search
Back to results

A Safety and Efficacy Study Evaluating CTX001 in Subjects With Severe Sickle Cell Disease

Primary Purpose

Sickle Cell Disease, Hematological Diseases, Hemoglobinopathies

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
CTX001
Sponsored by
Vertex Pharmaceuticals Incorporated
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease

Eligibility Criteria

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

Key Inclusion Criteria:

  • Diagnosis of severe sickle cell disease as defined by:
  • Documented severe sickle cell disease genotype
  • History of at least two severe vaso-occlusive crisis events per year for the previous two years prior to enrollment
  • Eligible for autologous stem cell transplant as per investigators judgment

Key Exclusion Criteria:

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

Other protocol defined inclusion/exclusion criteria may apply

Sites / Locations

  • Lucille Packard Children's Hospital of Stanford University
  • Ann & Robert Lurie Children's Hospital of Chicago
  • University of Illinois at Chicago Hospitals and Health Systems
  • Columbia University Medical Center (21+ years)
  • Columbia University Medical Center (≤21 years)
  • Children's Hospital of Philadelphia
  • St. Jude Children's Research Hospital
  • The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers
  • Methodist Children's Hospital/Texas Transplant Institute
  • Hopital Universitaire des Enfants Reine Fabiola (HUDERF)
  • The Hospital for Sick Children
  • Hopital Necker Enfants Malades
  • University Hospital Duesseldorf
  • Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine, Paediatric Haemotology, Oncology and Stem Cell Transplantation
  • Dipartimento di Onco-Ematologia e Terapia Cellulare e Genica Ospedale Pediatrico Bambino Gesu - IRCCS
  • Imperial College Healthcare NHS Trust, Hammersmith Hospital
  • Royal London and St Bartholomew's Hospital, Pathology and Pharmacy Building

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 who have not experienced any severe vaso-occlusive crisis (VOC) for at least 12 consecutive months (VF12)
Proportion of subjects with engraftment (first day of three consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days)
Time to engraftment
Frequency and severity of collected adverse events (AEs)
Incidence of transplant-related mortality (TRM) within 100 days after CTX001 infusion
Incidence of TRM within 1 year after CTX001 infusion
All-cause mortality

Secondary Outcome Measures

Proportion of subjects free from inpatient hospitalization for severe VOCs sustained for at least 12 months (HF12)
Proportion of subjects who have not experienced any severe VOC for at least 9 consecutive months (VF9) any time after CTX001 infusion
Proportion of subjects with 90 percent (%), 80%, 75% or 50% reduction in annualized rate of severe VOCs
Relative change from baseline in annualized rate of severe VOCs
Duration of severe VOC free in subjects who have achieved VF12
Relative Change from baseline in rate of inpatient hospitalization for severe VOCs
Relative change from baseline in annualized duration of hospitalization for severe VOCs
Proportion of subjects with sustained HbF ≥20% for at least 3 months
Proportion of subjects with sustained HbF ≥20% for at least 12 months
Proportion of subjects with sustained HbF ≥20% for at least 6 months
Change in number of units of RBC transfused for SCD-related indications
HbF concentration over time
Hb concentration over time
Change from baseline in indirect bilirubin over time
Change from baseline in reticulocyte count over time
Change from baseline in haptoglobin over time
Change from baseline in lactate dehydrogenase over time
Proportion of alleles with intended genetic modification present in peripheral blood leukocytes over time
Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time
Change in patient-reported outcome (PRO) over time assessed using weekly pain-scale (11-point numerical rating scale [NRS])
The NRS is a 1-dimensional measure of reporting intensity of pain. The score of NRS ranges from 0 to 10 points, with higher values indicating a higher level of pain.
Change in PRO over time assessed using EuroQol quality of life scale (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 PRO over time assessed using EQ-5D-Youth (EQ-5D-Y)
Change in PRO over time assessed using functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) questionnaire
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 then scored; the higher the score, the better the quality of life.
Change in PRO over time assessed using adult sickle cell quality of life measurement system (ASCQ-Me)
ASCQ-Me comprises measures to assess physical, mental and social health along with information on severity of disease. It includes the following domains: emotional impact, pain impact, pain episodes, sleep impact, social functioning impact, stiffness impact and SCD medical history checklist. ASCQ-Me domains are scored using T-score metric with mean of 50 for reference population and SD of 10. Higher scores indicate healthier status.
Change in PRO over time assessed using pediatric quality of life inventory (PedsQL)
Change in PRO over time assessed using PedsQL sickle cell disease module

Full Information

First Posted
November 9, 2018
Last Updated
December 2, 2022
Sponsor
Vertex Pharmaceuticals Incorporated
Collaborators
CRISPR Therapeutics
search

1. Study Identification

Unique Protocol Identification Number
NCT03745287
Brief Title
A Safety and Efficacy Study Evaluating CTX001 in Subjects With Severe Sickle Cell Disease
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
November 27, 2018 (Actual)
Primary Completion Date
October 2024 (Anticipated)
Study Completion Date
October 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
No
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 severe sickle cell disease (SCD). 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
Sickle Cell Disease, Hematological Diseases, 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
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 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 who have not experienced any severe vaso-occlusive crisis (VOC) for at least 12 consecutive months (VF12)
Time Frame
From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
Title
Proportion of subjects with engraftment (first day of three consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days)
Time Frame
Within 42 days after CTX001 infusion
Title
Time to engraftment
Time Frame
From CTX001 infusion up to 2 years after CTX001 infusion
Title
Frequency and severity of collected adverse events (AEs)
Time Frame
From screening to 2 years after CTX001 infusion
Title
Incidence of transplant-related mortality (TRM) within 100 days after CTX001 infusion
Time Frame
Within 100 days after CTX001 infusion
Title
Incidence of TRM within 1 year after CTX001 infusion
Time Frame
Within 1 year after CTX001 infusion
Title
All-cause mortality
Time Frame
2 years after mobilization
Secondary Outcome Measure Information:
Title
Proportion of subjects free from inpatient hospitalization for severe VOCs sustained for at least 12 months (HF12)
Time Frame
From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
Title
Proportion of subjects who have not experienced any severe VOC for at least 9 consecutive months (VF9) any time after CTX001 infusion
Time Frame
From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
Title
Proportion of subjects with 90 percent (%), 80%, 75% or 50% reduction in annualized rate of severe VOCs
Time Frame
From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
Title
Relative change from baseline in annualized rate of severe VOCs
Time Frame
From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
Title
Duration of severe VOC free in subjects who have achieved VF12
Time Frame
From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
Title
Relative Change from baseline in rate of inpatient hospitalization for severe VOCs
Time Frame
From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
Title
Relative change from baseline in annualized duration of hospitalization for severe VOCs
Time Frame
From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
Title
Proportion of subjects with sustained HbF ≥20% for at least 3 months
Time Frame
From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
Title
Proportion of subjects with sustained HbF ≥20% for at least 12 months
Time Frame
From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
Title
Proportion of subjects with sustained HbF ≥20% for at least 6 months
Time Frame
From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
Title
Change in number of units of RBC transfused for SCD-related indications
Time Frame
6 months up to 2 years after CTX001 infusion
Title
HbF concentration over time
Time Frame
1 month up to 2 years after CTX001 infusion
Title
Hb concentration over time
Time Frame
From the time of CTX001 up to 2 years after CTX001 infusion
Title
Change from baseline in indirect bilirubin over time
Time Frame
From baseline (pre-infusion) up to 2 years after CTX001 infusion
Title
Change from baseline in reticulocyte count over time
Time Frame
From baseline (pre-infusion) up to 2 years after CTX001 infusion
Title
Change from baseline in haptoglobin over time
Time Frame
From baseline (pre-infusion) up to 2 years after CTX001 infusion
Title
Change from baseline in lactate dehydrogenase over time
Time Frame
From baseline (pre-infusion) up to 2 years after CTX001 infusion
Title
Proportion of alleles with intended genetic modification present in peripheral blood leukocytes over time
Time Frame
1 month up to 2 years after CTX001 infusion
Title
Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time
Time Frame
6 months up to 2 years after CTX001 infusion
Title
Change in patient-reported outcome (PRO) over time assessed using weekly pain-scale (11-point numerical rating scale [NRS])
Description
The NRS is a 1-dimensional measure of reporting intensity of pain. The score of NRS ranges from 0 to 10 points, with higher values indicating a higher level of pain.
Time Frame
3 months up to 2 years after CTX001 infusion
Title
Change in PRO over time assessed using EuroQol quality of life scale (EQ-5D-5L)
Description
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"
Time Frame
3 months up to 2 years after CTX001 infusion
Title
Change in PRO over time assessed using EQ-5D-Youth (EQ-5D-Y)
Time Frame
3 months up to 2 years after CTX001 infusion
Title
Change in PRO over time assessed using functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) questionnaire
Description
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 then scored; the higher the score, the better the quality of life.
Time Frame
3 months up to 2 years after CTX001 infusion
Title
Change in PRO over time assessed using adult sickle cell quality of life measurement system (ASCQ-Me)
Description
ASCQ-Me comprises measures to assess physical, mental and social health along with information on severity of disease. It includes the following domains: emotional impact, pain impact, pain episodes, sleep impact, social functioning impact, stiffness impact and SCD medical history checklist. ASCQ-Me domains are scored using T-score metric with mean of 50 for reference population and SD of 10. Higher scores indicate healthier status.
Time Frame
3 months up to 2 years after CTX001 infusion
Title
Change in PRO over time assessed using pediatric quality of life inventory (PedsQL)
Time Frame
3 months up to 2 years after CTX001 infusion
Title
Change in PRO over time assessed using PedsQL sickle cell disease module
Time Frame
3 months up to 2 years after CTX001 infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria: Diagnosis of severe sickle cell disease as defined by: Documented severe sickle cell disease genotype History of at least two severe vaso-occlusive crisis events per year for the previous two years prior to enrollment Eligible for autologous stem cell transplant as per investigators judgment Key Exclusion Criteria: An available 10/10 human leukocyte antigen (HLA)-matched related donor Prior hematopoietic stem cell transplant (HSCT) Clinically significant and active bacterial, viral, fungal, or parasitic infection Other protocol defined inclusion/exclusion criteria may apply
Facility Information:
Facility Name
Lucille Packard Children's Hospital of Stanford University
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Ann & Robert Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Illinois at Chicago Hospitals and Health Systems
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Columbia University Medical Center (21+ years)
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Columbia University Medical Center (≤21 years)
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Methodist Children's Hospital/Texas Transplant Institute
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Hopital Universitaire des Enfants Reine Fabiola (HUDERF)
City
Brussels
Country
Belgium
Facility Name
The Hospital for Sick Children
City
Toronto
Country
Canada
Facility Name
Hopital Necker Enfants Malades
City
Paris
Country
France
Facility Name
University Hospital Duesseldorf
City
Dusseldorf
Country
Germany
Facility Name
Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine, Paediatric Haemotology, Oncology and Stem Cell Transplantation
City
Regensburg
Country
Germany
Facility Name
Dipartimento di Onco-Ematologia e Terapia Cellulare e Genica Ospedale Pediatrico Bambino Gesu - IRCCS
City
Rome
Country
Italy
Facility Name
Imperial College Healthcare NHS Trust, Hammersmith Hospital
City
London
Country
United Kingdom
Facility Name
Royal London and St Bartholomew's Hospital, Pathology and Pharmacy Building
City
London
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34175041
Citation
Brusson M, Miccio A. Genome editing approaches to beta-hemoglobinopathies. Prog Mol Biol Transl Sci. 2021;182:153-183. doi: 10.1016/bs.pmbts.2021.01.025. Epub 2021 Mar 1.
Results Reference
derived
PubMed Identifier
33283989
Citation
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 beta-Thalassemia. N Engl J Med. 2021 Jan 21;384(3):252-260. doi: 10.1056/NEJMoa2031054. Epub 2020 Dec 5.
Results Reference
derived
PubMed Identifier
32873924
Citation
Modarai SR, Kanda S, Bloh K, Opdenaker LM, Kmiec EB. Precise and error-prone CRISPR-directed gene editing activity in human CD34+ cells varies widely among patient samples. Gene Ther. 2021 Feb;28(1-2):105-113. doi: 10.1038/s41434-020-00192-z. Epub 2020 Sep 1.
Results Reference
derived

Learn more about this trial

A Safety and Efficacy Study Evaluating CTX001 in Subjects With Severe Sickle Cell Disease

We'll reach out to this number within 24 hrs