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    The EU Clinical Trials Register currently displays   43722   clinical trials with a EudraCT protocol, of which   7255   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2018-001145-14
    Sponsor's Protocol Code Number:ALD-104
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-02-25
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-001145-14
    A.3Full title of the trial
    A Phase 3 Study of Lenti-D Drug Product After Myeloablative Conditioning Using Busulfan and Fludarabine in Subjects ≤17 Years of Age With Cerebral Adrenoleukodystrophy (CALD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study to assess the efficacy and safety of gene therapy for the treatment of cerebral adrenoleukodystrophy (CALD)
    A.4.1Sponsor's protocol code numberALD-104
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03852498
    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 Sponsorbluebird bio, Inc.
    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 supportbluebird bio, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVoisin Consulting
    B.5.2Functional name of contact pointClinical Trials Operations
    B.5.3 Address:
    B.5.3.1Street Address64 avenue Pierre Grenier
    B.5.3.2Town/ cityBoulogne-Billancourt
    B.5.3.3Post code92100
    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/3/12/1003
    D.3 Description of the IMP
    D.3.1Product nameLenti-D Drug Product
    D.3.2Product code Not Applicable
    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 INNelivaldogene autotemcel
    D.3.9.2Current sponsor codeLenti-D Drug Product
    D.3.9.3Other descriptive nameAutologous haematopoietic stem cells transduced with lentiviral vector Lenti-D encoding the human ABCD1 cDNA
    D.3.9.4EV Substance CodeSUB127987
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number5000000
    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 Yes
    D. classification and reference numberGene Therapy Medicinal Product Reference Number: EMA/CAT/988313/2011
    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
    Cerebral Adrenoleukodystrophy (CALD)
    E.1.1.1Medical condition in easily understood language
    Cerebral Adrenoleukodystrophy (CALD)
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10051260
    E.1.2Term Adrenoleukodystrophy
    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 efficacy and safety of Lenti-D Drug Product after myeloablative conditioning with busulfan and fludarabine in subjects with CALD
    E.2.2Secondary objectives of the trial
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Informed consent is obtained from a competent custodial parent or guardian with legal capacity to execute a local IRB/IEC approved consent. Informed assent will be sought from capable subjects, in
    accordance with the directive of the IRB/IEC and with local requirements.
    2. Males aged 17 years and younger, at the time of parental/guardian consent and, where appropriate, subject assent.
    3. Active cerebral ALD as defined by:
    a. Elevated VLCFA values, and
    b. Active central nervous system (CNS) disease established by central radiographic review of brain MRI demonstrating
    i. Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and
    ii. Gadolinium enhancement on MRI of demyelinating lesions.
    4. Neurologic Function Score (NFS) ≤1.
    E.4Principal exclusion criteria
    1. Prior receipt of an allogeneic transplant or gene therapy.
    2. Use of statins, Lorenzo's Oil, or dietary regimens used to lower VLCFA levels.
    3. Receipt of an investigational study drug or procedure within 3 months before screening that might confound study outcomes. Use of investigational study drugs is prohibited throughout the course of the study.
    4. Any conditions that make it impossible to perform MRI studies (including allergies to anesthetics or contrast agents).
    5. Hematological compromise as evidenced by:
    a. Peripheral blood ANC count <1500 cells/mm3, and either
    b. Platelet count <100,000 cells/mm3, or
    c. Hemoglobin <10 g/dL.

    6. Hepatic compromise as evidenced by:
    a. Aspartate transaminase (AST) value >2.5 × ULN
    b. Alanine transaminase (ALT) value >2.5 × ULN
    c. Total bilirubin value >3.0 mg/dL, except if there is a diagnosis of
    Gilbert's Syndrome and the subject is otherwise stable
    7. Baseline estimated glomerular filtration rate <70 mL/min/1.73 m2
    8. Cardiac compromise as evidenced by left ventricular ejection fraction <40%
    9. Immediate family member with a known or suspected Familial Cancer Syndrome
    10. Clinically significant uncontrolled, active bacterial, viral, fungal, parasitic, or prion associated infection.
    11. Positive for HIV, hepatitis B or C virus, or human T lymphotrophic virus 1 (HTLV-1)
    12. Any clinically significant cardiovascular, hematological or pulmonary disease, or other disease or condition that would be contraindicated for any of the
    other study procedures.
    13. Absence of adequate contraception for fertile subjects.
    14. Any contraindications to the use of G-CSF or plerixafor during the mobilization of hematopoietic stem cells, and any contraindications to
    the use of busulfan or fludarabine, including known hypersensitivity to the active substances or to any of the excipients in their formulations.
    15. Known hypersensitivity to protamine sulfate.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is:
    Proportion of subjects who are alive and have none of the 6 MFDs at Month 24 (i.e. Month 24 MFD-free survival).
    MFDs are:
    o loss of communication
    o cortical blindness
    o tube feeding
    o total incontinence
    o wheelchair dependence
    o complete loss of voluntary movement

    The primary safety endpoint is:
    The proportion of subjects with neutrophil engraftment after drug product infusion.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Month 24
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints are the following:
    • Proportion of subjects without gadolinium enhancement on MRI (i.e., GdE-) at Month 24
    • Value and change in total NFS from Baseline to protocol scheduled visits
    • MFD-free survival over time
    • Overall survival
    • Detectable vector copy number (VCN) in peripheral blood cells by Month 6

    The secondary safety endpoints are the following:
    • The proportion of subjects who experience either acute (≥Grade II) or chronic GVHD at Month 24
    • Time to neutrophil engraftment after drug product infusion
    • The proportion of subjects with platelet engraftment by Month 24
    • Time to platelet engraftment post-drug product infusion
    • The proportion of subjects with loss of neutrophil engraftment postdrug product infusion by Month 24
    • The proportion of subjects who undergo a subsequent HSC infusion by Month 24
    • The proportion of subjects who experience transplant-related mortality through 100 and 365 days post-drug product infusion
    •Proportion of subjects with clinical ≥ Grade 3 AEs, all investigational
    medicinal product (IMP)-related AEs, all SAEs, ≥ Grade 3 infections, and clinically significant changes in laboratory parameters by Month 24
    • The proportion of subjects who experience ≥Grade II acute GVHD by Month 24
    • The proportion of subjects who experience chronic GVHD by Month 24
    • Number of emergency room visits (post-neutrophil engraftment) by Month 24
    • Number and duration of in-patient hospitalizations (post-neutrophil engraftment) by Month 24
    • Number and duration of ICU stays (post-neutrophil engraftment) by Month 24
    • The number of subjects in which vector-derived RCL is detected by Month 24
    • The number of subjects with insertional mutagenesis leading to clonal dominance by Month 24
    • The number of subjects with insertional mutagenesis leading to leukemia by Month 24
    E.5.2.1Timepoint(s) of evaluation of this end point
    Month 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 No
    E.6.7Pharmacodynamic No
    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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    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.8.3 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 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
    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
    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 months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    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 Yes
    F.1.1Number of subjects for this age range: 35
    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) Yes
    F. of subjects for this age range: 25
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 10
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    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 No
    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 Yes
    F. of subjects incapable of giving consent
    Paediatric patients
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 35
    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)
    Subjects will be asked to enroll into a long-term follow-up study (LTF-304, EudraCT number: 2015-002805-13).
    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 Decision2019-01-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-07-24
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