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

ClinicalTrials.gov processed this data on September 27, 2024. Link to the current ClinicalTrials.gov record.

Recruitment Status

ACTIVE, NOT RECRUITING (See Contacts and Locations)
Verified September 2024 by Vertex Pharmaceuticals Incorporated, CRISPR Therapeutics

Sponsor

Vertex Pharmaceuticals Incorporated

Information Provided by (Responsible Party)

Vertex Pharmaceuticals Incorporated

Clinicaltrials.gov Identifier

NCT03655678
Other Study ID Numbers: CTX001-111
First Submitted: August 29, 2018
First Posted: August 31, 2018
Last Update Posted: October 1, 2024
Last Verified: September 2024
History of Changes

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Study Description

Not Provided
Condition or Disease Intervention/Treatment
  • Beta-Thalassemia
  • Thalassemia
  • Genetic Diseases, Inborn
  • Hematologic Diseases
  • Hemoglobinopathies
  • Biological: CTX001

Study Design

Study TypeInterventional
Actual Enrollment59 participants
Design AllocationN/A
Interventional ModelSingle Group Assignment
MaskingNone (Open Label)
Primary PurposeTreatment
Official TitleA 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
Study Start DateSeptember 14, 2018
Anticipated Primary Completion DateDecember 2025
Anticipated Study Completion DateDecember 2025

Groups and Cohorts

Group/ CohortIntervention/ Treatment
  • 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

Primary Outcome Measures

  1. Proportion of subjects achieving transfusion independence for at least 12 consecutive months (TI12) [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) [Within 42 days after CTX001 infusion]
  3. Time to neutrophil and platelet engraftment [Days post-infusion to engraftment]
  4. Frequency and severity of collected adverse events (AEs) [Signing of informed consent through Month 24 visit]
  5. Incidence of transplant-related mortality (TRM) [Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion]
  6. All-cause mortality [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) [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 [From Day 60 up to 24 months post-CTX001 infusion]
  3. Relative change from baseline in transfusions 60 days after CTX001 infusion [From Day 60 up to 24 months post-CTX001 infusion]
  4. Duration of transfusion free in subjects who have achieved TI12 [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 [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 [Day 1 CTX001 infusion through Month 24 visit]
  7. Change in fetal hemoglobin concentration over time [Baseline (pre-transfusion) through Month 24 visit]
  8. Change in total hemoglobin concentration over time [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) [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) [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) [Screening visit through Month 24 visit]
  12. Change in PRO over time assessed using pediatric quality of life inventory (PedsQL) [Screening visit through Month 24 visit]
  13. Changes in liver iron concentration (LIC) and cardiac iron content (CIC) and ferritin parameters of iron overload [Screening visit through Month 24 visit]
  14. Proportion of subjects receiving iron chelation therapy [1 month post-CTX001 infusion through Month 24 visit]

Eligibility Criteria

Ages Eligible for Study 12 Years to 35 Years (Child, Adult)
Sexes Eligible for Study All
Accepts Healthy Volunteers No
Inclusion Criteria
  • a:
  • Diagnosis of transfusion-dependent β-thalassemia (TDT) as defined by:
  • 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.
  • 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.
  • Ke
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

Sponsors and Collaborators Vertex Pharmaceuticals Incorporated, CRISPR Therapeutics
CRISPR Therapeutics
Locations
  • Lucile Packard Children's Hospital | Palo Alto, California, United States, 94304
  • Ann & Robert Lurie Children's Hospital of Chicago | Chicago, Illinois, United States, 60611
  • Columbia University Medical Center (21+ years) | New York, New York, United States, 10032
  • Columbia University Medical Center | New York, New York, United States, 10032
  • Children's Hospital of Philadelphia | Philadelphia, Pennsylvania, United States, 19104
  • The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers | Nashville, Tennessee, United States, 37203
  • The Hospital for Sick Children | Toronto, Canada,
  • British Columbia Children's Hospital | Vancouver, Canada,
  • Universitätsklinikum Düsseldorf Hospital Duesseldorf | Düsseldorf, Germany,
  • Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine | Regensburg, Germany,
  • University Hospital Tübingen | Tuebingen, Germany,
  • Ospedale Pediatrico Bambino Gesù, IRCCS | Rome, Italy,
  • Imperial College Healthcare NHS Trust, Hammersmith Hospital | London, United Kingdom,
  • University College London Hospitals NHS Foundation Trust | London, United Kingdom,