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

Study Overview
=================
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.

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

Conditions
-----------------
β-thalassemia

Intervention / Treatment
-----------------
* Genetic: BD211


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Ages 5 to 18 years old, including: The parents or legal guardians must be able to understand and provide ICFs. If available, it is strongly recommended that children aged ≥8 years in treatment decisions and obtain written ICFs and be clearly documented; 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). No eligiblity for allogeneic hematopoietic stem cell transplantation. The treatment of erythrocyte maturation agent luspatercept cannot be financially supported. The subjects' parents/legal guardians must be willing and able to follow the study procedures in the study protocol. Good organs' functions. 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. Had autoimmune diseases that may make blood transfusions difficult. 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. There are bleeding diseases that have not been cured. The subject involved with another clinical study in a 30-day screening period. Allergic to the research drug and its excipients. 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. Had diseases that interfere with hematopoietic stem cells collections. Any other conditions being ineligible for HSC transplantation determined by the investigator.

Ages Eligible for Study
-----------------
Minimum Age: 5 Years
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BD211 Adult Single-Dose group<br>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 | Genetic: BD211<br>* Genetically modified CD34+ autologous stem cells were transfused intravenously with single dosing.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 months | 
| 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. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 months | 
| 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. | 24 months | 
| 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. | 24 months | 
| 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. | 24 months | 
| 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. | 24 months | 
| 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. | 12 months | 
| 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. | 24 months | 
| RCL incidence | Subjects blood RCL was detected with specific assay method, and the incidence was calculated at different scheduled timeslots. | 24 months | 
| 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. | 24 months | 
| 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. | 24 months |