A Phase 1/2/3 Study to Evaluate the Safety and Efficacy of a Single Dose of Autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (CTX001) in Subjects With Severe Sickle Cell Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Vertex Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

2 May 2019 → 8 Jul 2025

Decision date (initial)

2024-08-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-516067-83-00

EudraCT number

2018-001320-19

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Evaluate the safety and efficacy of a single dose of autologous CRISPR Cas9 modified CD34⁺ human hematopoietic stem and progenitor cells (hHSPCs) (CTX001) in subjects with severe sickle cell disease (SCD)

Secondary objectives 2

1. Assess the effects of infusion of CTX001 on disease-specific events and clinical status
2. Quantify gene editing efficiency

Conditions and MedDRA coding

Severe sickle cell disease (SCD)

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002730-PIP03-21

Plan to share IPD

No

IPD plan description

Details on Vertex data sharing criteria and process for requesting access can be found at: https://www.vrtx.com/independent-research/clinical-trial-data-sharing

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Diagnosis of severe sickle cell disease
2. Documented severe sickle cell disease genotype
3. History of at least two severe vaso-occlusive crisis events per year for the previous two years prior to enrollment
4. Eligible for autologous stem cell transplant as per investigators judgment

Exclusion criteria 3

1. An available 10/10 human leukocyte antigen (HLA)-matched related donor
2. Prior hematopoietic stem cell transplant (HSCT)
3. Clinically significant and active bacterial, viral, fungal, or parasitic infection

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 8

1. Successful neutrophil engraftment
2. Time to neutrophil engraftment
3. Time to platelet engraftment
4. Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, and vital signs
5. Transplant-related mortality (TRM) within 100 days after CTX001 infusion
6. TRM within 1 year after CTX001 infusion
7. All-cause mortality
8. Proportion of subjects who have not experienced any severe VOC for at least 12 consecutive months (VF12) after CTX001 infusion. The evaluation of VF12 starts 60 days after last RBC transfusion for posttransplant support or SCD disease management

Secondary endpoints 18

1. Proportion of subjects free from inpatient hospitalization for severe VOCs sustained for at least 12 months (HF12) after CTX001 infusion. The evaluation of HF12 starts 60 days after last RBC transfusion for post-transplant support or SCD disease management
2. Proportion of subjects with reduction in annualized rate of severe VOCs at the time of analysis from baseline by at least 90%, 80%, 75%, 50% up to 24 months after CTX001 infusion. The evaluation starts 60 days after last RBC transfusion for post-transplant support or SCD disease management
3. Relative change from baseline in annualized rate of severe VOCs up to 24 months after CTX001 infusion. The evaluation starts 60 days after last RBC transfusion for post-transplant support or SCD disease management
4. Duration of severe VOC free in subjects who have achieved VF12
5. Relative change from baseline in rate of inpatient hospitalizations for severe VOCs up to 24 months after CTX001 infusion. The evaluation starts 60 days after last RBC transfusion for post-transplant support or SCD disease management
6. Relative change from baseline in annualized duration of hospitalization for severe VOCs up to 24 months after CTX001 infusion. The evaluation starts 60 days after last RBC transfusion for post-transplant support or SCD disease management
7. Proportion of subjects with sustained HbF ≥20% at the time of analysis for at least 3 months, 6 months, or 12 months. The evaluation starts 60 days after last RBC transfusion for posttransplant support or SCD disease management
8. Change in number of units of RBCs transfused for SCD-related indications over time
9. HbF concentrations over time
10. Hemoglobin (Hb) concentrations over time
11. Change from baseline in reticulocyte count (percent reticulocytes and absolute reticulocyte count) over time
12. Change from baseline in indirect bilirubin over time
13. Change from baseline in haptoglobin over time
14. Change from baseline in lactate dehydrogenase over time
15. Proportion of alleles with intended genetic modification present in peripheral blood leukocytes over time
16. Proportion of alleles with intended genetic modification present in CD34+ cells of the bone marrow over time
17. Change in patient reported outcomes (PROs) over time in adults (≥18 years) using; - Pain-scale: 11-point numerical rating scale (NRS) - Functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) - Adult Sickle Cell Quality of Life Measurement System (ASCQ-Me) - EuroQol Quality of Life Scale (EQ-5D-5L)
18. Change in PROs over time in adolescents (12 to <18 years of age) using; - Pain-scale: 11-point NRS - Pediatric Quality of Life Inventory (PedsQL Teen selfreport and parent proxy versions) - PedsQL SCD module (Teen self-report and parent proxy versions) - EQ-5D-Youth (EQ-5D-Y self-report and parent proxy version)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Vertex Pharmaceuticals Inc.

Sponsor organisation

Vertex Pharmaceuticals Inc.

Address

50 Northern Avenue

City

Boston

Postcode

02210-1862

Country

United States

Scientific contact point

Organisation

Vertex Pharmaceuticals Inc.

Contact name

Clinical Trials and Medical Info

Public contact point

Organisation

Vertex Pharmaceuticals Inc.

Contact name

Clinical Trials and Medical Info

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 58 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications