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    Summary
    EudraCT Number:2019-002636-82
    Sponsor's Protocol Code Number:OTL-200-07
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-07-30
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-002636-82
    A.3Full title of the trial
    An open label, non-randomised trial to evaluate the safety and efficacy of a single infusion of OTL-200 in patients with Late Juvenile (LJ) Metachromatic Leukodystrophy (MLD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to evaluate the effect of OTL-200, a gene therapy treatment in patients with Late Juvenile (LJ) Metachromatic Leukodystrophy (MLD)
    A.4.1Sponsor's protocol code numberOTL-200-07
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/212/2018
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOrchard Therapeutics (Europe) Limited
    B.1.3.4CountryUnited Kingdom
    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 supportOrchard Therapeutics (Europe) Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOrchard Therapeutics (Europe) Limited
    B.5.2Functional name of contact pointClinical
    B.5.3 Address:
    B.5.3.1Street Address108 Cannon Street
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeEC4N 6EU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44(0)203384 6700
    B.5.5Fax number+44(0)203727 0797
    B.5.6E-mailclinical@orchard-tx.com
    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/3/07/446
    D.3 Description of the IMP
    D.3.2Product code OTL-200
    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 INNNot Applicable
    D.3.9.2Current sponsor codeOTL-200
    D.3.9.3Other descriptive nameOTL-200 Dispersion for Infusion
    D.3.10 Strength
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number10 x 1000000
    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 No
    D.3.11.3.2Gene therapy medical product Yes
    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
    Metachromatic Leukodystrophy
    E.1.1.1Medical condition in easily understood language
    Metachromatic Leukodystrophy, is an inherited genetic disease affecting
    mainly babies and young children, and more rarely also affecting
    adolescents and adults.
    E.1.1.2Therapeutic area Body processes [G] - Genetic Phenomena [G05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10067609
    E.1.2Term Metachromatic leukodystrophy
    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 pharmacodynamic effect of OTL-200 in CSF and the brain of patients with LJ MLD as compared to baseline
    E.2.2Secondary objectives of the trial
    -To evaluate the pharmacodynamic effect of OTL-200 in bone marrow and peripheral blood and on various brain metabolites in LJ MLD patients as compared to baseline, siblings and/or untreated historical controls

    -To evaluate engraftment of OTL-200

    -To evaluate the clinical efficacy of OTL-200 in LJ MLD participants as compared to baseline, untreated historical controls or siblings

    -To evaluate the safety and tolerability of the HSPC-GT procedure and OTL-200
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Documented biochemical and molecular diagnosis of MLD, based on ARSA activity below the normal range and identification of two disease causing ARSA alleles. Novel mutations will be analysed within silico prediction tool and excluded from being known common polymorphisms. In the case of a novel mutation(s), a 24-hour urine collection must show elevated sulfatide levels.
    2. O/R or R/R genotype or a genotype recognized as associated with the LJ variant of MLD.
    3. a) if symptomatic: age at disease onset between ≥7 and <17 years of age (i.e. before their 17th birthday) OR b) if pre-symptomatic: participant must be <17 years of age at treatment (i.e before their 17th birthday) AND must have a sibling with a diagnosis of late-juvenile MLD variant based on age at disease onset (≥7 and <17 years of age i.e before sibling's 17th birthday), with biochemical and molecular diagnosis.
    4. Normal cognitive function as defined by an IQ≥ 85 on age appropriate cognitive scales.
    5.a) If the participant is <7 years age (i.e before their 7th birthday): normal motor milestones achievement, normal gross motor function according to chronological age and normal neurological examination (if applicable based on the age of the subject, GMFC-MLD =0) OR b) If the participant is ≥7 years, normal gross motor function or mild gross motor function impairment, defined by a GMFC-MLD 0or 1 (i.e patient is able to walk independently).
    6. If applicable, participant willing and capable of compliance with contraceptive requirements as detailed further in Protocol Section 7.1 Contraceptive use by men or women should be consistent with local regulations regarding he methods of contraception for those participating in clinical studies.
    7. Participant (or if applicable, parent/legal guardian) providing signed informed consent as described in Section 17 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
    E.4Principal exclusion criteria
    1. Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies).
    2.Malignant neoplasia (except localised skin cancer) or a documented history of hereditary cancer syndrome. Participants with a prior successfully treated malignancy and a sufficient follow-up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the OTL-MM.
    3.Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) or other serious haematological disorders.
    4.Patients currently enrolled in other interventional trials.
    5.Has previously undergone allogeneic HSCT and has evidence of residual cells of donor origin.
    6.Previous gene therapy.
    7.Has symptomatic herpes zoster, not responsive to specific treatment
    8.Evidence of active tuberculosis (TB)
    9.Acute or chronic stable Hepatitis B (HBV)
    10.Presence of positive Hepatitis C RNA test result at screening
    11.End-organ dysfunction, severe active infection not responsive to treatment, or other severe disease or clinical condition which, in the judgement of the investigator, would make the participant inappropriate for entry into this study
    E.5 End points
    E.5.1Primary end point(s)
    Co-primary pharmacodynamic efficacy endpoints:
    •Change in ARSA activity levels in CSF
    •Change in neuronal metabolite ratio NAA: Cr in white matter regions of interest of the brain
    E.5.1.1Timepoint(s) of evaluation of this end point
    from baseline to 24 months post-treatment
    E.5.2Secondary end point(s)
    Efficacy:
    •Change in ARSA activity levels in CSF from baseline to multiple visits over time
    •Change from baseline to multiple visits over time in neuronal metabolite ratio NAA: Cr in white matter regions of interest of the brain (may include but not limited to the centrum semiovale; parieto-occipital white matter)
    •Change from baseline to 24 months and multiple visits over time in ARSA levels in total PBMC, CD14+ and CD15+
    •Neuronal metabolite ratios at 24 months and multiple visits over time relative to baseline and compared to untreated historical controls / siblings in treated participants (may include but not limited to Cho:Cr, mIns:Cr, Lac: Cr, Cho: NAA, NAA: H2O, Cho: H2O, mIns: H2O, Lac: H2O) in white matter regions of interest (may include but not limited to the centrum semiovale; frontal, occipital, and parieto-occipital white matter).
    •Engraftment as measured by %LV in BM progenitors (at D30 post gene therapy and at multiple visits over time)
    oBrain MRI assessments at 24 months and at multiple visits over time as compared to baseline, untreated historical controls or siblings
    oNeurocognitive assessments at 24 months and at multiple visits over time as compared to baseline, untreated historical controls or siblings
    oFull neurological clinical examination (NCE) at 24 months and at multiple visits over time as compared to baseline, untreated historical controls or siblings
    oGMFC-MLD at 24 months and at multiple visits over time as compared to baseline, untreated historical controls or siblings
    oAssessment of NCV at 24 months and at multiple visits over time as compared to baseline, untreated historical controls or siblings
    oVineland Adaptive Behavioural Scales at 24 months and at multiple visits over time as compared to baseline, untreated historical controls or siblings

    Safety as measured by:
    •Conditioning regimen related toxicity and AEs
    •Non-conditioning related AEs
    •Haematological reconstitution (ANC > 500/µL associated with evidence of BM recovery at day +60)
    •Infusion related reactions
    •Immunogenicity (e.g. anti-ARSA Antibodies)
    •Abnormal Clonal Proliferation (ACP)
    •Replication Competent Lentivirus
    •Insertion Site analysis findings
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy endpoints:
    •Change in ARSA activity levels in CSF from baseline to multiple visits over time
    •Change from baseline to multiple visits over time in neuronal metabolite ratio NAA: Cr
    •Change from baseline to 24 months and multiple visits over time in ARSA levels in total PBMC and CD15+
    •Engraftment as measured by %LV in BM progenitors (at D30 post gene therapy and at multiple visits over time)
    All the others: at 24 months and at multiple visits over time

    Safety: through the study
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other 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 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 No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    last subject last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months0
    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: 6
    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.1.1.5.1Number of subjects for this age range: 3
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 3
    F.1.2Adults (18-64 years) No
    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 No
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 6
    F.4.2.2In the whole clinical trial 6
    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)
    Due to the inherent nature of the gene therapy being a once-only
    treatment, there is no plan to offer further treatment / doses of OTL-
    200 following the end of the study
    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 Decision2019-12-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-26
    P. End of Trial
    P.End of Trial StatusOngoing
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