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    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
    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 SponsorCRISPR Therapeutics AG
    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 supportCRISPR Therapeutics AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCRISPR Therapeutics
    B.5.2Functional name of contact pointSenior Medical Director
    B.5.3 Address:
    B.5.3.1Street Address610 Main Street
    B.5.3.2Town/ cityCambridge, MA
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1617-307-7264
    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. cell therapy medicinal product Yes
    D. therapy medical product No
    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
    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
    Part A: 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)

    Part B: Evaluate long-term safety of CTX001 in subjects who received a single dose of CTX001 for treatment of TDT
    E.2.2Secondary objectives of the trial
    Part A:
    • 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

    Part B:
    • To evaluate efficacy up to 5 years after CTX001 infusion in subjects who received CTX001 for treatment of TDT
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part A:
    1. Age ≥18 and ≤35 years of age.

    2. Able to provide written informed consent.

    3. Diagnosis of transfusion-dependent β-thalassemia (TDT) as defined by:
    a. Documented homozygous β-thalassemia (with the exception of the β0/β0 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 β0/β0 genotypes are defined using the HbVar Database.
    b. A history of at least 100 mL/kg/year or 10 units/year of packed Red Blood Cell (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 (including condoms) from start of mobilization through at least 6 months after CTX001 infusion.

    9. Willing to participate in long-term follow-up for up to 15 years after CTX001 infusion

    Part B:
    1. Subjects must have received CTX001 infusion
    E.4Principal exclusion criteria
    Part A:
    1. An available 10/10 Human Leukocyte Antigen (HLA)-matched related donor.

    2. Prior allo-hematopoietic stem cell transplant (HSCT).

    3. Subjects with associated α-thalassemia and >1 alpha chain deletion.

    4. Subjects with a β0/β0 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 (WBC) count <3 × 10^9/L or platelet count <50 × 10^9/L not related to hypersplenism.

    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 mental disease.

    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 liver biopsy. Liver biopsy is required when liver iron concentration (LIC) is ≥15 mg/g on T2* MRI of liver. If a liver biopsy has been performed less than 6 months prior to consent, it does not need to be repeated.

    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 m^2.

    13. Diffusing capacity of the lungs for carbon monoxide (DLco) <50% of predicted (corrected for hemoglobin and/or alveolar volume).

    14. Prior treatment with gene therapy.

    15. Intolerance, contraindication, or known sensitivity to plerixafor, granulocyte colony stimulating factor (G-CSF) 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] and positive HBV polymerase chain reaction [PCR]), or hepatitis C virus (HCV) (positive HCV PCR). Positive serology for syphilis, toxoplasmosis or any other infectious disease marker as required by local testing for cellular processing.

    17. Participation in another clinical study with an investigational drug 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.

    Part B:
    1. There are no exclusion criteria.
    E.5 End points
    E.5.1Primary end point(s)
    Part A:
    • Proportion of subjects with engraftment. Engraftment is defined as ANC ≥500/µL for three consecutive days. Engraftment failure is defined as any subject not achieving neutrophil engraftment by Day +42 following CTX001 infusion or if backup unmodified CD34+ cells are utilized.
    • Time to engraftment.
    • Frequency and severity of collected AEs from signing of informed consent through Month 24 visit as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
    • Incidence of transplant related mortality (TRM) at 100 days and 1 year post-CTX001 infusion. TRM is defined as death possibly related to the transplantation procedure as assessed by the investigator.
    • All-cause mortality.

    Primary Efficacy:
    • Proportion of subjects achieving transfusion reduction for at least 6 months (TR6).

    Part B:
    • New malignancies
    • New or worsening hematologic disorders (e.g. immune-mediated cytopenias, aplastic anemia, primary immunodeficiencies)
    • All-cause mortality
    • Frequency and severity of serious adverse events (SAEs) occurring up to 5 years after CTX001 infusion
    • Frequency and severity of CTX001-related AEs
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A:
    • Safety: see above
    • Proportion of subjects achieving TR6: 3 months post-CTX001 infusion for at least 6 months at the time of analysis

    Part B:
    Safety: up to 15 years after CTX001 infusion
    E.5.2Secondary end point(s)
    Part A:
    Key Secondary Efficacy:
    • Proportion of subjects achieving transfusion independence for at least 6 months (TI6).

    Secondary Endpoints:
    • Proportion of subjects achieving transfusion reduction for at least 12 months (TR12).
    • Proportion of subjects achieving transfusion independence for at least 12 months (TI12).
    • Proportion of alleles with intended genetic modification present in peripheral blood leukocytes.
    • Proportion of alleles with intended genetic modification present in bone marrow cells.
    • Change in fetal hemoglobin concentration (pre-transfusion) over time.
    • Change in health-related quality of life (HRQoL) from baseline over time using EQ-5D-5L and FACT-BMT.
    • Change in parameters of iron overload, including:
    o Liver iron concentration (LIC) 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.

    Part B:
    • Change in Hb concentrations over time
    • Change in HbF concentrations over time
    • Annualized frequency of TDT related transfusions, and annualized number of units of transfusion
    • Change in parameters of iron overload, including:
    liver iron concentration (LIC) over 4 years after CTX001 infusion as assessed by T2* MRI
    o Cardiac iron concentration (CIC) over 4 years after CTX001 infusion as assessed by T2* MRI
    o Change in serum ferritin level over 5 years after CTX001 infusion
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part A:
    • Proportion of subjects achieving TI6: 3 months post-CTX001 infusion for at least 6 months
    • Proportion of subjects achieving TR12: 3 months post-CTX001 infusion for at least 12 months
    • Proportion of subjects achieving TI12: 3 months post-CTX001 infusion for at least 12 months
    • Proportion of alleles with intended genetic modification present in peripheral blood leukocytes and bone marrow cells, change in HbF levels (pre-transfusion): at Months 1, 2, 3, 4, 5, 6, 9, 12, 18, 24
    • Change in HRQoL: at Months 3, 6, 12, 18, 24
    • Change in parameters of iron overload:
    o Change in serum ferritin level: continuous variable over time.
    o Change in LIC: at Months 12 and 24
    o Change in Cardiac T2*: at Months 12 and 24

    Part B:
    Up to 5 years after CTX001 infusion
    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. 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
    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
    End of study will be defined as the date the last subject completes the 15-year follow-up period. 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 years16
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years16
    E.8.9.2In all countries concerned by the trial months9
    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: 12
    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 10
    F.4.2.2In the whole clinical trial 12
    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 continue in the long-term follow up part of the study (Part B)
    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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