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

• ClinicalTrials.gov Identifier: NCT03655678
• Recruitment Status: Recruiting
• First Posted: August 31, 2018
• Last Update Posted: February 16, 2021
• Sponsor: Vertex Pharmaceuticals Incorporated
• Collaborator: CRISPR Therapeutics
• Information provided by (Responsible Party): Vertex Pharmaceuticals Incorporated

Tracking Information

• First Submitted Date: August 29, 2018
• First Posted Date: August 31, 2018
• Last Update Posted Date: February 16, 2021
• Actual Study Start Date: September 14, 2018
• Estimated Primary Completion Date: February 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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 ]

Current Secondary Outcome Measures (submitted: June 15, 2020)

• 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.
• Change in patient reported outcome (PRO) over time assessed using EQ-5D-Youth (EQ-5D-Y) [ Time Frame: Screening visit through Month 24 visit ]
• Change in PRO over time assessed using pediatric quality of life inventory (PedsQL) [ Time Frame: Screening visit through Month 24 visit ]
• 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 ]
• Proportion of subjects receiving iron chelation therapy [ Time Frame: 1 month post-CTX001 infusion through Month 24 visit ]

Original Secondary Outcome Measures (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: A Safety and Efficacy Study Evaluating CTX001 in Subjects With Transfusion-Dependent β-Thalassemia
• 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
• Brief Summary: This is a single-arm, open-label, multi-site, single-dose Phase 1/2 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Beta-Thalassemia
• Thalassemia
• Genetic Diseases, Inborn
• Hematologic Diseases
• Hemoglobinopathies

Intervention

Biological: CTX001

Administered by IV infusion following myeloablative conditioning with busulfan

Study Arms

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 *: Frangoul H, Altshuler D, Cappellini MD, Chen YS, Domm J, Eustace BK, Foell J, de la Fuente J, Grupp S, Handgretinger R, Ho TW, Kattamis A, Kernytsky A, Lekstrom-Himes J, Li AM, Locatelli F, Mapara MY, de Montalembert M, Rondelli D, Sharma A, Sheth S, Soni S, Steinberg MH, Wall D, Yen A, Corbacioglu S. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. N Engl J Med. 2021 Jan 21;384(3):252-260. doi: 10.1056/NEJMoa2031054. Epub 2020 Dec 5.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 5, 2018): 45
• Original Estimated Enrollment (submitted: August 30, 2018): 30
• Estimated Study Completion Date: May 2022
• Estimated Primary Completion Date: February 2021 (Final data collection date for primary outcome measure)

Eligibility 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:

• 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

• Sexes Eligible for Study: All

• Ages: 12 Years to 35 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Medical Information; 6173416777; medicalinfo@vrtx.com

• Listed Location Countries: Canada, Germany, Italy, United Kingdom, United States

Administrative Information

• NCT Number: NCT03655678
• Other Study ID Numbers: 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

• Plan to Share IPD: No

• Responsible Party: Vertex Pharmaceuticals Incorporated
• Study Sponsor: Vertex Pharmaceuticals Incorporated
• Collaborators: CRISPR Therapeutics
• Investigators: Not Provided
• PRS Account: Vertex Pharmaceuticals Incorporated
• Verification Date: February 2021