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

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ClinicalTrials.gov Identifier: NCT03745287
Recruitment Status : Recruiting
First Posted : November 19, 2018
Last Update Posted : May 3, 2019
Sponsor:
Collaborator:
CRISPR Therapeutics
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Tracking Information
First Submitted Date  ICMJE November 9, 2018
First Posted Date  ICMJE November 19, 2018
Last Update Posted Date May 3, 2019
Actual Study Start Date  ICMJE November 27, 2018
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03745287 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 30, 2019)
  • 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 ]
  • Relative Change from baseline in annualized rate of hospitalization for severe VOC 6 months after CTX001 infusion [ 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 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.
Original Secondary Outcome Measures  ICMJE
 (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  ICMJE A Safety and Efficacy Study Evaluating CTX001 in Subjects With Severe Sickle Cell Disease
Official Title  ICMJE A Phase 1/2 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 study in up to 12 subjects 18 to 35 years of age 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 The study may be expanded to include up to 45 subjects.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Sickle Cell Disease
  • Hematological Diseases
  • Hemoglobinopathies
Intervention  ICMJE Biological: CTX001
Administered by IV infusion following myeloablative conditioning with busulfan.
Study Arms  ICMJE 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 * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 15, 2018)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2022
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  • Subjects ≥ 18 and ≤ 35 years of age
  • Diagnosis of severe sickle cell disease as defined by:
  • Documented βS/βS 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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 35 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Medical Information 6173416777 medicalinfo@vrtx.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03745287
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party Vertex Pharmaceuticals Incorporated
Study Sponsor  ICMJE Vertex Pharmaceuticals Incorporated
Collaborators  ICMJE CRISPR Therapeutics
Investigators  ICMJE Not Provided
PRS Account Vertex Pharmaceuticals Incorporated
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP