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

Phase 2

Active, not recruiting

• Conditions: Thalassemia; Hemoglobinopathies; Hematologic Diseases; Beta-Thalassemia; Genetic Diseases, Inborn
• Interventions: Biological: CTX001

• Registration Number: NCT03655678
• Lead Sponsor: Vertex Pharmaceuticals Incorporated

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-08-29
• Study First Submitted QC: 2018-08-30
• Study First Posted: 2018-08-31
• Study Start: 2018-09-14
• Status Verified: 2024-09
• Last Update Submitted: 2024-09-27
• Last Update Posted: 2024-09-30
• Primary Completion: 2025-12
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 59

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
CTX001	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.

Primary Outcome Measures

Name	Time	Method
Frequency and severity of collected adverse events (AEs)	Signing of informed consent through Month 24 visit
Time to neutrophil and platelet engraftment	Days post-infusion to engraftment
Incidence of transplant-related mortality (TRM)	Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion
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]
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
All-cause mortality	Signing of informed consent through Month 24 visit

Secondary Outcome Measures

Name	Time	Method
Relative change from baseline in transfusions 60 days after CTX001 infusion	From Day 60 up to 24 months post-CTX001 infusion
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."
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.
Change in patient reported outcome (PRO) over time assessed using EQ-5D-Youth (EQ-5D-Y)	Screening visit through Month 24 visit
Changes in liver iron concentration (LIC) and cardiac iron content (CIC) and ferritin parameters of iron overload	Screening visit through Month 24 visit
Proportion of subjects receiving iron chelation therapy	1 month post-CTX001 infusion through Month 24 visit
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
Duration of transfusion free in subjects who have achieved TI12	From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion
Change in fetal hemoglobin concentration over time	Baseline (pre-transfusion) through Month 24 visit
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
Proportion of alleles with intended genetic modification in peripheral blood leukocytes over time	Day 1 CTX001 infusion through Month 24 visit
Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time	Day 1 CTX001 infusion through Month 24 visit
Change in total hemoglobin concentration over time	Baseline (pre-transfusion) through Month 24 visit
Change in PRO over time assessed using pediatric quality of life inventory (PedsQL)	Screening visit through Month 24 visit

Trial Locations

Locations (14)

Lucile Packard Children's Hospital; 🇺🇸 Palo Alto, California, United States

Columbia University Medical Center (21+ years); 🇺🇸 New York, New York, United States

Columbia University Medical Center; 🇺🇸 New York, New York, United States

Universitätsklinikum Düsseldorf Hospital Duesseldorf; 🇩🇪 Düsseldorf, Germany

Ospedale Pediatrico Bambino Gesù, IRCCS; 🇮🇹 Rome, Italy

Ann & Robert Lurie Children's Hospital of Chicago; 🇺🇸 Chicago, Illinois, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers; 🇺🇸 Nashville, Tennessee, United States

British Columbia Children's Hospital; 🇨🇦 Vancouver, Canada

Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine; 🇩🇪 Regensburg, Germany

University Hospital Tübingen; 🇩🇪 Tuebingen, Germany

The Hospital for Sick Children; 🇨🇦 Toronto, Canada

University College London Hospitals NHS Foundation Trust; 🇬🇧 London, United Kingdom

Imperial College Healthcare NHS Trust, Hammersmith Hospital; 🇬🇧 London, United Kingdom