|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|Severe Sickle Cell Disease (SCD)
|E.1.1.1||Medical condition in easily understood language ||
|Severe Sickle Cell Disease
|E.1.1.2||Therapeutic area ||Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
|E.1.2 Medical condition or disease under investigation
|E.1.2||Classification code ||10040641
|E.1.2||Term ||Sickle cell anaemia
|E.1.2||System Organ Class ||10010331 - Congenital, familial and genetic disorders
|E.1.3||Condition being studied is a rare disease || Yes
|E.2 Objective of the trial
|E.2.1||Main objective of the trial ||
|Evaluate the safety and efficacy of a single dose of autologous CRISPR-Cas9 modified CD34+ hHSPCs (CTX001) in subjects with severe SCD
|E.2.2||Secondary objectives of the trial ||
|• Assess the effects of infusion of CTX001 on disease-specific events and clinical status
• Quantify gene editing efficiency
|E.2.3||Trial contains a sub-study || No
|E.3||Principal inclusion criteria ||
|1. Subject (or their legally authorized representative or guardian) will
sign and date an informed consent form (ICF) and, where applicable, an
2. Subjects 12 to 35 years of age, inclusive on the date of informed
3. Documented βS/βS or βS/β0 genotype. Subjects can be enrolled
based on historical genotype results, but confirmation of genotype is
required before busulfan conditioning. The β0 genotypes are defined
using the HbVar Database.
4. Subjects with severe SCD. Severe SCD is defined by the occurrence of
at least 2 of the following events per year during the 2-year period
before screening, while receiving appropriate supportive care (e.g., pain
management plan, HU):
• Acute pain events that requires a visit to a medical facility and administration of pain medications (opioids or intravenous [IV] non-steroidal anti-inflammatory drugs [NSAIDs]) or RBC transfusions
• Acute chest syndrome, as indicated by the presence of a new pulmonary infiltrate associated with pneumonia-like symptoms, pain, or fever
• Priapism lasting >2 hours and requiring a visit to a medical facility
• Splenic sequestration, as defined by an enlarged spleen, left upper quadrant pain, and an acute decrease in hemoglobin concentration of ≥2
Historical severe VOCs will be adjudicated by the Endpoint Adjudication Committee (EAC).
5. Normal transcranial Doppler (TCD) velocity (time-averaged mean of
the maximum velocity [TAMMV] <170 cm/sec) in the middle cerebral
artery (MCA) and the internal carotid artery (ICA) for subjects 12 to 16
years of age.
6. Karnofsky performance status of ≥80% for subjects ≥16 years of age
or Lansky performance status of ≥80% for subjects <16 years of age.
7. Eligible for autologous stem cell transplant as per investigator's
8. Female subjects of childbearing potential (postmenarcheal, has an
intact uterus and at least 1 ovary, and is less than 1 year
postmenopausal) must agree to use acceptable method(s) of
contraception from consent through at least 6 months after CTX001
9. Male subjects of reproductive capacity must agree to use effective
contraception from start of mobilization through at least 6 months after
10. Willing and able to comply with scheduled visits, treatment plan,
laboratory tests, contraceptive guidelines, and other study procedures.
11. Willing to participate in the long-term follow-up study (Study VX18-
CTX001-131), after completion of this study.
|E.4||Principal exclusion criteria||
|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 as determined by the investigator.
4. White blood cell (WBC) count <3 × 109/L or platelet count <50 × 109/L, not related to hypersplenism per investigator judgment.
5. Treatment with regular RBC transfusions that, in the opinion of the investigator, cannot be interrupted after engraftment.
6. Subjects with history of alloimmunization to RBC antigens and for whom the investigator anticipates that there will be insufficient RBC units available for the duration of the study.
7. More than 10 unplanned hospitalizations or emergency department
visits related to SCD in the 1 year before screening that, in the opinion of
the investigator, are consistent with significant chronic pain rather than
acute pain crises.
8. HbF level >15.0%, irrespective of concomitant treatment with HbF-inducing treatments such as HU.
9. History of abnormal TCD (TAMMV ≥200 cm/sec) for subjects 12 to 18
years of age.
10. History of untreated Moyamoya disease or presence of Moyamoya
disease at Screening that in the opinion of the investigator puts the
subjects at the risk of bleeding.
11. History of a significant bleeding disorder.
12. History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk to the subject. This may include, but is not limited to: history of relevant drug allergies; history of cardiovascular or central nervous system disease; history or presence of clinically significant pathology; history of mental disease, or history of familial cancer syndrome.
13. Any prior or current malignancy or myeloproliferative disorder or a significant immunodeficiency disorder.
14. Advanced liver disease, defined as
a. Alanine transaminase (ALT) >3 × the upper limit of normal (ULN) or direct bilirubin value >2.5 × ULN, or
b. Baseline prothrombin time (PT) (international normalized ratio [INR]) >1.5 × ULN, or
c. History of cirrhosis or any evidence of bridging fibrosis, or active hepatitis on liver biopsy
15. Baseline estimated glomerular filtration rate <60 mL/min/1.73 m2.
16. Lung diffusing capacity for carbon monoxide (DLco) <50% of predicted value (corrected for hemoglobin and/or alveolar volume).
17. Left ventricular ejection fraction (LVEF) <45% by echocardiogram.
18. Prior treatment with gene therapy/editing product.
19. Intolerance, contraindication, or known sensitivity to plerixafor or
busulfan. Prior anaphylactic reaction with excipients of CTX001 product
(dimethylsulfoxide [DMSO], dextran).
20. Positive for the presence of human immunodeficiency virus-1 (HIV-
1) or human immunodeficiency virus-2 (HIV-2) (positive
antigen/antibody AND nucleic acid tests [NAT]), hepatitis B virus (HBV)
(positive Hepatitis B core antibody [HBcAb] AND NAT tests), syphilis
(positive screening AND confirmatory tests), or hepatitis C virus (HCV;
positive antibody [HCAb] AND NAT tests). Additional infectious disease
markers should be obtained and tested as required by the local authority
for the collection and processing of cellular therapy products. These
additional tests (e.g., HTLV-1, HTLV-2, malaria, tuberculosis,
toxoplasmosis, Trypanosoma cruzi, or West Nile virus) will be evaluated
to determine overall impact to the subject and manufacturing of CTX001.
21. Participation in another clinical study with an investigational
drug/product within 30 days of screening or fewer than 5 half-lives of
the investigational agent, whichever is longer from screening.
22. Subjects who are not able to comply with the study procedures outlined in the protocol as judged by the investigator.
23. Pregnancy or breastfeeding.
|E.5 End points
|E.5.1||Primary end point(s)||
• Successful neutrophil engraftment within 42 days after CTX001 infusion
• Time to neutrophil engraftment
• Time to platelet engraftment
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, and vital signs
• Transplant-related mortality (TRM) within 100 days after CTX001 infusion
• TRM within 1 year after CTX001 infusion
• All-cause mortality
Primary Efficacy Endpoint
• Proportion of subjects with sustained HbF ≥20% at the time of analysis for at least 3 months starting 6 months after CTX001 infusion, in the absence of treatment with HU
|E.5.1.1||Timepoint(s) of evaluation of this end point||
|E.5.2||Secondary end point(s)||
|Key Secondary Efficacy Endpoint
• Relative change from baseline in annualized rate of severe Vaso-Occlusive Crises (VOCs) starting 6 months after CTX001 infusion
• Reduction in annualized rate of severe VOCs at the time of analysis from baseline by at least 50%, starting 6 months after CTX001 infusion
• Reduction in annualized rate of severe VOCs at the time of analysis from baseline by at least 65%, starting 6 months after CTX001 infusion
• Absence of severe VOCs for at least 12 months at the time of the analysis, starting 6 months after CTX001 infusion
• Relative change from baseline in annualized duration of hospitalization for severe VOCs, starting 6 months after CTX001 infusion
• Relative change from baseline in annualized rate of hospitalization for
severe VOCs starting 6 months after CTX001 infusion
• Proportion of subjects with sustained HbF ≥20% at the time of analysis for at least 3 months, starting 3 months after CTX001 infusion,
in the absence of treatment with HU
• Proportion of subjects with sustained HbF ≥20% at the time of
analysis for at least 3 months, starting at the time of CTX001 infusion, in
the absence of treatment with HU
• Proportion of subjects with sustained HbF ≥20% at the time of
analysis for 6 months, starting 6 months after CTX001 infusion, in the
absence of treatment with HU
• Change in number of units of red blood cells (RBC) transfused for SCD
related indications over time
• HbF concentrations over time
• Hemoglobin (Hb) concentrations 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 bone marrow cells over time
• Change in patient reported outcomes (PROs) over time using
o Pain-Scale:11-point numerical rating scale (NRS) – all subjects
o Functional assessment of cancer therapy bone marrow transplant
(FACT-BMT), Adult Sickle Cell Quality of Life Measurement System
(ASCQ-Me), and EuroQol Quality of Life Scale (EQ-5D-5L) for ≥18 years
o EQ-5D-Youth (EQ-5D-Y; self-report and parent proxy), Pediatric
Quality of Life Inventory (PedsQL; Teen self report and parent proxy),
and PedsQL SCD Module (Teen self-report and parent proxy): 12 to <18
|E.5.2.1||Timepoint(s) of evaluation of this end point||
|See in section E.5.2
• Any transfusion received will be documented from the time of consent through the end of the study.
• HbF concentrations: at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24
• Hb concentrations over time
• Proportion of alleles with intended genetic modification present in peripheral blood leukocytes: at Months 1, 2, 3, 4, 5, 6, 9, 12, 18, 24
• Proportion of alleles with intended genetic modification present in bone marrow cells: at Months 6, 12, 24
• Change in patient reported outcomes (PROs):
- EQ-5D-5L, FACT BMT and ASCQ-Me (patients ≥18 years), EQ-5D-Y,
Pediatric Quality of Life Inventory and PedsQL SCD Module (patients 12
to <18 years): at Months 3, 6, 12, 18, 24
- Pain-Scale [11-point NRS]: at Months 3, 4, 5, 6, 9, 12, 15, 18, 21, 24
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| No
|E.7||Trial type and phase
|E.7.1||Human pharmacology (Phase I)|| Yes
|E.7.1.1||First administration to humans|| No
|E.7.1.2||Bioequivalence study|| No
|E.220.127.116.11||Other trial type description||
|E.7.2||Therapeutic exploratory (Phase II)|| No
|E.7.3||Therapeutic confirmatory (Phase III)|| No
|E.7.4||Therapeutic use (Phase IV)|| No
|E.8 Design of the trial
|E.8.1.3||Single blind|| No
|E.8.1.4||Double blind || No
|E.8.1.5||Parallel group|| No
|E.8.1.6||Cross over || No
|E.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| No
|E.8.2.2||Placebo || No
|E.8.2.4||Number of treatment arms in the trial||1
The trial involves single site in the Member State concerned
|E.8.4|| The trial involves multiple sites in the Member State concerned || No
|E.8.5||The trial involves multiple Member States|| Yes
|E.8.5.1||Number of sites anticipated in the EEA||10
|E.8.6 Trial involving sites outside the EEA
|E.8.6.1||Trial being conducted both within and outside the EEA|| Yes
|E.8.6.2||Trial being conducted completely outside of the EEA|| No
|E.8.6.3||If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned||
|E.8.7||Trial has a data monitoring committee|| Yes
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|The end of study is defined as the last scheduled visit (or contact) of the last subject.
End of study will be defined as the date the last subject completes the 24-month follow-up period or date of early withdrawal from the study.
|E.8.9 Initial estimate of the duration of the trial
|E.8.9.1||In the Member State concerned years||3
|E.8.9.1||In the Member State concerned months||10
|E.8.9.1||In the Member State concerned days||0
|E.8.9.2||In all countries concerned by the trial years||5
|E.8.9.2||In all countries concerned by the trial months||2
|E.8.9.2||In all countries concerned by the trial days||0