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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2015-003031-35
    Trial protocol
    		 GB  
    Global end of trial date
    31 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Feb 2020
    First version publication date
    09 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    R04049
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Manchester University NHS Foundation Trust
    Sponsor organisation address
    Oxford Road, Manchester, United Kingdom, M13 9WL
    Public contact
    Dr Lynne Webster, Manchester University NHS Foundation Trust, 0044 01612674125, lynne.webster@mft.nhs.uk
    Scientific contact
    Dr Lynne Webster, Manchester University NHS Foundation Trust, 0044 01612674125, lynne.webster@mft.nhs.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main 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.
    Protection of trial subjects
    To minimise the inconvenience to families participating in the study, patients enrolled on the trial received their doses around the first infusion of laronidase. All other treatment was as standard of care and the protocol did not interfere with routine timescales for enzyme replacement therapy (ERT) and scheduling of haematopoietic stem cell transplantation (HSCT). The main study procedure was urine and blood sampling. All patients received standard care for Hurler syndrome and therefore required peripheral venous cannulation for ERT infusions as well as central venous catheter insertion in preparation for HSCT. Most study related blood tests were therefore taken at the point of cannulation or from the central venous catheter, minimising the need for additional venepunctures. This study did not involve any significant invasive procedures or radiographic imaging. Methotrexate is a drug commonly used in children with inflammatory disorders and its side effect and toxicity profile is well understood. Participants were monitored closely throughout the study and were made aware of the known risks and side effects prior to participation so that they could make an informed decision.
    Background therapy
    		 There was no background therapy
    Evidence for comparator
    		 There was no comparator in the study as it is a single arm study where everyone received the IMP.
    Actual start date of recruitment
    01 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    3
    EEA total number of subjects
    3
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    3
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started on 11th Feb 2016 at Manchester Royal Infirmary. Recruitment and the trial ended on 31st Oct 2017.

    Pre-assignment
    Screening details
    		 Screening and baseline was to be completed within 7 days prior to first infusion of laronidase. A maximum of 7 days from informed consent, however due to the fact many patients travel long distances this will often take place on the same day as the first laronidase treatment.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The trial was open label

    Arms
    Arm title
    		 methotrexate
    Arm description
    		 Participants enter a treatment phase where patients receive methotrexate for 3 weeks (three doses per week) in addition to standard care. Following this all patients continue on weekly ERT until transplantation as per standard of care, receiving a minimum of 4 weeks of ERT in total. It was anticipated that all patients would receive at least 8 weeks of ERT and therefore have study samples collected at 8 weeks for the primary endpoint. However in the unlikely event that HSCT is scheduled earlier, study samples will be collected at 4 weeks after commencing ERT and immediately prior to HSCT for secondary endpoints only.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotraxate
    Investigational medicinal product code
    PL 00427/0233
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    0.4mg/kg per day is the maximum allowed dose. Three doses, given 1 hour prior to the infusion of laronidase and 24 hours and 48 hours after infusion. This treatment pattern will be repeated at weeks 1 and 2 meaning 9 doses in total. All other treatment will be as standard care

    Number of subjects in period 1
    		methotrexate
    Started
    3
    Completed
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 3 3
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 3 3
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: months
        median (full range (min-max))
    		 11.5 (4.5 to 13.6) -
    Gender categorical
    Units: Subjects
        Female
    		 1 1
        Male
    		 2 2
    Genotype
    Units: Subjects
        c.1205G > A/c.1205 G > A [p.(Trp402Ter)/
    		 1 1
        c.1205G > A/c.979G > C [p.(Trp402Ter)/
    		 1 1
        c.1205G > A/c.46_57del12 [p.(Trp402Ter) /
    		 1 1
    Iduronidase Enzyme Activity
    Units: Subjects
        0.02
    		 1 1
        0.17
    		 1 1
        undetectable
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    methotrexate
    Reporting group description
    		 Participants enter a treatment phase where patients receive methotrexate for 3 weeks (three doses per week) in addition to standard care. Following this all patients continue on weekly ERT until transplantation as per standard of care, receiving a minimum of 4 weeks of ERT in total. It was anticipated that all patients would receive at least 8 weeks of ERT and therefore have study samples collected at 8 weeks for the primary endpoint. However in the unlikely event that HSCT is scheduled earlier, study samples will be collected at 4 weeks after commencing ERT and immediately prior to HSCT for secondary endpoints only.

    Primary: Peak anti-laronidase IgG titres of < 1:4000

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    End point title
    		 Peak anti-laronidase IgG titres of < 1:4000 [1]
    End point description
    End point type
    Primary
    End point timeframe
    between 4 weeks post-ERT and pre-HSCT
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No participants had a peak anti-laronidase IgG titre of less than 1:4000 (i.e. 0 out of 3 participants met the endpoint).
    End point values
    Number of subjects analysed
    Units: Subjects
        Yes
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From consent to commencement of conditioning therapy for haematopoietic stem cell transplantation.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Methotrexate
    Reporting group description
    		 -

    Serious adverse events
    		 Methotrexate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Admission to commence ACE inhibitors for mitral reguritation
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Planned hospital admission for hip arthroscopy
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Methotrexate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    Investigations
    Deranged LFTs
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Cardiac disorders
    Mitral regurgitation
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    2
    General disorders and administration site conditions
    Pyrexia
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    3
    Immune system disorders
    Allergic reaction
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Gastrointestinal disorders
    Vomiting
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    hair thinning and hair loss
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    arthrogram and removal of hip spica
    alternative dictionary used: CTCAE 3
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jul 2016
    The first two participants received three doses of oral methotrexate around the first laronidase infusion only. A minimum of 2 further participants will be enrolled and will receive three doses of oral methotrexate around each of the first three laronidase infusions. This was due to the fact the first 2 patients developed antibodies to the methotrexate.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was terminated early after 3 patients. Following the development of antibodies by the first 2 subjects, the duration of the Methotrexate regimen was increased. The 3rd participant on this extended dose also developed antibodies.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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