Severe Sickle Cell Disease (SCD) MedDRA version: 21.0 Level: PT Classification code 10040641 Term: Sickle cell anaemia System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Sponsors
Vertex Pharmaceuticals Incorporated
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Subject (or their legally authorized representative or guardian) will sign and date an informed consent form (ICF) and, where applicable, an assent form. 2. Subjects 12 to 35 years of age, inclusive on the date of informed consent. 3. Documented ßS/ßS, ßS/ß0 or ßS/ß+ genotype. Subjects can be enrolled based on historical genotype results, but confirmation of genotype is required before busulfan conditioning. The ß0 genotypes are defined using the HbVar Database. 4. Subjects with severe SCD. Severe SCD is defined by the occurrence of at least 2 of the following events per year during the 2-year period before screening, while receiving appropriate supportive care (e.g., pain management plan, HU): • Acute pain events that requires a visit to a medical facility and administration of pain medications (opioids or intravenous [IV] non-steroidal anti-inflammatory drugs [NSAIDs]) or RBC transfusions • Acute chest syndrome, as indicated by the presence of a new pulmonary infiltrate associated with pneumonia-like symptoms, pain, or fever • Priapism lasting >2 hours and requiring a visit to a medical facility • Splenic sequestration, as defined by an enlarged spleen, left upper quadrant pain, and an acute decrease in hemoglobin concentration of =2 g/dL. Historical severe VOCs will be adjudicated by the Endpoint Adjudication Committee (EAC). 5. Normal transcranial Doppler (TCD) velocity (time-averaged mean of the maximum velocity [TAMMV] =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. An available 10/10 human leukocyte antigen (HLA)-matched related donor. 2. Prior Hematopoietic Stem Cell Transplant (HSCT). 3. Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator. 4. White blood cell (WBC) count 15.0%, irrespective of concomitant treatment with HbF-inducing treatments such as HU. 9. History of abnormal TCD (TAMMV =200 cm/sec for non-imaging TCD and = 185 cm/sec for imaging TCD) for subjects 12 to 18 years of age. 10. History of untreated Moyamoya disease or presence of Moyamoya disease at Screening that in the opinion of the investigator puts the subjects at the risk of bleeding. 11. History of a significant bleeding disorder. 12. History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk to the subject. This may include, but is not limited to: history of relevant drug allergies; history of cardiovascular or central nervous system disease; history or presence of clinically significant pathology; history of mental disease, or history of familial cancer syndrome. 13. Any prior or current malignancy or myeloproliferative disorder or a significant immunodeficiency disorder. 14. Advanced liver disease, defined as a. Alanine transaminase (ALT) >3 × the upper limit of normal (ULN) or direct bilirubin value >2.5 × ULN, or b. Baseline prothrombin time (PT) (international normalized ratio [INR]) >1.5 × ULN, or c. History of cirrhosis or any evidence of bridging fibrosis, or active hepatitis on liver biopsy 15. Baseline estimated glomerular filtration rate <60 mL/min/1.73 m2. 16. Lung diffusing capacity for carbon monoxide (DLco) <50% of predicted value (corrected for hemoglobin and/or alveolar volume). 17. Left ventricular ejection fraction (LVEF) <45% by echocardiogram. 18. Prior treatment with gene therapy/editing product. 19. Intolerance, contraindication, or known sensitivity to plerixafor or busulfan. Subject must not have any risk factors in the opinion of the investigator that would increase the likelihood of busulfan-related toxicities. Prior anaphylactic reaction with excipients of CTX001 product (dimethylsulfoxide [DMSO], dextran). 20. Positive for the presence of human immunodeficiency virus-1 (HIV-1) or human immunodeficiency virus-2 (HIV-2) (positive for both antigen/antibody AND nucleic acid tests [NAT]), hepatitis B virus (HBV) (positive for Hepatitis B core antibody [HBcAb] or positive hepatitis B surface antigen [HBsAg] AND NAT tests), syphilis (positive screening AND positive confirmatory tests), or hepatitis C virus (HCV; positive for both antibody [HCAb] AND for NAT tests). Additional infectious disease markers should be obtained and tested as required by the local authority for the col
Design outcomes
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key Secondary Efficacy Endpoint • Proportion of subjects free from inpatient hospitalization for severe VOCs sustained for at least 12 months (HF12) after CTX001 infusion. The evaluation of HF12 starts 60 days after last RBC transfusion for posttransplant support or SCD disease management Secondary Endpoints • Proportion of subjects with reduction in annualized rate of severe VOCs at the time of analysis from baseline by at least 90%, 80%, 75%, 50% up to 24 months after CTX001 infusion. The evaluation starts 60 days after last RBC transfusion for post-transplant support or SCD disease management • Relative change from baseline in annualized rate of severe VOCs up to 24 months after CTX001 infusion. The evaluation starts 60 days after last RBC transfusion for post-transplant support or SCD disease management • Duration of severe VOC free in subjects who have achieved VF12 • Relative change from baseline in rate of inpatient hospitalizations for severe VOCs up to 24 months after CTX001 infusion. The evaluation starts 60 days after last RBC transfusion for post-transplant support or SCD disease management • Relative change from baseline in annualized duration of hospitalization for severe VOCs up to 24 months after CTX001 infusion. The evaluation starts 60 days after last RBC transfusion for post-transplant support or SCD disease management • Proportion of subjects with sustained HbF =20% at the time of analysis for at least 3 months, 6 months, or 12 months. The evaluation starts 60 days after last RBC transfusion for post-transplant support or SCD disease management • Change in number of units of red blood cells (RBC) transfused for SCD related indications over time • HbF concentrations over time • Hemoglobin (Hb) concentrations over time • Change from baseline in reticulocyte count (percent reticulocytes and absolute reticulocyte count) over time • Change from baseline in indirect bilirubin over time • Change from baseline in haptoglobin ove | — |
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Evaluate the safety and efficacy of a single dose of autologous CRISPR-Cas9 modified CD34+ hHSPCs (CTX001) in subjects with severe SCD;Secondary Objective: • Assess the effects of infusion of CTX001 on disease-specific events and clinical status • Quantify gene editing efficiency ;Primary end point(s): Safety Endpoints • Successful neutrophil engraftment • Time to neutrophil engraftment • Time to platelet engraftment • Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, and vital signs • Transplant-related mortality (TRM) within 100 days after CTX001 infusion • TRM within 1 year after CTX001 infusion • All-cause mortality Primary Efficacy Endpoint • Proportion of subjects who have not experienced any severe VOC for at least 12 consecutive months (VF12) after CTX001 infusion. The evaluation of VF12 starts 60 days after last RBC transfusion for post-transplant support or SCD disease management;Timepoint(s) of evaluation of this end point: See in section E.5.1 | — |
Countries
Belgium, Canada, France, Germany, Italy, United Kingdom, United States
Contacts
Public ContactClinical Trials and Medical Info
Vertex Pharmaceuticals Incorporated
Outcome results
None listed