A Phase 1/2/3 Study to Evaluate the Safety and Efficacy of a Single Dose of Autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (CTX001) in Subjects With Severe Sickle Cell Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 63
- 试验地点
- 27
- 主要终点
- Incidence of transplant-related mortality (TRM) within 100 days after CTX001 infusion
研究概览
简要总结
This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in participants with severe sickle cell disease (SCD). The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) using CTX001.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 35 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of severe sickle cell disease as defined by:
- •Documented severe sickle cell disease genotype
- •History of at least two severe vaso-occlusive crisis events per year for the previous two years prior to enrollment
- •Eligible for autologous stem cell transplant as per investigators judgment
排除标准
- •An available 10/10 human leukocyte antigen (HLA)-matched related donor
- •Prior hematopoietic stem cell transplant (HSCT)
- •Clinically significant and active bacterial, viral, fungal, or parasitic infection
- •Other protocol defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Exa-cel
Exa-cel (autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene). Participants received a single infusion of exa-cel through a central venous catheter on Day 1.
干预措施: Exa-cel (Biological)
结局指标
主要结局
Incidence of transplant-related mortality (TRM) within 100 days after CTX001 infusion
时间窗: Within 100 days after CTX001 infusion
Proportion of subjects with engraftment (first day of three consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days)
时间窗: Within 42 days after CTX001 infusion
Time to engraftment
时间窗: From CTX001 infusion up to 2 years after CTX001 infusion
Frequency and severity of collected adverse events (AEs)
时间窗: From screening to 2 years after CTX001 infusion
Incidence of TRM within 1 year after CTX001 infusion
时间窗: Within 1 year after CTX001 infusion
Proportion of subjects who have not experienced any severe vaso-occlusive crisis (VOC) for at least 12 consecutive months (VF12)
时间窗: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
All-cause mortality
时间窗: 2 years after mobilization
Percentage of Participants Who Have Not Experienced Any Severe Vaso-occlusive Crisis (VOC) for at Least 12 Consecutive Months (VF12) After Exa-cel Infusion
时间窗: From 60 days after last RBC transfusion up to 2 years after exa-cel infusion
A VOC is a condition of SCD characterized by vaso-occlusion presenting as recurrent pain episodes. The percentage of participants who remain VOC free after achieving VF12 were data reported in the outcome measure.
Percentage of Participants Who Achieve Neutrophil Engraftment
时间窗: Up to 24 months post exa-cel infusion.
Neutrophil engraftment is defined as the first day of 3 consecutive measurements of absolute neutrophil count (ANC)≥500/μL on 3 different days, within 42 days after exa-cel infusion without the use of unmodified CD34+ cells after reaching the nadir, defined as ANC \<500/µL.
Time to Neutrophil Engraftment for Participants Who Achieve Neutrophil Engraftment
时间窗: Up to 24 months post exa-cel infusion.
Neutrophil engraftment is defined as the first day of 3 consecutive measurements of absolute neutrophil count (ANC)≥500/μL on 3 different days, without use of the unmodified CD34+ cells after reaching the nadir, defined as ANC\<500/μL. Time to neutrophil engraftment was calculated by the neutrophil engraftment date subtract exa-cel infusion date +1.
Time to Platelet Engraftment for Participants Who Achieve Platelet Engraftment
时间窗: From Exa-cel infusion up to 2 years after exa-cel infusion
Platelet engraftment is defined as the first day of 3 consecutive measurements of unsupported (no platelet transfusions for the last 7 days) platelet ≥50,000/μL on 3 different days after Exa-cel infusion. For participants discharged early day 7 after the last platelet transfusion will be the day of platelet engraftment, as long as 3 subsequent and consecutive unsupported measurements on 3 different days are \>50,000/μL. For participants who have been discharged prior to platelet engraftment, it is recommended to collect blood every 2 to 3 days to obtain an accurate assessment of platelet engraftment. Time to platelet engraftment was defined as first of 3 consecutive measurements on 3 different days with platelet ≥50 × 109/L without a platelet transfusion for 7 consecutive days.
Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
时间窗: From receiving exa-cel infusion up to 2 years
Transplant-related Mortality (TRM) Within 100 Days After Exa-cel Infusion
时间窗: Within 100 days after exa-cel infusion
The transplant-related mortality is defined as death related to Busulfan and/or exa-cel infusion. The number and proportion of TRM participants who have died within 100 days, or with at least 100 days post exa-cel infusion.
Transplant-related Mortality Within 12 Months Post Exa-cel Infusion
时间窗: Within 12 months post exa-cel infusion
The transplant-related mortality is defined as death related to Busulfan and/or exa-cel infusion. The number and proportion of TRM within 12 months will be summarized for participants who have died within 12 months, or with at least 12 months post exa-cel infusion.
All-cause Mortality
时间窗: From exa-cel infusion up to 2 years
All-cause mortality from exa-cel infusion up to 2 years
次要结局
- Change in PRO over time assessed using EQ-5D-Youth (EQ-5D-Y)(3 months up to 2 years after CTX001 infusion)
- Duration of severe VOC free in subjects who have achieved VF12(From 60 days after last RBC transfusion up to 2 years after CTX001 infusion)
- Proportion of subjects free from inpatient hospitalization for severe VOCs sustained for at least 12 months (HF12)(From 60 days after last RBC transfusion up to 2 years after CTX001 infusion)
- Proportion of subjects who have not experienced any severe VOC for at least 9 consecutive months (VF9) any time after CTX001 infusion(From 60 days after last RBC transfusion up to 2 years after CTX001 infusion)
- Proportion of subjects with 90 percent (%), 80%, 75% or 50% reduction in annualized rate of severe VOCs(From 60 days after last RBC transfusion up to 2 years after CTX001 infusion)
- Relative change from baseline in annualized rate of severe VOCs(From 60 days after last RBC transfusion up to 2 years after CTX001 infusion)
- Relative Change from baseline in rate of inpatient hospitalization for severe VOCs(From 60 days after last RBC transfusion up to 2 years after CTX001 infusion)
- Relative change from baseline in annualized duration of hospitalization for severe VOCs(From 60 days after last RBC transfusion up to 2 years after CTX001 infusion)
- Proportion of subjects with sustained HbF ≥20% for at least 12 months(From 60 days after last RBC transfusion up to 2 years after CTX001 infusion)
- Proportion of subjects with sustained HbF ≥20% for at least 3 months(From 60 days after last RBC transfusion up to 2 years after CTX001 infusion)
- Proportion of subjects with sustained HbF ≥20% for at least 6 months(From 60 days after last RBC transfusion up to 2 years after CTX001 infusion)
- Change in number of units of RBC transfused for SCD-related indications(6 months up to 2 years after CTX001 infusion)
- HbF concentration over time(1 month up to 2 years after CTX001 infusion)
- Hb concentration over time(From the time of CTX001 up to 2 years after CTX001 infusion)
- Change from baseline in lactate dehydrogenase over time(From baseline (pre-infusion) up to 2 years after CTX001 infusion)
- Proportion of alleles with intended genetic modification present in peripheral blood leukocytes over time(1 month up to 2 years after CTX001 infusion)
- Change in PRO over time assessed using adult sickle cell quality of life measurement system (ASCQ-Me)(3 months up to 2 years after CTX001 infusion)
- Change from baseline in indirect bilirubin over time(From baseline (pre-infusion) up to 2 years after CTX001 infusion)
- Change from baseline in reticulocyte count over time(From baseline (pre-infusion) up to 2 years after CTX001 infusion)
- Change from baseline in haptoglobin over time(From baseline (pre-infusion) up to 2 years after CTX001 infusion)
- Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time(6 months up to 2 years after CTX001 infusion)
- Change in patient-reported outcome (PRO) over time assessed using weekly pain-scale (11-point numerical rating scale [NRS])(3 months up to 2 years after CTX001 infusion)
- Change in PRO over time assessed using EuroQol quality of life scale (EQ-5D-5L)(3 months up to 2 years after CTX001 infusion)
- Change in PRO over time assessed using functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) questionnaire(3 months up to 2 years after CTX001 infusion)
- Change in PRO over time assessed using pediatric quality of life inventory (PedsQL)(3 months up to 2 years after CTX001 infusion)
- Change in PRO over time assessed using PedsQL sickle cell disease module(3 months up to 2 years after CTX001 infusion)
- Change From Baseline in Reticulocyte Count Over Time(2 years after exa-cel infusion)
- Percentage of Participants Free From Inpatient Hospitalization for Severe VOCs Sustained for at Least 12 Months (HF12)(From 60 days after last RBC transfusion up to 2 years after exa-cel infusion)
- Relative Reduction From Baseline in Annualized Rate of Severe VOCs for Participants Who do Not Achieve VF12 up to 24 Months After Exa-cel Infusion(From 60 days after last RBC transfusion up to 2 years after exa-cel infusion)
- Percentage of Participants With at Least 90% Relative Reduction From Baseline in Annualized Rate of Severe VOCs for Participants Who do Not Achieve VF12 up to 24 Months After Exa-cel Infusion(From 60 days after last RBC transfusion up to 2 years after exa-cel infusion)
- Percentage of Participants With at Least 80% Relative Reduction From Baseline in Annualized Rate of Severe VOCs for Participants Who do Not Achieve VF12 up to 24 Months After Exa-cel Infusion(From 60 days after last RBC transfusion up to 2 years after exa-cel infusion)
- Percentage of Participants With at Least 75% Relative Reduction From Baseline in Annualized Rate of Severe VOCs for Participants Who do Not Achieve VF12 up to 24 Months After Exa-cel Infusion(From 60 days after last RBC transfusion up to 2 years after exa-cel infusion)
- Percentage of Participants With at Least 50% Relative Reduction From Baseline in Annualized Rate of Severe VOCs for Participants Who do Not Achieve VF12 up to 24 Months After Exa-cel Infusion(From 60 days after last RBC transfusion up to 2 years after exa-cel infusion)
- Total Hemoglobin (Hb) Concentration Over Time(2 years after exa-cel infusion)
- Duration of Severe VOC Free in Participant Who Have Achieved VF12(From 60 days after last RBC transfusion up to 2 years after exa-cel infusion)
- Relative Reduction From Baseline in Annualized Rate of Inpatient Hospitalizations for Severe VOCs Up to 24 Months After Exa-cel Infusion(From 60 days after last RBC transfusion up to 2 years after exa-cel infusion)
- Relative Reduction From Baseline in Annualized Duration of Hospitalization for Severe VOCs Who Did Not Achieve HF12 Up to 24 Months After Exa-cel Infusion(From 60 days after last RBC transfusion up to 2 years after exa-cel infusion)
- Percentage of Participants With Sustained Fetal Hemoglobin (HbF) Greater Than or Equal to (≥) 20% for at Least 3 Months(From 60 days after last RBC transfusion up to 2 years after exa-cel infusion)
- Percentage of Participants With Sustained HbF ≥ 20% for at Least 6 Months(From 60 days after last RBC transfusion up to 2 years after exa-cel infusion)
- Percentage of Participants With Sustained HbF ≥20% for at Least 12 Months(From 60 days after last RBC transfusion up to 2 years after exa-cel infusion)
- Number of Annualized Red Blood Cells (RBC) Units Transfused After Exa-cel Infusion(2 years after exa-cel infusion)
- Participants With Relative Reduction From Baseline in Number of Annualized Units of Red Blood Cells Transfused(2 years after exa-cel infusion)
- Total Fetal Hemoglobin (HbF) Concentration Over Time(2 years after exa-cel infusion)
- Change From Baseline in Indirect Bilirubin Over Time(2 years after exa-cel infusion)
- Percentage of Participants With Detectable Haptoglobin Over Time(2 years after exa-cel infusion)
- Percentage of Participants With Lactate Dehydrogenase (LDH) Level <300 Units Per Liter (U/L) Over Time(2 years after exa-cel infusion)
- Percentage of Alleles With Intended Genetic Modification Present in Peripheral Blood Leukocytes Over Time(2 years after exa-cel infusion)
- Percentage of Alleles With Intended Genetic Modification Present in CD34+ Cells of Bone Marrow Over Time(2 years after exa-cel infusion)
- Change in Patient-reported Outcome (PRO) Over Time Assessed Using on a 11-point Numerical Rating Scale [NRS]) for Participants ≥12 and <18 Years of Age(2 years after exa-cel infusion)
- Change in Patient-reported Outcome (PRO) Over Time Assessed Using on a 11-point Numerical Rating Scale [NRS]) for Participants ≥18 and ≤35 Years of Age(2 years after exa-cel infusion)
- Change in PRO Over Time Assessed Using EuroQol Quality of Life Scale (EQ-5D-Y)Visual Analogue Scale (VAS) for Participants ≥12 and <18 Years of Age(2 years after exa-cel infusion)
- Change in PRO Over Time Assessed Using EuroQol Quality of Life Scale (EQ-5D-5L) for Participants ≥18 and ≤35 Years of Age(2 years after exa-cel infusion)
- Change in PRO Over Time Assessed Using Functional Assessment of Cancer Therapy-bone Marrow Transplant (FACT-BMT) Score for Participants ≥18 and ≤35 Years of Age(2 years after exa-cel infusion)
- Change in PRO Over Time Assessed Using Adult Sickle Cell Quality of Life Measurement System (ASCQ-Me) Score on Different Domains for Participants ≥18 and ≤35 Years of Age(2 years after exa-cel infusion)
- Change in PRO Over Time Assessed Using Pediatric Quality of Life Inventory (PedsQL) for Participants Greater Than or Equal to (≥) 12 and Less Than (<) 18 Years of Age(2 years after Exa-cel infusion)
- Change in PRO Over Time Assessed Using Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module (SCD) for Participants Greater Than or Equal to (≥) 12 and Less Than (<) 18 Years of Age(2 years after exa-cel infusion)