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A Safety and Efficacy Study Evaluating CTX001 in Subjects With Severe Sickle Cell Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03745287
Recruitment Status : Active, not recruiting
First Posted : November 19, 2018
Last Update Posted : December 20, 2021
Sponsor:
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Study Description
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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
Sickle Cell Disease Hematological Diseases Hemoglobinopathies Biological: CTX001 Phase 2 Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 27, 2018
Estimated Primary Completion Date : October 2024
Estimated Study Completion Date : October 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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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.


Outcome Measures
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Primary Outcome Measures :
  1. Proportion of subjects who have not experienced any severe vaso-occlusive crisis (VOC) for at least 12 consecutive months (VF12) [ Time Frame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion ]
  2. Proportion of subjects with engraftment (first day of three consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days) [ Time Frame: Within 42 days after CTX001 infusion ]
  3. Time to engraftment [ Time Frame: From CTX001 infusion up to 2 years after CTX001 infusion ]
  4. Frequency and severity of collected adverse events (AEs) [ Time Frame: From screening to 2 years after CTX001 infusion ]
  5. Incidence of transplant-related mortality (TRM) within 100 days after CTX001 infusion [ Time Frame: Within 100 days after CTX001 infusion ]
  6. Incidence of TRM within 1 year after CTX001 infusion [ Time Frame: Within 1 year after CTX001 infusion ]
  7. All-cause mortality [ Time Frame: 2 years after mobilization ]

Secondary Outcome Measures :
  1. Proportion of subjects free from inpatient hospitalization for severe VOCs sustained for at least 12 months (HF12) [ Time Frame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion ]
  2. Proportion of subjects with 90 percent (%), 80%, 75% or 50% reduction in annualized rate of severe VOCs [ Time Frame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion ]
  3. Relative change from baseline in annualized rate of severe VOCs [ Time Frame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion ]
  4. Duration of severe VOC free in subjects who have achieved VF12 [ Time Frame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion ]
  5. Relative Change from baseline in rate of inpatient hospitalization for severe VOCs [ Time Frame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion ]
  6. Relative change from baseline in annualized duration of hospitalization for severe VOCs [ Time Frame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion ]
  7. Proportion of subjects with sustained HbF ≥20% for at least 3 months [ Time Frame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion ]
  8. Proportion of subjects with sustained HbF ≥20% for at least 6 months [ Time Frame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion ]
  9. Proportion of subjects with sustained HbF ≥20% for at least 12 months [ Time Frame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion ]
  10. Change in number of units of RBC transfused for SCD-related indications [ Time Frame: 6 months up to 2 years after CTX001 infusion ]
  11. HbF concentration over time [ Time Frame: 1 month up to 2 years after CTX001 infusion ]
  12. Hb concentration over time [ Time Frame: From the time of CTX001 up to 2 years after CTX001 infusion ]
  13. Change from baseline in reticulocyte count over time [ Time Frame: From baseline (pre-infusion) up to 2 years after CTX001 infusion ]
  14. Change from baseline in indirect bilirubin over time [ Time Frame: From baseline (pre-infusion) up to 2 years after CTX001 infusion ]
  15. Change from baseline in haptoglobin over time [ Time Frame: From baseline (pre-infusion) up to 2 years after CTX001 infusion ]
  16. Change from baseline in lactate dehydrogenase over time [ Time Frame: From baseline (pre-infusion) up to 2 years after CTX001 infusion ]
  17. Proportion of alleles with intended genetic modification present in peripheral blood leukocytes over time [ Time Frame: 1 month up to 2 years after CTX001 infusion ]
  18. Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time [ Time Frame: 6 months up to 2 years after CTX001 infusion ]
  19. Change in patient-reported outcome (PRO) over time assessed using weekly pain-scale (11-point numerical rating scale [NRS]) [ Time Frame: 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.

  20. Change in PRO over time assessed using EuroQol quality of life scale (EQ-5D-5L) [ Time Frame: 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"

  21. Change in PRO over time assessed using EQ-5D-Youth (EQ-5D-Y) [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
  22. Change in PRO over time assessed using functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) questionnaire [ Time Frame: 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.

  23. Change in PRO over time assessed using adult sickle cell quality of life measurement system (ASCQ-Me) [ Time Frame: 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.

  24. Change in PRO over time assessed using pediatric quality of life inventory (PedsQL) [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
  25. Change in PRO over time assessed using PedsQL sickle cell disease module [ Time Frame: 3 months up to 2 years after CTX001 infusion ]

Eligibility Criteria
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Ages Eligible for Study:   12 Years to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03745287


Locations
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Sponsors and Collaborators
Vertex Pharmaceuticals Incorporated
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier: NCT03745287    
Other Study ID Numbers: CTX001-121
First Posted: November 19, 2018    Key Record Dates
Last Update Posted: December 20, 2021
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Hemoglobinopathies
Hematologic Diseases
Anemia, Hemolytic, Congenital
 Anemia, Hemolytic
Anemia
Genetic Diseases, Inborn