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    EudraCT Number:2018-001320-19
    Sponsor's Protocol Code Number:CTX001-121
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-05-17
    Trial results
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2018-001320-19
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to learn about the safety and efficacy of CTX001 (the "study drug product") to treat Severe Sickle Cell Disease
    A.4.1Sponsor's protocol code numberCTX001-121
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03745287
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorVertex Pharmaceuticals Incorporated
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportVertex Pharmaceuticals Incorporated
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVertex Pharmaceuticals Incorporated
    B.5.2Functional name of contact pointClinical Trials and Medical Info
    B.5.3 Address:
    B.5.3.1Street Address50 Northern Avenue
    B.5.3.2Town/ cityBoston
    B.5.3.3Post codeMA 02210
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1877634 8789
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/19/2242
    D.3 Description of the IMP
    D.3.1Product nameCTX001
    D.3.2Product code CTX001
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAutologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs)
    D.3.9.2Current sponsor codeCTX001
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number3
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D. cell therapy medicinal product No
    D. therapy medical product Yes
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Severe Sickle Cell Disease (SCD)
    E.1.1.1Medical condition in easily understood language
    Severe Sickle Cell Disease
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10040641
    E.1.2Term Sickle cell anaemia
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary objectives of the trial
    • Assess the effects of infusion of CTX001 on disease-specific events and clinical status
    • Quantify gene editing efficiency
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject (or their legally authorized representative or guardian) will
    sign and date an informed consent form (ICF) and, where applicable, an
    assent form.
    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
    CTX001 infusion.
    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.4Principal 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.5.1Primary end point(s)
    Safety Endpoints
    • 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.5.1.1Timepoint(s) of evaluation of this end point
    See in section E.5.1
    E.5.2Secondary 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

    Secondary Endpoints
    • 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E. trial type description
    Phase 1/2
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 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.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 5
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 45
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    All subjects infused with CTX001 will be asked to enroll into an additional long-term follow-up study, protocol number VX18-CTX001-131.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-08-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-05
    P. End of Trial
    P.End of Trial StatusOngoing
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