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    Summary
    EudraCT Number:2015-003031-35
    Sponsor's Protocol Code Number:R04049
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-10-27
    Trial results View 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 ConcernedUK - MHRA
    A.2EudraCT number2015-003031-35
    A.3Full title of the trial
    A Single Centre Study Investigating the Safety and Efficacy of an Immune Modulation Regimen in Mitigating the Alloimmune Response to Intravenous Laronidase in Infants With Severe Mucopolysaccharidosis type I (Hurler syndrome) Prior to Haematopoietic Stem Cell Transplantation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Immune Tolerance Induction with Methotrexate in Hurler Syndrome
    A.3.2Name or abbreviated title of the trial where available
    Immune Tolerance Induction with Methotrexate in Hurler Syndrome
    A.4.1Sponsor's protocol code numberR04049
    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 SponsorCentral Manchester University Hospitals NHS Foundation Trust
    B.1.3.4Country
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCentral Manchester University Hospitals NHS Foundation Trust
    B.5.2Functional name of contact pointCMFT Research Office
    B.5.3 Address:
    B.5.3.1Street Address39 Grafton Street
    B.5.3.2Town/ cityManchester
    B.5.3.3Post codeM13 9WU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01612674125
    B.5.6E-maillynne.webster@cmft.nhs.uk
    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 Yes
    D.2.1.1.2Name of the Marketing Authorisation holderRosemont Pharmaceuticals
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameMethotrexate
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMethotrexate
    D.3.9.1CAS number 59-05-2
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    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 No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Severe Mucopolysaccharidosis Type I (Hurler syndrome, MPS IH)
    E.1.1.1Medical condition in easily understood language
    MPS IH is an inherited disorder caused by an enzyme deficiency. Complex molecules accumulate in the body, affecting multiple organs and causing skeletal problems and developmental delay.
    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 18.1
    E.1.2Level LLT
    E.1.2Classification code 10028094
    E.1.2Term Mucopolysaccharidosis IH
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The objective of this trial is to investigate the safety and efficacy of methotrexate as an immune tolerance induction agent in mitigating the alloimmune response to enzyme replacement therapy with laronidase in severe MPS I.
    E.2.2Secondary objectives of the trial
    n/a
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Written informed consent of a legally authorised guardian(s)
    • A diagnosis of MPS I as defined by deficient α-L-iduronidase activity in leukocytes or cultured fibroblasts, in a laboratory accepted by the investigators
    • Clinical status consistent with severe Hurler phenotype
    OR
    If available, mutations consistent with a classical Hurler genotype e.g. homozygosity or compound heterozygosity for nonsense mutations (Q70X, W402X) in IDUA gene
    • Age ≥3 months and ≤2.5 years at diagnosis
    • Decision to offer HSCT with an appropriate donor after a short period (minimum 4 weeks) of ERT
    E.4Principal exclusion criteria
    • The patient has previously received intravenous laronidase
    • The patient has undergone haematopoietic stem cell transplantation
    • The patient has a known primary immune defect
    • The patient has a known sensitivity or allergy to methotrexate
    • The patient has known contraindications to receiving methotrexate such as pre-existing hepatic or renal dysfunction, or the patient is receiving concomitant medications that interact with methotrexate
    • The patient has received any immunomodulatory or immunosuppressive medication within 90 days prior to enrolment
    • The patient has been exposed to any other investigational product within 90 days prior to enrolment in the trial
    • The patient has any clinically significant organic disease (with the exception of symptoms relating to MPS I), including cardiovascular, hepatic, pulmonary, neurologic or renal disease, other serious intercurrent illness or extenuating circumstances, that, in the opinion of the investigator would preclude participation in the trial or potentially decrease survival
    E.5 End points
    E.5.1Primary end point(s)
    Peak anti-laronidase IgG titre (between 4 weeks post-ERT and pre-HSCT) of <1:4000
    E.5.1.1Timepoint(s) of evaluation of this end point
    Anti-laronidase IgG samples will be taken at baseline, 4 weeks post-ERT, 8 weeks post-ERT, pre-HSCT and 12 weeks post-HSCT.
    E.5.2Secondary end point(s)
    Secondary endpoints:
    Safety and toxicity of methotrexate as measured by haematological parameters and biochemical markers of renal and hepatic function.
    Absolute value of peak anti-laronidase IgG titre (between 4 weeks post-ERT and pre-HSCT).

    Tertiary (exploratory only) endpoints:
    Incidence of neutralising antibodies to laronidase at time of highest anti-laronidase antibody titres
    Urinary glycosaminoglycans (GAGs), urinary DS/CS ratio and blood heparan/dermatan sulfate derived disaccharides
    Anti-laronidase IgM titres
    Immune phenotyping and B/T cell functional studies
    Sleep oximetry (oxygen desaturation index 4%)
    Exploratory biomarkers in blood and urine
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints:
    Clinical laboratory tests for haematological parameters and liver and renal function will be taken at baseline, 1, 2, 3, 4, 8 weeks post-ERT, pre-HSCT and 12 weeks post-HSCT.
    Anti-laronidase IgG samples will be taken at baseline, 4 weeks post-ERT, 8 weeks post-ERT, pre-HSCT and 12 weeks post-HSCT.

    Tertiary endpoints:
    Samples for neutralising antibodies, IgM titres, urine GAGs, urine DS/CS ratio, heparan/dermatan sulfate derived disaccharides and exploratory biomarkers will be collected at baseline, 4 weeks post-ERT, 8 weeks post-ERT, pre-HSCT and 12 weeks post-HSCT
    Sleep oximetry will be performed at baseline and pre-HSCT
    Immune phenotyping will be performed at baseline, 1 week post-ERT, 4 weeks post-ERT, 8 weeks post-ERT, pre-HSCT and 12 weeks post-HSCT.
    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 No
    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.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 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.8.4.1Number of sites anticipated in Member State concerned1
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days21
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days21
    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: 4
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 2
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 2
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 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 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 4
    F.4.2.2In the whole clinical trial 4
    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)
    The IMP is intended to be given as a short course rather than ongoing therapy, and no subjects will be receiving the IMP at the end of the trial.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-11-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-10-31
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