
Regenerative Medicine Center
City
Tianjin
State/Province
Tianjin
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jun Shi, PhD
Email
shijun@ihcams.ac.cn
First Name & Middle Initial & Last Name & Degree
Jingyu Zhao, MPH
Phone
(86)13752253515
Email
zhaojingyu@ihcams.ac.cn

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Safety and Efficacy Evaluation of Autologous CRISPR-Cas12b Edited Hematopoietic Stem Cells

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