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Safety and Efficacy of Gene Modified Autologous Hematopoietic Stem Cells to Treat Transfusion-dependent β-thalassemia

Primary Purpose

β-thalassemia

Status
Not yet recruiting
Phase
Not Applicable
Locations
China
Study Type
Interventional
Intervention
BD211
Sponsored by
Shanghai BDgene Co., Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for β-thalassemia

Eligibility Criteria

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

Inclusion Criteria: Ages 14 to 35 years old, including: Adult subjects who be able to provide a ICF. Diagnosed as Transfusion Dependent β-thalassemia with any genotype (β0, β+, βE/β0, βS/S, βS/β0, βS/β+), confirmed the Hb analysis. No alfa chain genetic abnormalities. Subjects must stabilize and maintain an appropriate iron chelation regimen. Transfusion-dependent types are defined as requiring at least 100 mL/kg/ year of red blood cells (pRBCs). The tumor genes chip detection results about acute leukemia and myeloid tumor gene mutations (panel) showed no abnormality. There were candidates for HLA gene semi-compatible hematopoietic stem cell transplantation. No eligiblity for allogeneic hematopoietic stem cell transplantation. The treatment of erythrocyte maturation agent luspatercept cannot be financially supported. The investigator confirmed that subject was willing to follow the research procedures. Having complete medical records including a history of blood transfusions testified subject received treatment and followed up for at least two years prior to screening. Exclusion Criteria: Availability of voluntary, fully HLA-matched hematopoietic cell donors, unless recommended for inclusion by the Monitoring Committee. HIV-1 and HIV-2 were positive, and / or HTLV-1, HTLV-2 and VSV-G antibodies were positive. An active bacterial, viral, fungal or parasitic infection. Contraindicated for the extraction of bone marrow under anesthesia. Any malignancy, myeloproliferative, or immunodeficient disease and relevant medical history. Peripheral blood white blood cell (WBC) count < 3×10^9/L or platelet count < 120×10^9/L. A history of allo-transplantation. Erythropoietin was used within 3 months prior to HSC cell collection. Immediate family members with known or suspected familial cancer syndromes (including but not limited to breast, colorectal, ovarian, prostate, and pancreatic cancers). Subjects with a diagnosis of major mental illness may had a serious disability to participate in the study. Active recurrent malaria. Pregnant or postpartum nursing or unable to use contraception. History of major organ injury including: Liver disease, transaminase > 3 times the upper limit of normal. (If the liver biopsy does not reveal evidence of widespread bridging fibrosis, cirrhosis, or acute hepatitis, this indicator will not be used as a criterion for the exclusion); Widely bridging fibrosis, histopathological evidence of acute hepatitis or cirrhosis showed in liver biopsy Heart disease, left ventricular ejection fraction < 25%; Kidney disease, creatinine clearance < 30% normal level; Of severe iron overload, confirmed by the study doctor; An heart MRI detection of T2 * < 10 ms; Significant pulmonary hypertension needing clinical medical intervention. Any other conditions being ineligible for HSC transplantation determined by the investigator. The subject involved with another clinical study in a 30-day screening period. Subjects who expected to become parents during the 27-month study period. Prior treatment with any type of gene and/or cell therapy. As assessed by the investigator, the subjects or their parents are unable to comply well with the study procedures per protocol. Hydroxyurea treatment within 3 months prior to hematopoietic stem cell collection.

Sites / Locations

  • Shanghai Ruijin Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

BD211 Adult Single-Dose group

Arm Description

Route of Administrate: infusion intravenously. Dosage form: injection solution. Dose: 5×10*6 cells /kg ~ 10×10*6 cells /kg. Frequency of administration: One dosing intravenously. Intervention: Single dose of BD211 for adults

Outcomes

Primary Outcome Measures

Red blood cell (RBCs) transfusion requirements, whether reaching TI
The changes of blood transfusion requirements and frequency of packed red blood cells (PRBCS) during the 2 years after administrating BD211 were compared with baseline values at 6, 12, and 24 months after transfusing BD211.
Total hospitalizing days at 6, 12, and 24 months (discharge after transplant)
Total hospitalizing days at 6, 12, and 24 months after transplantation were counted.

Secondary Outcome Measures

Percentage of Treated Participants With Transfusion-Dependent β-Thalassemia (TDT) WhoAchieved Transfusion Independence for at least 6 months
TI was defined as a weighted average hemoglobin (Hb) > or =9 grams per deciliter (g/dL) withoutany pRBC transfusions for a continuous period of > or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when participantsachieve a Hb > or =9 g/dL with no transfusions in the preceding 60 days.
Change in RBCs infusion from baseline at 6 to 24 months
The quantity of RBCs transfusions at 6 to 24 months will be measured and compared with baseline level.
Mean Hb (g/dL) at 6, 12 and 24 months after treatment
Mean Hb (g/dL) in 6, 12, and 24 months after drug product infusion are tested and calculated.
Change in ferritin/liver iron levels from baseline
The Ferritin/liver iron levels are assayed per protocol plan, and evaluate the changes from those baseline level.
Neutrophil engraftment, platelet engraftment and vector copy number
Neutrophil engraftment was defined as the first of absolute neutrophil count (ANC) > or = 0.5 ×10^9/ L for 3 consecutive days (or 3 consecutive measurements done on separate days), after a post-transplant value less than (<) 0.5 × 10^9/L. Platelet engraftment was defined as the first of 3 consecutive platelet values > or =20 × 10^9/L for participants on different days with no platelet transfusionsadministered for 7 days immediately preceding. The day of engraftment is the first day of the 3 consecutive platelet measurements. Vector copy number will be detected per investigating time schedule.
Transplant-related mortality in 3 months and 12 months
Transplant related mortality was definedas any death occurring in the study post drug product infusion deemed related to the transplant bythe investigator.
Overall survival
Overall survival was defined as time from date of BD211 Drug Product infusion (Day 1) to date of death. Overall survival was censored at the date of last visit if the participant was still alive.
RCL incidence
Subjects blood RCL was detected with specific assay method, and the incidence was calculated at different scheduled timeslots.
Characterized insertion mutagenesis events that lead to clonal dominance or leukemia
The number of insertion mutagenesis events that characterized clonal dominance or leukemia was collected.
Frequency and severity of AE
An AE was any untoward medical occurrence associated with the use of a drug in participants, whether or not considered drug related. An AE may include a change in physical signs, symptoms, and/or clinically significant laboratory change occurring in any phase of a clinical study.

Full Information

First Posted
March 3, 2023
Last Updated
March 16, 2023
Sponsor
Shanghai BDgene Co., Ltd.
Collaborators
Ruijin Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05776173
Brief Title
Safety and Efficacy of Gene Modified Autologous Hematopoietic Stem Cells to Treat Transfusion-dependent β-thalassemia
Official Title
Safety and Efficacy of Lentiviral Vector Transduction of β-globin Genetically Modified Autologous CD34+ Hematopoietic Stem Cells in Patients With Transfusion-dependent β-thalassemia
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
March 2023 (Anticipated)
Primary Completion Date
March 2026 (Anticipated)
Study Completion Date
October 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shanghai BDgene Co., Ltd.
Collaborators
Ruijin Hospital

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 study will be intented to evaluate the safety and efficacy of lentiviral vector transduction of β-globin genetically modified autologous CD34+ hematopoietic stem cells in patients with transfusion-dependent β-thalassemia.
Detailed Description
This is an open-label, single-dose study of BD211 in patients with transfusion-dependent β-thalassemia aged 14 to 35 years. It is estimated that 10 subjects will be enrolled. BD211 is a gene modified gene therapy product designed to produce healthy β-globin in red blood cells in beta-thalassemia patients. The total follow-up duration was 24 months, the safe endpoints and effectiveness endpoints will be used to assess the safety and efficacy profiles in patients with transfusion-dependent β-thalassemia.

6. Conditions and Keywords

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

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
BD211 Adult Single-Dose group
Arm Type
Experimental
Arm Description
Route of Administrate: infusion intravenously. Dosage form: injection solution. Dose: 5×10*6 cells /kg ~ 10×10*6 cells /kg. Frequency of administration: One dosing intravenously. Intervention: Single dose of BD211 for adults
Intervention Type
Genetic
Intervention Name(s)
BD211
Intervention Description
Genetically modified CD34+ autologous stem cells were transfused intravenously with single dosing.
Primary Outcome Measure Information:
Title
Red blood cell (RBCs) transfusion requirements, whether reaching TI
Description
The changes of blood transfusion requirements and frequency of packed red blood cells (PRBCS) during the 2 years after administrating BD211 were compared with baseline values at 6, 12, and 24 months after transfusing BD211.
Time Frame
24 months
Title
Total hospitalizing days at 6, 12, and 24 months (discharge after transplant)
Description
Total hospitalizing days at 6, 12, and 24 months after transplantation were counted.
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Percentage of Treated Participants With Transfusion-Dependent β-Thalassemia (TDT) WhoAchieved Transfusion Independence for at least 6 months
Description
TI was defined as a weighted average hemoglobin (Hb) > or =9 grams per deciliter (g/dL) withoutany pRBC transfusions for a continuous period of > or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when participantsachieve a Hb > or =9 g/dL with no transfusions in the preceding 60 days.
Time Frame
24 months
Title
Change in RBCs infusion from baseline at 6 to 24 months
Description
The quantity of RBCs transfusions at 6 to 24 months will be measured and compared with baseline level.
Time Frame
24 months
Title
Mean Hb (g/dL) at 6, 12 and 24 months after treatment
Description
Mean Hb (g/dL) in 6, 12, and 24 months after drug product infusion are tested and calculated.
Time Frame
24 months
Title
Change in ferritin/liver iron levels from baseline
Description
The Ferritin/liver iron levels are assayed per protocol plan, and evaluate the changes from those baseline level.
Time Frame
24 months
Title
Neutrophil engraftment, platelet engraftment and vector copy number
Description
Neutrophil engraftment was defined as the first of absolute neutrophil count (ANC) > or = 0.5 ×10^9/ L for 3 consecutive days (or 3 consecutive measurements done on separate days), after a post-transplant value less than (<) 0.5 × 10^9/L. Platelet engraftment was defined as the first of 3 consecutive platelet values > or =20 × 10^9/L for participants on different days with no platelet transfusionsadministered for 7 days immediately preceding. The day of engraftment is the first day of the 3 consecutive platelet measurements. Vector copy number will be detected per investigating time schedule.
Time Frame
24 months
Title
Transplant-related mortality in 3 months and 12 months
Description
Transplant related mortality was definedas any death occurring in the study post drug product infusion deemed related to the transplant bythe investigator.
Time Frame
12 months
Title
Overall survival
Description
Overall survival was defined as time from date of BD211 Drug Product infusion (Day 1) to date of death. Overall survival was censored at the date of last visit if the participant was still alive.
Time Frame
24 months
Title
RCL incidence
Description
Subjects blood RCL was detected with specific assay method, and the incidence was calculated at different scheduled timeslots.
Time Frame
24 months
Title
Characterized insertion mutagenesis events that lead to clonal dominance or leukemia
Description
The number of insertion mutagenesis events that characterized clonal dominance or leukemia was collected.
Time Frame
24 months
Title
Frequency and severity of AE
Description
An AE was any untoward medical occurrence associated with the use of a drug in participants, whether or not considered drug related. An AE may include a change in physical signs, symptoms, and/or clinically significant laboratory change occurring in any phase of a clinical study.
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
14 Years
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Ages 14 to 35 years old, including: Adult subjects who be able to provide a ICF. Diagnosed as Transfusion Dependent β-thalassemia with any genotype (β0, β+, βE/β0, βS/S, βS/β0, βS/β+), confirmed the Hb analysis. No alfa chain genetic abnormalities. Subjects must stabilize and maintain an appropriate iron chelation regimen. Transfusion-dependent types are defined as requiring at least 100 mL/kg/ year of red blood cells (pRBCs). The tumor genes chip detection results about acute leukemia and myeloid tumor gene mutations (panel) showed no abnormality. There were candidates for HLA gene semi-compatible hematopoietic stem cell transplantation. No eligiblity for allogeneic hematopoietic stem cell transplantation. The treatment of erythrocyte maturation agent luspatercept cannot be financially supported. The investigator confirmed that subject was willing to follow the research procedures. Having complete medical records including a history of blood transfusions testified subject received treatment and followed up for at least two years prior to screening. Exclusion Criteria: Availability of voluntary, fully HLA-matched hematopoietic cell donors, unless recommended for inclusion by the Monitoring Committee. HIV-1 and HIV-2 were positive, and / or HTLV-1, HTLV-2 and VSV-G antibodies were positive. An active bacterial, viral, fungal or parasitic infection. Contraindicated for the extraction of bone marrow under anesthesia. Any malignancy, myeloproliferative, or immunodeficient disease and relevant medical history. Peripheral blood white blood cell (WBC) count < 3×10^9/L or platelet count < 120×10^9/L. A history of allo-transplantation. Erythropoietin was used within 3 months prior to HSC cell collection. Immediate family members with known or suspected familial cancer syndromes (including but not limited to breast, colorectal, ovarian, prostate, and pancreatic cancers). Subjects with a diagnosis of major mental illness may had a serious disability to participate in the study. Active recurrent malaria. Pregnant or postpartum nursing or unable to use contraception. History of major organ injury including: Liver disease, transaminase > 3 times the upper limit of normal. (If the liver biopsy does not reveal evidence of widespread bridging fibrosis, cirrhosis, or acute hepatitis, this indicator will not be used as a criterion for the exclusion); Widely bridging fibrosis, histopathological evidence of acute hepatitis or cirrhosis showed in liver biopsy Heart disease, left ventricular ejection fraction < 25%; Kidney disease, creatinine clearance < 30% normal level; Of severe iron overload, confirmed by the study doctor; An heart MRI detection of T2 * < 10 ms; Significant pulmonary hypertension needing clinical medical intervention. Any other conditions being ineligible for HSC transplantation determined by the investigator. The subject involved with another clinical study in a 30-day screening period. Subjects who expected to become parents during the 27-month study period. Prior treatment with any type of gene and/or cell therapy. As assessed by the investigator, the subjects or their parents are unable to comply well with the study procedures per protocol. Hydroxyurea treatment within 3 months prior to hematopoietic stem cell collection.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sujiang Zhang, MD
Phone
17717285030
Email
zbruce.zhang@hotmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sujiang Zhang, MD
Organizational Affiliation
Ruijin Hospital, Shanghai, China
Official's Role
Principal Investigator
Facility Information:
Facility Name
Shanghai Ruijin Hospital
City
Shanghai
ZIP/Postal Code
200025
Country
China
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sujiang Zhang, MD
Phone
+86-17717285030
Email
zbruce.zhang@hotmail.com

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Safety and Efficacy of Gene Modified Autologous Hematopoietic Stem Cells to Treat Transfusion-dependent β-thalassemia

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