A Safety and Efficacy Study Evaluating CTX001 in Subjects With Severe Sickle Cell Disease
- Conditions
- Sickle Cell DiseaseHemoglobinopathiesHematological Diseases
- Interventions
- Registration Number
- NCT03745287
- Lead Sponsor
- Vertex Pharmaceuticals Incorporated
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 63
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description CTX001 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.
- Primary Outcome Measures
Name Time Method 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 Incidence of transplant-related mortality (TRM) within 100 days after CTX001 infusion Within 100 days after CTX001 infusion Frequency and severity of collected adverse events (AEs) From screening to 2 years after CTX001 infusion Incidence of TRM within 1 year after CTX001 infusion 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) From 60 days after last RBC transfusion up to 2 years after CTX001 infusion All-cause mortality 2 years after mobilization
- Secondary Outcome Measures
Name Time Method Change in PRO over time assessed using EQ-5D-Youth (EQ-5D-Y) 3 months 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 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 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 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.
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 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 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 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
Trial Locations
- Locations (17)
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
University of Illinois at Chicago Hospitals and Health Systems
🇺🇸Chicago, Illinois, United States
Columbia University Medical Center (21+ years)
🇺🇸New York, New York, United States
Methodist Children's Hospital/Texas Transplant Institute
🇺🇸San Antonio, Texas, United States
The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers
🇺🇸Nashville, Tennessee, United States
Hopital Universitaire des Enfants Reine Fabiola (HUDERF)
🇧🇪Brussels, Belgium
Dipartimento di Onco-Ematologia e Terapia Cellulare e Genica Ospedale Pediatrico Bambino Gesu - IRCCS
🇮🇹Rome, Italy
Columbia University Medical Center (≤21 years)
🇺🇸New York, New York, United States
Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine, Paediatric Haemotology, Oncology and Stem Cell Transplantation
🇩🇪Regensburg, Germany
Ann & Robert Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Hopital Necker Enfants Malades
🇫🇷Paris, France
Lucile Packard Children's Hospital of Stanford University
🇺🇸Palo Alto, California, United States
University Hospital Duesseldorf
🇩🇪Dusseldorf, Germany
Imperial College Healthcare NHS Trust, Hammersmith Hospital
🇬🇧London, United Kingdom
The Hospital for Sick Children
🇨🇦Toronto, Canada
Royal London and St Bartholomew's Hospital, Pathology and Pharmacy Building
🇬🇧London, United Kingdom