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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 : Recruiting
First Posted : August 31, 2018
Last Update Posted : June 21, 2019
Sponsor:
Collaborator:
CRISPR Therapeutics
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Brief Summary:
This is a single-arm, open-label, multi-site, single-dose Phase 1/2 study in up to 12 subjects 18 to 35 years of age with transfusion-dependent β-thalassemia (TDT), non-β0/β0. 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 1 Phase 2

Detailed Description:
The study may be expanded to include up to 45 subjects.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 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 : February 2021
Estimated Study Completion Date : May 2022


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




Primary Outcome Measures :
  1. Proportion of subjects achieving transfusion reduction for at least 6 months (TR6) [ Time Frame: From 3 to 24 months post-CTX001 infusion ]
  2. Proportion of subjects with engraftment (absolute neutrophil count [ANC] ≥500/µL for three consecutive 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 months (TI6) [ Time Frame: From 3 to 24 months post-CTX001 infusion ]
  2. Proportion of subjects achieving TR12 [ Time Frame: From 3 to 24 months post-CTX001 infusion ]
  3. Proportion of subjects achieving TI12 [ Time Frame: From 3 to 24 months post-CTX001 infusion ]
  4. Proportion of alleles with intended genetic modification in peripheral blood leukocytes over time [ Time Frame: Day 1 CTX001 infusion through Month 24 visit ]
  5. Proportion of alleles with intended genetic modification in bone marrow cells over time [ Time Frame: Day 1 CTX001 infusion through Month 24 visit ]
  6. Change in fetal hemoglobin concentration over time [ Time Frame: Baseline (pre-transfusion) through Month 24 visit ]
  7. 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."

  8. 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.

  9. Changes in liver iron concentration (LIC) and cardiac iron content (CIC) parameters of iron overload [ Time Frame: Screening visit through Month 24 visit ]
  10. Proportion of subjects receiving iron chelation therapy [ Time Frame: 1 month post-CTX001 infusion through Month 24 visit ]


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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Subjects ≥18 and ≤35 years of age.
  • Diagnosis of transfusion-dependent β-thalassemia (TDT) as defined by:

    1. Documented homozygous β-thalassemia (with the exception of the β0/β0 genotype) 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.
  • Eligible for autologous stem cell transplant as per investigator's judgment.

Key Exclusion Criteria:

  • An available 10/10 Human Leukocyte Antigen (HLA)-matched related donor.
  • Prior allo-HSCT.
  • Subjects with associated α-thalassemia and >1 alpha chain deletion or alpha multiplications.
  • β0/β0 thalassemia genotype or 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.


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


Contacts
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Contact: Medical Information 6173416777 medicalinfo@vrtx.com

Locations
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Canada
Hospital for Sick Children Recruiting
Toronto, Canada
BC Children's Hospital Recruiting
Vancouver, Canada
Germany
University Hospital Regensburg Recruiting
Regensburg, Germany
University Hospital Tübingen Recruiting
Tuebingen, Germany
United Kingdom
Imperial College Healthcare Recruiting
London, United Kingdom
Sponsors and Collaborators
Vertex Pharmaceuticals Incorporated
CRISPR Therapeutics

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Responsible Party: Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier: NCT03655678     History of Changes
Other Study ID Numbers: CTX001-111
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: June 21, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
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