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    EudraCT Number:2019-002051-42
    Sponsor's Protocol Code Number:R119861
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-04-09
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2019-002051-42
    A.3Full title of the trial
    A phase I-II, study of autologous CD34+ haematopoietic stem cells transduced ex vivo with CD11b lentiviral vector encoding for human SGSH in patients with mucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo syndrome type A)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study testing a gene therapy to treat mucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo syndrome type A)
    A.4.1Sponsor's protocol code numberR119861
    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 SponsorUniversity of Manchester
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    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 organisationUniversity of Manchester
    B.5.2Functional name of contact pointProject Management
    B.5.3 Address:
    B.5.3.1Street AddressChristie Building
    B.5.3.2Town/ cityManchester
    B.5.3.3Post codeM13 9PL
    B.5.3.4CountryUnited Kingdom
    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/3/14/1280
    D.3 Description of the IMP
    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 INNno recommended INN
    D.3.9.4EV Substance CodeSUB197543
    D.3.10 Strength
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number17.5 10e6 TNC/ml
    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
    MPS IIIA, mucopolysaccharidosis type IIIA
    E.1.1.1Medical condition in easily understood language
    Sanfilippo Syndrome type A
    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 20.1
    E.1.2Level PT
    E.1.2Classification code 10028093
    E.1.2Term Mucopolysaccharidosis
    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
    1) To evaluate the safety and tolerability of the IMP in patients with MPS IIIA. The study will include safety measures for immunosuppressed individuals post HSCT to monitor conditioning regimen related toxicity and haematological reconstitution as well as those related to the IMP

    2) To evaluate biological efficacy of the IMP post treatment as primarily measured by peripheral expression of SGSH activity in total leukocytes
    E.2.2Secondary objectives of the trial
    1) To evaluate overall survival

    2) To evaluate peripheral engraftment of the IMP

    3) To evaluate clinical efficacy on cognitive function as assessed by standard scores, age equivalent scores and development quotient (DQ)

    4) To evaluate the impact of the IMP on patient behaviour, adaptive function, QoL and the impact of treatment on parents or caregivers
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of written informed consent prior to any study related procedures. This study consent must be provided by the parents/legal guardians

    2. Age at baseline ≥3 months and ≤24 months

    3. Normal cognitive function or mild cognitive deterioration at baseline (Development Quotient ≥80) as determined by the Bayley Scale of Infant Development-third edition (BSID-III), cognitive domain, or assessed as normal or only mildly impaired by experienced neuropsychologist and agreed by independent expert reviewer

    4. Sibling or relative of known MPS IIIA patients with rapidly progressing phenotype or genotype associated with rapidly progressing phenotype or presence of somatic features predictive of rapid progression (including but not limited to mild facial dysmorphism, frequent ear infections, frequent upper respiratory infections, umbilical/inguinal hernia, diarrhoea, speech delay, sleeping difficulties, hyperactivity, attention deficit and hearing difficulties, early behavioural problems including perseverative chewing and difficulty with toilet training)

    5. Diagnosis of MPS IIIA based on evidence of SGSH deficiency, defined as Sulfoglucosamine Sulfohydrolase (SGSH) activity ≤10% of the Lower Limit of Normal as measured in total leukocytes, plus either (1) a normal enzyme activity level of at least one other sulfatase (to rule out multiple sulfatase deficiency) as measured in leukocytes, or (2) two documented mutations in the SGSH gene

    6. Medically stable and able to accommodate the protocol requirements (including travel) and protocol assessments without placing an undue burden on the subject/subject’s family, as determined by the CI

    7. Subjects and their parents/legal guardians must be willing and able to comply with study restrictions and to commit to attend clinic for the required duration during the study and follow up period as specified in the protocol
    E.4Principal exclusion criteria
    1. The subject has previously received stem cell therapy, gene therapy or enzyme replacement therapy (any route of administration)

    2. Subject currently enrolled in other interventional trial

    3. Contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, or aneurysm clip in the brain)

    4. The subject has a history of poorly controlled seizures

    5. Homozygous or compound heterozygous for the S298P mutation or any other mutation known to be associated to slow progressing phenotype

    6. The patient is currently receiving psychotropic or other medications which, in the CI’s opinion, would be likely to substantially confound test results

    7. The patient has received any investigational medication (including Genistein) within 30 days prior to the Baseline visit or is scheduled to receive any investigational drug during the course of the study

    8. Documented Human Immunodeficiency Virus (HIV) infection (positive HIV ribonucleic acid [RNA] and/or anti p24 antibodies)

    9. Malignant neoplasia (except local skin cancer) or a documented history of hereditary cancer syndrome. Subjects 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 Medical Monitor

    10. Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome and acute myeloid leukaemia, or other serious haematological disorders

    11. Medical condition or extenuating circumstance that, in the opinion of the CI might compromise the subject’s ability to comply with protocol requirements, the subject’s well being or safety, or the interpretability of the subject’s clinical data

    12. Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing

    13. Severe behavioural disturbances due to reasons other than MPS IIIA and likely to interfere with protocol compliance, as determined by the CI

    14. Known sensitivity to busulfan

    15. The receipt of live vaccinations within 30 days prior to study start
    E.5 End points
    E.5.1Primary end point(s)
    A demonstration of normal or above normal SGSH activity in total leukocytes 12 Months post-IMP treatment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months
    E.5.2Secondary end point(s)
     Change in cognitive scores (standard scores, age equivalent scores and development quotient) measured using the Bayley Scales of Infant Development, 3rd Edition [BSID III] or Kaufman Assessment Battery for Children, 2nd Edition [KABC II] at 36 months post IMP treatment and multiple visits over time according to the schedule of assessments

    For subjects reaching the developmental age ceiling of the BSID III (42 months), the KABC II will be administered. Transition between neurocognitive scales will be done by overlapping both tests from visit prior to reaching a developmental age of 42 months and continue with both tests, if at all possible, for as many visits as possible. When both tests are administered, tests will be performed in two consecutive days per visit.

    The choice of the appropriate test for developmental assessment will be made using the algorithm provided in Appendix 3: Cognitive assessment algorithm

     Measurement of the proportion of cells containing the inserted SGSH gene in total leukocytes at multiple visits over time
     Evaluation of VCN in total leukocytes at multiple other visits over time
     Change from baseline in SGSH activity in total leukocytes at 3 months post treatment and at multiple other visits over time
     Change in adaptive behaviour measured using the Vineland Adaptive Behaviour Scales, 2nd Edition (VABS II) at multiple visits over time
     Change in subject’s behaviour and activities of daily living measured using:
    o Sanfilippo Behaviour Rating Scale (SBRS)
    o Infant Toddler Quality of Life questionnaire (ITQoL)
    o Children Sleep Questionnaire (CSHQ)
    o Child Health Assessment Questionnaire (CHAQ)
     Change in parent/caregiver QoL, measured using:
    o Parenting Stress Index (Overall level of parenting stress experienced by parents of children)
    o Beck Depression Inventory, second edition.
    o Paediatric QoL Inventory (PedsQL) Family Impact Module
    E.5.2.1Timepoint(s) of evaluation of this end point
    36 months
    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) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    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.8.3 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 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
    Each subject’s participation in the study will have ended at the time of his/her last visit, withdrawal of consent or death.
    The study will have ended after the last subject has completed the last study visit at 36 months post-IMP treatment.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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) Yes
    F. of subjects for this age range: 5
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    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 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
    Age at baseline ≥3 months and ≤24 months
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    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 who meet any of the criteria for early termination will be encouraged to return for an early termination visit.
    After completion of 36 months follow-up on the current study protocol and after their last post-treatment evaluation, all subjects will be invited to participate, subject to consent, in a observational long term follow-up study, in order to monitor the long term safety treatment with the IMP.
    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 Decision2019-09-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-25
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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