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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 : December 5, 2019
Sponsor:
Collaborator:
CRISPR Therapeutics
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Tracking Information
First Submitted Date  ICMJE August 29, 2018
First Posted Date  ICMJE August 31, 2018
Last Update Posted Date December 5, 2019
Actual Study Start Date  ICMJE September 14, 2018
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 30, 2019)
  • Proportion of subjects achieving transfusion reduction for at least 6 months (TR6) [ Time Frame: From 3 to 24 months post-CTX001 infusion ]
  • Proportion of subjects with engraftment (absolute neutrophil count [ANC] ≥500/µL for three consecutive days) [ Time Frame: Within 42 days after CTX001 infusion ]
  • Time to neutrophil and platelet engraftment [ Time Frame: Days post-infusion to engraftment ]
  • Frequency and severity of collected adverse events (AEs) [ Time Frame: Signing of informed consent through Month 24 visit ]
  • Incidence of transplant-related mortality (TRM) [ Time Frame: Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion ]
  • All-cause mortality [ Time Frame: Signing of informed consent through Month 24 visit ]
Original Primary Outcome Measures  ICMJE
 (submitted: August 30, 2018)
Proportion of subjects achieving transfusion reduction for at least 6 months (TR6) [ Time Frame: From 9 to 24 months post-CTX001 infusion ]
Change History Complete list of historical versions of study NCT03655678 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 3, 2019)
  • Proportion of subjects achieving transfusion independence for at least 6 months (TI6) [ Time Frame: From 3 to 24 months post-CTX001 infusion ]
  • Proportion of subjects achieving TR12 [ Time Frame: From 3 to 24 months post-CTX001 infusion ]
  • Proportion of subjects achieving TI12 [ Time Frame: From 3 to 24 months post-CTX001 infusion ]
  • Proportion of alleles with intended genetic modification in peripheral blood leukocytes over time [ Time Frame: Day 1 CTX001 infusion through Month 24 visit ]
  • Proportion of alleles with intended genetic modification in bone marrow cells over time [ Time Frame: Day 1 CTX001 infusion through Month 24 visit ]
  • Change in fetal hemoglobin concentration over time [ Time Frame: Baseline (pre-transfusion) through Month 24 visit ]
  • Change in total hemoglobin concentration over time [ Time Frame: Baseline (pre-transfusion) through Month 24 visit ]
  • 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."
  • 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.
  • Changes in liver iron concentration (LIC) and cardiac iron content (CIC) parameters of iron overload [ Time Frame: Screening visit through Month 24 visit ]
  • Proportion of subjects receiving iron chelation therapy [ Time Frame: 1 month post-CTX001 infusion through Month 24 visit ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 30, 2018)
  • Proportion of subjects achieving transfusion independence for at least 6 months (TI6) [ Time Frame: From 9 to 24 months post-CTX001 infusion ]
  • Proportion of subjects with engraftment (absolute neutrophil count [ANC] ≥500/µL for three consecutive days) [ Time Frame: From 15 to 24 months post-CTX001 infusion ]
  • Proportion of subjects achieving TR12 [ Time Frame: From 15 to 24 months post-CTX001 infusion ]
  • Proportion of subjects achieving TI12 [ Time Frame: From 15 to 24 months post-CTX001 infusion ]
  • Time to neutrophil and platelet engraftment [ Time Frame: Days post-infusion to engraftment ]
  • Frequency and severity of collected adverse events (AEs) [ Time Frame: Signing of informed consent through Month 24 visit ]
  • Incidence of transplant-related mortality (TRM) [ Time Frame: Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion ]
  • All-cause mortality [ Time Frame: Signing of informed consent through Month 24 visit ]
  • Proportion of alleles with intended genetic modification in peripheral blood leukocytes over time [ Time Frame: Day 1 CTX001 infusion through Month 24 visit ]
  • Proportion of alleles with intended genetic modification in bone marrow cells over time [ Time Frame: Day 1 CTX001 infusion through Month 24 visit ]
  • Change in fetal hemoglobin concentration over time [ Time Frame: Baseline (pre-transfusion) through Month 24 visit ]
  • 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."
  • 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.
  • Changes in liver iron concentration (LIC) and cardiac iron content (CIC) parameters of iron overload [ Time Frame: Screening visit through Month 24 visit ]
  • Proportion of subjects receiving iron chelation therapy [ Time Frame: Baseline (pre-transfusion) through Month 24 visit ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Safety and Efficacy Study Evaluating CTX001 in Subjects With Transfusion-Dependent β-Thalassemia
Official Title  ICMJE 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
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). The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) using CTX001.
Detailed Description The study may be expanded to include up to 45 subjects.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Beta-Thalassemia
  • Thalassemia
  • Genetic Diseases, Inborn
  • Hematologic Diseases
  • Hemoglobinopathies
Intervention  ICMJE Biological: CTX001
Administered by IV infusion following myeloablative conditioning with busulfan
Study Arms  ICMJE 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.
Intervention: Biological: CTX001
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 5, 2018)
45
Original Estimated Enrollment  ICMJE
 (submitted: August 30, 2018)
30
Estimated Study Completion Date  ICMJE May 2022
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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:

  • 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.
  • 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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 35 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Medical Information 6173416777 medicalinfo@vrtx.com
Listed Location Countries  ICMJE Canada,   Germany,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03655678
Other Study ID Numbers  ICMJE CTX001-111
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Vertex Pharmaceuticals Incorporated
Study Sponsor  ICMJE Vertex Pharmaceuticals Incorporated
Collaborators  ICMJE CRISPR Therapeutics
Investigators  ICMJE Not Provided
PRS Account Vertex Pharmaceuticals Incorporated
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP