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

• ClinicalTrials.gov Identifier: NCT03745287
• Recruitment Status: Active, not recruiting
• First Posted: November 19, 2018
• Last Update Posted: May 16, 2024
• Sponsor: Vertex Pharmaceuticals Incorporated
• Collaborator: CRISPR Therapeutics
• Information provided by (Responsible Party): Vertex Pharmaceuticals Incorporated

Tracking Information

• First Submitted Date: November 9, 2018
• First Posted Date: November 19, 2018
• Last Update Posted Date: May 16, 2024
• Actual Study Start Date: November 27, 2018
• Estimated Primary Completion Date: October 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 3, 2021)

• 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 ]
• 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 ]
• Time to engraftment [ Time Frame: From CTX001 infusion up to 2 years after CTX001 infusion ]
• Frequency and severity of collected adverse events (AEs) [ Time Frame: From screening to 2 years after CTX001 infusion ]
• Incidence of transplant-related mortality (TRM) within 100 days after CTX001 infusion [ Time Frame: Within 100 days after CTX001 infusion ]
• Incidence of TRM within 1 year after CTX001 infusion [ Time Frame: Within 1 year after CTX001 infusion ]
• All-cause mortality [ Time Frame: 2 years after mobilization ]

Original Primary Outcome Measures (submitted: November 15, 2018)

• Proportion of subjects with HbF ≥20%, sustained for at least 3 months at the time of analysis, starting 6 months after CTX001 infusion [ Time Frame: 6 months up to 2 years after 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 engraftment [ Time Frame: From CTX001 infusion up to 2 years after CTX001 infusion ]
• Frequency and severity of collected adverse events (AEs) [ Time Frame: From screening to 2 years after CTX001 infusion ]
• Incidence of transplant-related mortality (TRM) within 100 days after CTX001 infusion [ Time Frame: Within 100 days after CTX001 infusion ]
• Incidence of TRM within 1 year after CTX001 infusion [ Time Frame: Within 1 year after CTX001 infusion ]
• All-cause mortality [ Time Frame: 2 years after mobilization ]

Current Secondary Outcome Measures (submitted: December 2, 2022)

• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• Change in number of units of RBC transfused for SCD-related indications [ Time Frame: 6 months up to 2 years after CTX001 infusion ]
• HbF concentration over time [ Time Frame: 1 month up to 2 years after CTX001 infusion ]
• Hb concentration over time [ Time Frame: From the time of CTX001 up to 2 years after CTX001 infusion ]
• Change from baseline in indirect bilirubin over time [ Time Frame: From baseline (pre-infusion) up to 2 years after CTX001 infusion ]
• Change from baseline in reticulocyte count over time [ Time Frame: From baseline (pre-infusion) up to 2 years after CTX001 infusion ]
• Change from baseline in haptoglobin over time [ Time Frame: From baseline (pre-infusion) up to 2 years after CTX001 infusion ]
• Change from baseline in lactate dehydrogenase over time [ Time Frame: From baseline (pre-infusion) up to 2 years after CTX001 infusion ]
• 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 ]
• 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 ]
• Change in patient-reported outcome (PRO) over time assessed using weekly pain-scale (11-point numerical rating scale [NRS]) [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
  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) [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
  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) [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
• Change in PRO over time assessed using functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) questionnaire [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
  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) [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
  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) [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
• Change in PRO over time assessed using PedsQL sickle cell disease module [ Time Frame: 3 months up to 2 years after CTX001 infusion ]

Original Secondary Outcome Measures (submitted: November 15, 2018)

• Relative change from baseline in annualized rate of severe vaso-occlusive crises (VOC) 6 months after CTX001 infusion [ Time Frame: 6 months up to 2 years after CTX001 infusion ]
• Change from baseline in annualized rate of severe VOC by at least 50% [ Time Frame: 6 months up to 2 years after CTX001 infusion ]
• Change from baseline in annualized rate of severe VOC by at least 65% [ Time Frame: 6 months up to 2 years after CTX001 infusion ]
• Number of subjects with absence of severe VOC events for at least 12 months [ Time Frame: 6 months up to 2 years after CTX001 infusion ]
• Change from baseline in annualized duration of hospitalization for severe VOC 6 months after CTX001 infusion [ Time Frame: 6 months up to 2 years after CTX001 infusion ]
• Proportion of subjects with sustained HbF ≥20% for at least 3 months [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
• Proportion of subjects with sustained HbF ≥20% for at least 3 months [ Time Frame: From the time of CTX001 infusion up to 2 years after CTX001 infusion ]
• Proportion of subjects with sustained HbF ≥20% for 6 months starting 6 months after CTX001 infusion [ Time Frame: 6 months up to 2 years after CTX001 infusion ]
• Change in number of units of RBC transfused for SCD-related indications [ Time Frame: 6 months up to 2 years after CTX001 infusion ]
• HbF concentration over time [ Time Frame: 1 month up to 2 years after CTX001 infusion ]
• Hb concentration over time [ Time Frame: From the time of CTX001 up to 2 years after CTX001 infusion ]
• 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 ]
• Proportion of alleles with intended genetic modification present in bone marrow cells over time [ Time Frame: 6 months up to 2 years after CTX001 infusion ]
• Change in patient-reported outcome (PRO) over time assessed using weekly pain-scale (11-point numerical rating scale [NRS]) [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
  The NRS is a 1-dimensional measure of reporting intensity of pain in adults. 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) [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
  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 functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) questionnaire [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
  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 patient-reported outcome measurement information system (PROMIS) [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
  PROMIS item bank contains over 300 items of illness-related PROs. PROMIS-Fatigue evaluates self-reported symptoms such as feeling tired and extreme exhaustion, and the impact of these symptoms on daily activities and normal functioning. PROMIS-Cognitive function evaluates the ability to think and concentrate. PROMIS measures are scored using T-score metric with a mean of 50 for reference population and SD of 10. Higher scores indicate healthier status.
• Change in PRO over time assessed using adult sickle cell quality of life measurement system (ASCQ-Me) [ Time Frame: 3 months up to 2 years after CTX001 infusion ]
  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.

• 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 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Sickle Cell Disease
• Hematological Diseases
• Hemoglobinopathies

Intervention

Biological: CTX001

Administered by IV infusion following myeloablative conditioning with busulfan.

Other Names:

• Exagamglogene autotemcel
• Exa-cel

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 *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: November 15, 2018): 45
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 2024
• Estimated Primary Completion Date: October 2024 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years to 35 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, France, Germany, Italy, United Kingdom, United States

Administrative Information

• NCT Number: NCT03745287
• Other Study ID Numbers: CTX001-121
• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Vertex Pharmaceuticals Incorporated
• Original Responsible Party: CRISPR Therapeutics
• Current Study Sponsor: Vertex Pharmaceuticals Incorporated
• Original Study Sponsor: CRISPR Therapeutics
• Collaborators: CRISPR Therapeutics
• Investigators: Not Provided
• PRS Account: Vertex Pharmaceuticals Incorporated
• Verification Date: November 2023