A Safety and Efficacy Study Evaluating CTX001 in Subjects With Severe Sickle Cell Disease
Study Details
Study Description
Brief Summary
This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in subjects 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2/Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: CTX001 CTX001 (autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene). Subjects will receive a single infusion of CTX001 through a central venous catheter. |
Biological: CTX001
Administered by IV infusion following myeloablative conditioning with busulfan.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Proportion of subjects who have not experienced any severe vaso-occlusive crisis (VOC) for at least 12 consecutive months (VF12) [From 60 days after last RBC transfusion up to 2 years 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) [Within 42 days after CTX001 infusion]
- Time to engraftment [From CTX001 infusion up to 2 years after CTX001 infusion]
- Frequency and severity of collected adverse events (AEs) [From screening to 2 years after CTX001 infusion]
- Incidence of transplant-related mortality (TRM) within 100 days after CTX001 infusion [Within 100 days after CTX001 infusion]
- Incidence of TRM within 1 year after CTX001 infusion [Within 1 year after CTX001 infusion]
- All-cause mortality [2 years after mobilization]
Secondary Outcome Measures
- 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 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]
- 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]
- 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 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]
- 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]
- 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 reticulocyte count over time [From baseline (pre-infusion) 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 haptoglobin over time [From baseline (pre-infusion) 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]
- 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]
The NRS is a 1-dimensional measure of reporting intensity of pain. The score of NRS ranges from 0 to 10 points, with higher values indicating a higher level of pain.
- Change in PRO over time assessed using EuroQol quality of life scale (EQ-5D-5L) [3 months up to 2 years after CTX001 infusion]
The EQ-5D-5L Questionnaire consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and 5 levels: no problems to extreme problems. The subject marks the most appropriate statement in each dimension, resulting in a 1-digit number for that dimension. The digits can be combined in a 5-digit number describing the subject's health state. The EQ VAS records the subject's self-rated health on a 100-point VAS, endpoints labelled "the best health you can imagine" and "the worst health you can imagine"
- Change in PRO over time assessed using EQ-5D-Youth (EQ-5D-Y) [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]
The FACT-BMT Questionnaire includes physical, social, family, emotional, and functional well-being, and treatment specific concerns of bone marrow transplantation. Each statement has a 5-point Likert-type response scale ranging from 0=not at all to 4=very much. The subject marks one number per line as it applies to the past 7 days. Questionnaires are then scored; the higher the score, the better the quality of life.
- 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]
ASCQ-Me comprises measures to assess physical, mental and social health along with information on severity of disease. It includes the following domains: emotional impact, pain impact, pain episodes, sleep impact, social functioning impact, stiffness impact and SCD medical history checklist. ASCQ-Me domains are scored using T-score metric with mean of 50 for reference population and SD of 10. Higher scores indicate healthier status.
- 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]
Eligibility Criteria
Criteria
Key Inclusion Criteria:
-
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
Key Exclusion Criteria:
-
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Lucille Packard Children's Hospital of Stanford University | Palo Alto | California | United States | 94304 |
| 2 | Ann & Robert Lurie Children's Hospital of Chicago | Chicago | Illinois | United States | 60611 |
| 3 | University of Illinois at Chicago Hospitals and Health Systems | Chicago | Illinois | United States | 60612 |
| 4 | Columbia University Medical Center (21+ years) | New York | New York | United States | 10032 |
| 5 | Columbia University Medical Center (≤21 years) | New York | New York | United States | 10032 |
| 6 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
| 7 | St. Jude Children's Research Hospital | Memphis | Tennessee | United States | 38105 |
| 8 | The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers | Nashville | Tennessee | United States | 37203 |
| 9 | Methodist Children's Hospital/Texas Transplant Institute | San Antonio | Texas | United States | 78229 |
| 10 | Hopital Universitaire des Enfants Reine Fabiola (HUDERF) | Brussels | Belgium | ||
| 11 | The Hospital for Sick Children | Toronto | Canada | ||
| 12 | Hopital Necker Enfants Malades | Paris | France | ||
| 13 | University Hospital Duesseldorf | Dusseldorf | Germany | ||
| 14 | Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine, Paediatric Haemotology, Oncology and Stem Cell Transplantation | Regensburg | Germany | ||
| 15 | Dipartimento di Onco-Ematologia e Terapia Cellulare e Genica Ospedale Pediatrico Bambino Gesu - IRCCS | Rome | Italy | ||
| 16 | Imperial College Healthcare NHS Trust, Hammersmith Hospital | London | United Kingdom | ||
| 17 | Royal London and St Bartholomew's Hospital, Pathology and Pharmacy Building | London | United Kingdom |
Sponsors and Collaborators
- Vertex Pharmaceuticals Incorporated
- CRISPR Therapeutics
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CTX001-121