Clinical trial NCT03745287: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Sickle Cell Disease
Hematological Diseases
Hemoglobinopathies
Lead sponsor: Vertex Pharmaceuticals Incorporated
Sponsor class: INDUSTRY
Collaborators: name: CRISPR Therapeutics
First posted: 2018-11-19
Enrollment: 63
Sex: ALL
Minimum age (years): 12
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Proportion of subjects who have not experienced any severe vaso-occlusive crisis (VOC) for at least 12 consecutive months (VF12)
timeFrame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
measure: Proportion of subjects with engraftment (first day of three consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days)
timeFrame: Within 42 days after CTX001 infusion
measure: Time to engraftment
timeFrame: From CTX001 infusion up to 2 years after CTX001 infusion
measure: Frequency and severity of collected adverse events (AEs)
timeFrame: From screening to 2 years after CTX001 infusion
measure: Incidence of transplant-related mortality (TRM) within 100 days after CTX001 infusion
timeFrame: Within 100 days after CTX001 infusion
measure: Incidence of TRM within 1 year after CTX001 infusion
timeFrame: Within 1 year after CTX001 infusion
measure: All-cause mortality
timeFrame: 2 years after mobilization
Secondary outcomes:
measure: Proportion of subjects free from inpatient hospitalization for severe VOCs sustained for at least 12 months (HF12)
timeFrame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
measure: Proportion of subjects who have not experienced any severe VOC for at least 9 consecutive months (VF9) any time after CTX001 infusion
timeFrame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
measure: Proportion of subjects with 90 percent (%), 80%, 75% or 50% reduction in annualized rate of severe VOCs
timeFrame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
measure: Relative change from baseline in annualized rate of severe VOCs
timeFrame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
measure: Duration of severe VOC free in subjects who have achieved VF12
timeFrame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
measure: Relative Change from baseline in rate of inpatient hospitalization for severe VOCs
timeFrame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
measure: Relative change from baseline in annualized duration of hospitalization for severe VOCs
timeFrame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
measure: Proportion of subjects with sustained HbF ≥20% for at least 3 months
timeFrame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
measure: Proportion of subjects with sustained HbF ≥20% for at least 12 months
timeFrame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
measure: Proportion of subjects with sustained HbF ≥20% for at least 6 months
timeFrame: From 60 days after last RBC transfusion up to 2 years after CTX001 infusion
measure: Change in number of units of RBC transfused for SCD-related indications
timeFrame: 6 months up to 2 years after CTX001 infusion
measure: HbF concentration over time
timeFrame: 1 month up to 2 years after CTX001 infusion
measure: Hb concentration over time
timeFrame: From the time of CTX001 up to 2 years after CTX001 infusion
measure: Change from baseline in indirect bilirubin over time
timeFrame: From baseline (pre-infusion) up to 2 years after CTX001 infusion
measure: Change from baseline in reticulocyte count over time
timeFrame: From baseline (pre-infusion) up to 2 years after CTX001 infusion
measure: Change from baseline in haptoglobin over time
timeFrame: From baseline (pre-infusion) up to 2 years after CTX001 infusion
measure: Change from baseline in lactate dehydrogenase over time
timeFrame: From baseline (pre-infusion) up to 2 years after CTX001 infusion
measure: Proportion of alleles with intended genetic modification present in peripheral blood leukocytes over time
timeFrame: 1 month up to 2 years after CTX001 infusion
measure: Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time
timeFrame: 6 months up to 2 years after CTX001 infusion
measure: Change in patient-reported outcome (PRO) over time assessed using weekly pain-scale (11-point numerical rating scale [NRS])
timeFrame: 3 months up to 2 years after CTX001 infusion
measure: Change in PRO over time assessed using EuroQol quality of life scale (EQ-5D-5L)
timeFrame: 3 months up to 2 years after CTX001 infusion
measure: Change in PRO over time assessed using EQ-5D-Youth (EQ-5D-Y)
timeFrame: 3 months up to 2 years after CTX001 infusion
measure: Change in PRO over time assessed using functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) questionnaire
timeFrame: 3 months up to 2 years after CTX001 infusion
measure: Change in PRO over time assessed using adult sickle cell quality of life measurement system (ASCQ-Me)
timeFrame: 3 months up to 2 years after CTX001 infusion
measure: Change in PRO over time assessed using pediatric quality of life inventory (PedsQL)
timeFrame: 3 months up to 2 years after CTX001 infusion
measure: Change in PRO over time assessed using PedsQL sickle cell disease module
timeFrame: 3 months up to 2 years after CTX001 infusion
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital of Stanford University
state: California
city: Chicago
country: United States
facility: Ann & Robert Lurie Children's Hospital of Chicago
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago Hospitals and Health Systems
state: Illinois
city: New York
country: United States
facility: Columbia University Medical Center (21+ years)
state: New York
city: New York
country: United States
facility: Columbia University Medical Center (≤21 years)
state: New York
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers
state: Tennessee
city: San Antonio
country: United States
facility: Methodist Children's Hospital/Texas Transplant Institute
state: Texas
city: Brussels
country: Belgium
facility: Hopital Universitaire des Enfants Reine Fabiola (HUDERF)
city: Toronto
country: Canada
facility: The Hospital for Sick Children
city: Paris
country: France
facility: Hopital Necker Enfants Malades
city: Dusseldorf
country: Germany
facility: University Hospital Duesseldorf
city: Regensburg
country: Germany
facility: Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine, Paediatric Haemotology, Oncology and Stem Cell Transplantation
city: Rome
country: Italy
facility: Dipartimento di Onco-Ematologia e Terapia Cellulare e Genica Ospedale Pediatrico Bambino Gesu - IRCCS
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust, Hammersmith Hospital
city: London
country: United Kingdom
facility: Royal London and St Bartholomew's Hospital, Pathology and Pharmacy Building
Study officials:
References:
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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.
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.