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A Safety and Efficacy Study Evaluating CTX001 in Subjects With Transfusion-Dependent β-Thalassemia

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ClinicalTrials.gov Identifier: NCT03655678
Recruitment Status : Active, not recruiting
First Posted : August 31, 2018
Last Update Posted : December 22, 2023
Sponsor:
Collaborator:
CRISPR Therapeutics
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 transfusion-dependent β-thalassemia (TDT). 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
Beta-Thalassemia Thalassemia Genetic Diseases, Inborn Hematologic 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 of the Safety and Efficacy of a Single Dose of Autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) in Subjects With Transfusion-Dependent β-Thalassemia
Actual Study Start Date : September 14, 2018
Estimated Primary Completion Date : August 2024
Estimated Study Completion Date : August 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
Other Names:
  • Exagamglogene autotemcel
  • Exa-cel


Outcome Measures
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Primary Outcome Measures :
  1. Proportion of subjects achieving transfusion independence for at least 12 consecutive months (TI12) [ Time Frame: From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion] ]
  2. Proportion of subjects with engraftment (first day of 3 consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days) [ Time Frame: Within 42 days after CTX001 infusion ]
  3. Time to neutrophil and platelet engraftment [ Time Frame: Days post-infusion to engraftment ]
  4. Frequency and severity of collected adverse events (AEs) [ Time Frame: Signing of informed consent through Month 24 visit ]
  5. Incidence of transplant-related mortality (TRM) [ Time Frame: Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion ]
  6. All-cause mortality [ Time Frame: Signing of informed consent through Month 24 visit ]

Secondary Outcome Measures :
  1. Proportion of subjects achieving transfusion independence for at least 6 consecutive months (TI6) [ Time Frame: From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion ]
  2. Proportion of subjects achieving at least 95 percent (%), 90%, 85%, 75%, and 50% reduction from baseline in annualized transfusions 60 days after CTX001 infusion [ Time Frame: From Day 60 up to 24 months post-CTX001 infusion ]
  3. Relative change from baseline in transfusions 60 days after CTX001 infusion [ Time Frame: From Day 60 up to 24 months post-CTX001 infusion ]
  4. Duration of transfusion free in subjects who have achieved TI12 [ Time Frame: From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion ]
  5. Proportion of alleles with intended genetic modification in peripheral blood leukocytes over time [ Time Frame: Day 1 CTX001 infusion through Month 24 visit ]
  6. Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time [ Time Frame: Day 1 CTX001 infusion through Month 24 visit ]
  7. Change in fetal hemoglobin concentration over time [ Time Frame: Baseline (pre-transfusion) through Month 24 visit ]
  8. Change in total hemoglobin concentration over time [ Time Frame: Baseline (pre-transfusion) through Month 24 visit ]
  9. Change in health-related quality of life (HRQoL) from baseline over time using EuroQol Questionnaire (5 dimensions - 5 levels of severity - EQ-5D-5L) [ Time Frame: Screening visit through Month 24 visit ]
    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."

  10. Change in health-related quality of life (HRQoL) from baseline over time using the Functional assessment of cancer therapy-bone marrow transplant questionnaire (FACT-BMT) [ Time Frame: Screening visit through Month 24 visit ]
    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 scored; the higher the score, the better the QOL.

  11. Change in patient reported outcome (PRO) over time assessed using EQ-5D-Youth (EQ-5D-Y) [ Time Frame: Screening visit through Month 24 visit ]
  12. Change in PRO over time assessed using pediatric quality of life inventory (PedsQL) [ Time Frame: Screening visit through Month 24 visit ]
  13. Changes in liver iron concentration (LIC) and cardiac iron content (CIC) and ferritin parameters of iron overload [ Time Frame: Screening visit through Month 24 visit ]
  14. Proportion of subjects receiving iron chelation therapy [ Time Frame: 1 month post-CTX001 infusion through Month 24 visit ]

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 transfusion-dependent β-thalassemia (TDT) as defined by:

    1. Documented homozygous β-thalassemia or compound heterozygous β-thalassemia including β-thalassemia/hemoglobin E (HbE). Subjects can be enrolled based on historical data, but a confirmation of the genotype using the study central laboratory will be required before busulfan conditioning.
    2. History of at least 100 mL/kg/year or ≥10 units/year of packed RBC transfusions in the prior 2 years before signing the consent or the last rescreening for patients going through re-screening.
  • Eligible for autologous stem cell transplant as per investigator's judgment.

Key Exclusion Criteria:

  • A willing and healthy 10/10 Human Leukocyte Antigen (HLA)-matched related donor is available per investigator's judgement.
  • Prior allo-HSCT.
  • Subjects with associated α-thalassemia and >1 alpha deletion or alpha multiplications.
  • Subjects with sickle cell beta thalassemia variant.
  • Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator.
  • White blood cell (WBC) count <3 × 10^9/L or platelet count <50 × 10^9/L not related to hypersplenism.

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): NCT03655678


Locations
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United States, California
Stanford University
Stanford, California, United States, 94305
United States, Illinois
Ann & Robert Lurie Children's Hospital of Chicago
Chicago, Illinois, United States, 60611
United States, New York
Columbia University
Manhattan, New York, United States, 10027
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers
Nashville, Tennessee, United States, 37203
Canada
Hospital for Sick Children
Toronto, Canada
BC Children's Hospital
Vancouver, Canada
Germany
University Hospital Duesseldorf
Düsseldorf, Germany
University Hospital Regensburg
Regensburg, Germany
University Hospital Tübingen
Tuebingen, Germany
Italy
Bambino Gesu
Rome, Italy
United Kingdom
Imperial College Healthcare
London, United Kingdom
University College London Hospitals NHS Foundation Trust
London, United Kingdom
Sponsors and Collaborators
Vertex Pharmaceuticals Incorporated
CRISPR Therapeutics
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: NCT03655678    
Other Study ID Numbers: CTX001-111
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: December 22, 2023
Last Verified: November 2023
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
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Vertex Pharmaceuticals Incorporated:
CRISPR-Cas9
Beta-Thalassemia
Hemoglobinopathies
Additional relevant MeSH terms:
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Thalassemia
Hematologic Diseases
beta-Thalassemia
Hemoglobinopathies
 Genetic Diseases, Inborn
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia