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

Primary Purpose

Beta-Thalassemia, Thalassemia, Genetic Diseases, Inborn

Status

Active

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

CTX001

About this trial

This is an interventional treatment trial for Beta-Thalassemia focused on measuring CRISPR-Cas9, Beta-Thalassemia, Hemoglobinopathies

Eligibility Criteria

12 Years - 35 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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:

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.

Sites / Locations

Stanford University
Ann & Robert Lurie Children's Hospital of Chicago
Columbia University
The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers
Hospital for Sick Children
BC Children's Hospital
University Hospital Duesseldorf
University Hospital Regensburg
University Hospital Tübingen
Bambino Gesu
Imperial College Healthcare
University College London Hospitals NHS Foundation Trust

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CTX001

Arm Description

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.

Outcomes

Primary Outcome Measures

Proportion of subjects achieving transfusion independence for at least 12 consecutive months (TI12)

Proportion of subjects with engraftment (first day of 3 consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days)

Time to neutrophil and platelet engraftment

Frequency and severity of collected adverse events (AEs)

Incidence of transplant-related mortality (TRM)

All-cause mortality

Secondary Outcome Measures

Proportion of subjects achieving transfusion independence for at least 6 consecutive months (TI6)

Proportion of subjects achieving at least 95 percent (%), 90%, 85%, 75%, and 50% reduction from baseline in annualized transfusions 60 days after CTX001 infusion

Relative change from baseline in transfusions 60 days after CTX001 infusion

Duration of transfusion free in subjects who have achieved TI12

Proportion of alleles with intended genetic modification in peripheral blood leukocytes over time

Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time

Change in fetal hemoglobin concentration over time

Change in total hemoglobin concentration over time

Change in health-related quality of life (HRQoL) from baseline over time using EuroQol Questionnaire (5 dimensions - 5 levels of severity - EQ-5D-5L)

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)

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)

Change in PRO over time assessed using pediatric quality of life inventory (PedsQL)

Changes in liver iron concentration (LIC) and cardiac iron content (CIC) and ferritin parameters of iron overload

Proportion of subjects receiving iron chelation therapy

Full Information

NCT ID

NCT03655678

First Posted

August 29, 2018

Last Updated

November 30, 2022

Sponsor

Vertex Pharmaceuticals Incorporated

Collaborators

CRISPR Therapeutics

1. Study Identification

Unique Protocol Identification Number

NCT03655678

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

September 14, 2018 (Actual)

Primary Completion Date

August 2024 (Anticipated)

Study Completion Date

August 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Vertex Pharmaceuticals Incorporated

Collaborators

CRISPR Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

CRISPR-Cas9, Beta-Thalassemia, Hemoglobinopathies

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

CTX001

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

CTX001

Other Intervention Name(s)

Exagamglogene autotemcel, Exa-cel

Intervention Description

Administered by IV infusion following myeloablative conditioning with busulfan

Primary Outcome Measure Information:

Title

Proportion of subjects achieving transfusion independence for at least 12 consecutive months (TI12)

Time Frame

From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion]

Title

Proportion of subjects with engraftment (first day of 3 consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days)

Time Frame

Within 42 days after CTX001 infusion

Title

Time to neutrophil and platelet engraftment

Time Frame

Days post-infusion to engraftment

Title

Frequency and severity of collected adverse events (AEs)

Time Frame

Signing of informed consent through Month 24 visit

Title

Incidence of transplant-related mortality (TRM)

Time Frame

Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion

Title

All-cause mortality

Time Frame

Signing of informed consent through Month 24 visit

Secondary Outcome Measure Information:

Title

Proportion of subjects achieving transfusion independence for at least 6 consecutive months (TI6)

Time Frame

From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion

Title

Proportion of subjects achieving at least 95 percent (%), 90%, 85%, 75%, and 50% reduction from baseline in annualized transfusions 60 days after CTX001 infusion

Time Frame

From Day 60 up to 24 months post-CTX001 infusion

Title

Relative change from baseline in transfusions 60 days after CTX001 infusion

Time Frame

From Day 60 up to 24 months post-CTX001 infusion

Title

Duration of transfusion free in subjects who have achieved TI12

Time Frame

From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion

Title

Proportion of alleles with intended genetic modification in peripheral blood leukocytes over time

Time Frame

Day 1 CTX001 infusion through Month 24 visit

Title

Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time

Time Frame

Day 1 CTX001 infusion through Month 24 visit

Title

Change in fetal hemoglobin concentration over time

Time Frame

Baseline (pre-transfusion) through Month 24 visit

Title

Change in total hemoglobin concentration over time

Time Frame

Baseline (pre-transfusion) through Month 24 visit

Title

Change in health-related quality of life (HRQoL) from baseline over time using EuroQol Questionnaire (5 dimensions - 5 levels of severity - EQ-5D-5L)

Description

Time Frame