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    Summary
    EudraCT Number:2017-003351-38
    Sponsor's Protocol Code Number:CTX001-111
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-12-07
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2017-003351-38
    A.3Full title of the trial
    A Phase 1/2 Study of the Safety and Efficacy of a Single Dose of Autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) in Subjects with Transfusion-Dependent β Thalassemia
    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 beta-thalassemia
    A.4.1Sponsor's protocol code numberCTX001-111
    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 pointRegulatory Affairs
    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+16173416617
    B.5.6E-maillynette_hopkinson@vrtx.xom
    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 No
    D.2.5.1Orphan drug designation number
    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 number 3
    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.3.11.3.1Somatic cell therapy medicinal product Yes
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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
    Transfusion-Dependent β Thalassemia
    E.1.1.1Medical condition in easily understood language
    Transfusion-Dependent β Thalassemia
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10043391
    E.1.2Term Thalassaemia beta
    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
    To evaluate the safety and efficacy of a single dose of autologous CRISPR-Cas9 modified CD34+ hHSPCs (CTX001) in subjects with transfusion-dependent β-thalassemia (TDT)
    E.2.2Secondary objectives of the trial
    • To quantify percentage of edited alleles in peripheral blood leukocytes and bone marrow cells
    • To assess the production of HbF post-CTX001 infusion
    • To assess the effects of infusion of CTX001 on disease-specific events and clinical status
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects 18 to 35 years of age, inclusive on the date of informed consent
    2. Subject will sign and date an informed consent form (ICF)
    3. Diagnosis of transfusion-dependent β-thalassemia (TDT) as defined by:
    a. Documented homozygous β-thalassemia (with the exception of the β^0/β^0 genotype) or compound heterozygous β-thalassemia including
    β-thalassemia/hemoglobin E (HbE). Subjects can be enrolled based on historical data, but a confirmation of the genotype using the study
    central laboratory will be required before busulfan conditioning. The β^0 and non β^0 genotypes are defined using the HbVar Database.
    b. A history of at least 100 mL/kg/year or 10 units/year of packed RBC transfusions in the prior 2 years before signing the consent.
    4. Karnofsky performance status of ≥80%.
    5. Eligible for autologous stem cell transplant as per investigator's judgment.
    6. Access to detailed medical records on packed RBC transfusions, including volume or units of packed RBCs and associated pre-transfusion
    Hb values, and in-patient hospitalizations, for at least the 2 years prior to consent.
    7. 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 infusion.
    8. Male subjects must agree to use effective contraception from start of
    mobilization through at least 6 months after CTX001 infusion (Section 3.6 of the protocol).
    9. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, contraceptive guidelines, and other study procedures.
    10. Willing to participate in an additional 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 allogeneic HSCT.
    3. Subjects with associated α-thalassemia and >1 alpha chain deletion or alpha multiplications.
    4. Subjects with a β^0/β^0 thalassemia genotype or sickle cell beta thalassemia variant.
    5. Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator.
    6. White blood cell count <3 × 10^9/L or platelet count <50 × 10^9/L not related to hypersplenism per investigator judgment.
    7. History of a significant bleeding disorder.
    8. 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 in administering study drug to the subject. This may include, but is not limited to: immediate family member with a known family cancer syndrome, history of relevant drug allergies; history of cardiovascular or central nervous system disease; history or presence of clinically significant pathology; history of uncontrolled seizure disorders, or history of psychiatric disorders.
    9. Any prior or current malignancy or myeloproliferative disorder or a significant immunodeficiency disorder.
    10. Advanced liver disease, defined as:
    a. Aspartate transaminase (AST), alanine transaminase (ALT) >3 x the upper limit of normal (ULN), or direct bilirubin value >2 x the ULN, or:
    b. Baseline prothrombin time (International Normalized Ratio; INR) >1.5 x ULN, or
    c. History of cirrhosis or any evidence of bridging fibrosis, or active hepatitis on previous liver biopsy.
    d. Liver iron content (LIC) ≥15 mg/g on R2* MRI of liver.
    11. A cardiac T2* <10 ms by MRI or left ventricular ejection fraction (LVEF) <45% by echocardiogram.
    12. Baseline estimated glomerular filtration rate <60 mL/min/1.73 m2.
    13. Diffusion capacity of the lungs for carbon monoxide (DLco) <50% of predicted (corrected for hemoglobin and/or alveolar volume).
    14. Prior treatment with gene therapy/editing product.
    15. Intolerance, contraindication, or known sensitivity to plerixafor, GCSF products (e.g., filgrastim), or busulfan. Prior anaphylaxis with
    excipients of CTX001 product (dimethyl sulfoxide [DMSO], Dextran).
    16. Positive serology for human immunodeficiency virus-1 (HIV-1) or human immunodeficiency virus-2 (HIV-2), hepatitis B virus (HBV) (Hepatitis B core antibody [HBcAb] or nuclei acid testing [NAT]), syphilis [RPR or treponemal specific test], or hepatitis C virus (HCV) (NAT).
    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 will be evaluated to determine overall impact to the patient and manufacturing of CTX001.
    17. 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.
    18. An assessment by the investigator that the subject would not comply with the study procedures outlined in the protocol.
    19. Pregnant or breastfeeding females.
    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
    • Incidence of transplant related mortality (TRM) within 100 days and
    within 1 year post-CTX001 infusion.
    • All-cause mortality.
    Primary Efficacy Endpoint:
    • Proportion of subjects achieving sustained transfusion reduction for at
    least 6 months (sustained TR6) at the time of analysis starting 3 months
    after CTX001 infusion.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Refer to E.5.1
    E.5.2Secondary end point(s)
    Key Secondary Efficacy Endpoint:
    • Proportion of subjects achieving sustained transfusion independence
    for at least 6 months (sustained TI6) at the time of analysis starting 3
    months after CTX001 infusion.
    Secondary Endpoints:
    • Proportion of subjects achieving sustained transfusion reduction for at
    least 12 months (sustained TR12) at the time of analysis starting 3
    months after CTX001 infusion.
    • Proportion of subjects achieving sustained transfusion independence
    for at least 12 months (sustained TI12) at the time of analysis starting 3
    months after CTX001 infusion.
    • Proportion of alleles with intended genetic modification present in
    peripheral blood leukocytes over time. Intended genetic modifications
    are indels that modify the sequence of the erythrocyte-specific enhancer
    in intron 2 of BCL11A
    • Proportion of alleles with intended genetic modification present in
    bone marrow cells over time
    • Fetal hemoglobin concentration (pre-transfusion) over time
    • Change in patient reported outcomes (PROs) over time using EuroQol
    Quality of Life Scale (EQ 5D 5L), and functional assessment of cancer therapy bone marrow transplant (FACT-BMT).
    • Change in parameters of iron overload, including:
    o Liver iron concentration (LIC) from baseline as assessed by R2*
    magnetic resonance imaging (MRI) and cardiac iron content (CIC) from
    baseline as assessed by T2* MRI
    o Change in serum ferritin level from baseline over time
    • Proportion of subjects receiving iron chelation therapy over time
    E.5.2.1Timepoint(s) of evaluation of this end point
    Refer to E.5.2
    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 Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase 1/2
    E.7.2Therapeutic exploratory (Phase II) Yes
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    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
    Canada
    Germany
    Italy
    United Kingdom
    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.
    The Sponsor will notify all applicable regulatory agencies in accordance
    with local requirements when the study has ended.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    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 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 45
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    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 in the longterm
    follow-up study (Study 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 Decision2018-07-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-25
    P. End of Trial
    P.End of Trial StatusOngoing
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