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    Clinical Trial Results:
    An Open Label Randomised Controlled Trial of Mycophenolate Mofetil Versus Cyclophosphamide for the Induction of Remission of Childhood Polyarteritis Nodosa

    Summary
    EudraCT number
    2013-004668-71
    Trial protocol
    GB   IT   PT   ES   BE  
    Global end of trial date
    26 Jun 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Jan 2021
    First version publication date
    03 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    11/0499
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    EudraCT: 2013-004668-71
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Gower Street, London, United Kingdom,
    Public contact
    Professor Paul Brogan, University College London, p.brogan@ucl.ac.uk
    Scientific contact
    Professor Paul Brogan, University College London, p.brogan@ucl.ac.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
    24 Aug 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Is mycophenelate mofetil (MMF) as effective as cyclophosphamide (CYC) at inducing remission in children with polyarteritis nodosa (PAN)?
    Protection of trial subjects
    The identification and recruitment of participants to the MYPAN trial and the administration of the trial treatments was carried out by trained health care professionals in a hospital environment following standard, routine procedures. All those who oversaw treatment were trained on the study, evidenced by the collection of site delegation logs. Current CVs and GCP certificates were also obtained for all staff members who had a delegated duty within the study. All members of site staff who approached the participant’s family for consent were trained on the study and equipped with sufficient knowledge to answer any trial related questions. In addition, these members of staff had the required clinical skills to provide additional support to those families that were emotionally distressed by their child’s condition. Patient data was collected at site using CRFs specifically designed for the MYPAN trial. All collected information was pseudo-anonymised and transferred to the Liverpool Clinical Trials Centre (LCTC) in an agreed secure format. The management of the study was done in line with Ethical, Regulatory and LCTC policies/procedures. Protocol procedures included mechanisms to manage anticipated adverse reactions due to the established safety profiles of the trial interventions. For example, the trial interventions are immunosuppressants that can be associated with opportunistic infection, and mandatory prophylaxis with cotrimoxazole was required to prevent this occurrence. Other examples of risk mitigation were the prescribing of MMF at half the recommended dose for the first week, thereafter increasing to the full dose in order to mitigate against gastrointestinal adverse effects, and the use of anti-emetics and recommended co-administration of MESNA and adequate hydration as standard for CYC allocated participants.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Aug 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    United Kingdom: 7
    Worldwide total number of subjects
    11
    EEA total number of subjects
    8
    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)
    0
    Children (2-11 years)
    8
    Adolescents (12-17 years)
    3
    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
    11 subjects were recruited: 7 from the UK (3 sites), 1 from Spain, and 3 from Turkey (1 site). The first subject was randomised on 09/03/2015, and the last on 06/06/2018. 8 participating sites did not recruit.

    Pre-assignment
    Screening details
    13 subjects were screened. 1 did not meet eligibility criteria, and 1 did not agree to participate.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Mycophenolate mofetil (MMF)
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Mycophenolate mofetil
    Investigational medicinal product code
    24280-93-1
    Other name
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    For ease of administration, for the tablets and capsules the dose should be rounded to the nearest multiple of 250 (as long as within 10% of target dose). The 1g/5ml powder should be reconstituted in accordance with the manufacturer’s SmPC. The starting dose is 600 mg/m² per day (maximum 1g per day) for the first week. Thereafter the dose is 1200 mg/m² per day, maximum 2g per day, in two divided doses. MMF may be stopped from 3 months onward provided patient in remission (PVAS 0 for 2 consecutive study assessments at least 1 month apart). After completion of MMF, AZA to be commenced the next day. If the target dose is not tolerated, patients should receive the maximum tolerated dose.

    Arm title
    Intravenous Cyclophosphamide (CYC)
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The preparation of CYC should be in accordance with the manufacturer’s instructions on intravenous infusion, provided on the relevant SmPC. MESNA and IV fluids will be administered as per existing local practice. - CYC is given as intravenous pulses at weeks 0, 2, 4 and then every 3 weeks until remission is reached from start of therapy (max 10 doses, min 6 doses) at a dose of 500-750 mg/m2 (maximum 1.2g). - The dose is adjusted based on Leukocyte count, hepatic, and renal function according to a standard protocol (see Table 1). - CYC may be stopped after a minimum of 6 doses (week 13) provided patient in remission (PVAS 0 for 2 consecutive study assessments at least a month (4 weeks) apart and adhering to protocol steroid taper).

    Number of subjects in period 1
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Started
    6
    5
    Completed
    6
    5
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Mycophenolate mofetil (MMF)
    Arm description
    3-6 months (12-24 weeks) induction therapy with oral MMF
    Arm type
    Experimental

    Investigational medicinal product name
    Mycophenolate mofetil
    Investigational medicinal product code
    24280-93-1
    Other name
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    For ease of administration, for the tablets and capsules the dose should be rounded to the nearest multiple of 250 (as long as within 10% of target dose). The 1g/5ml powder should be reconstituted in accordance with the manufacturer’s SmPC. The starting dose is 600 mg/m² per day (maximum 1g per day) for the first week. Thereafter the dose is 1200 mg/m² per day, maximum 2g per day, in two divided doses. MMF may be stopped from 3 months onward provided patient in remission (PVAS 0 for 2 consecutive study assessments at least 1 month apart). After completion of MMF, AZA to be commenced the next day. If the target dose is not tolerated, patients should receive the maximum tolerated dose.

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Prednisone / Methylprednisolone
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Both groups will receive the same protocolised prednisolone/prednisone starting at 1mg/kg/day weaning to 0.1 mg/kg/day by 6 months (24 weeks)

    Arm title
    Intravenous Cyclophosphamide (CYC)
    Arm description
    3-6 months (12-24 weeks) induction therapy with intravenous CYC regimen
    Arm type
    Active comparator

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The preparation of CYC should be in accordance with the manufacturer’s instructions on intravenous infusion, provided on the relevant SmPC. MESNA and IV fluids will be administered as per existing local practice. - CYC is given as intravenous pulses at weeks 0, 2, 4 and then every 3 weeks until remission is reached from start of therapy (max 10 doses, min 6 doses) at a dose of 500-750 mg/m2 (maximum 1.2g). - The dose is adjusted based on Leukocyte count, hepatic, and renal function according to a standard protocol (see Table 1). - CYC may be stopped after a minimum of 6 doses (week 13) provided patient in remission (PVAS 0 for 2 consecutive study assessments at least a month (4 weeks) apart and adhering to protocol steroid taper).

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Prednisone / Methylprednisolone
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Both groups will receive the same protocolised prednisolone/prednisone starting at 1mg/kg/day weaning to 0.1 mg/kg/day by 6 months (24 weeks)

    Number of subjects in period 2
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Started
    6
    5
    Completed
    6
    5
    Period 3
    Period 3 title
    Follow-up
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Mycophenolate mofetil (MMF)
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Azathioprine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose is 2 mg/kg/day, maximum 200 mg/day, rounded to the nearest 25 mg. Weight at time of commencing azathioprine to be used for dose calculation. - Check FBC and alanine transaminase (ALT) or aspartate transaminase (AST) (for hepatotoxicity): a. Every two weeks for one month (4 weeks) b. Every two months (8 weeks) for the first 12 months (48 weeks) c. Then three-monthly (every 12 weeks) - Stop if leukocytes <4.0 x 109 cells/l. Restart when leukocytes ≥ 4.0 x109 cells/l with AZA dose reduced by at least 25%. Monitor weekly for one month (4 weeks). - If liver transaminases are over twice upper limit of normal level then Azathioprine should be temporarily discontinued. - Thiopurine s-methyltransferase (TPMT) activity or polymorphism assessment to be used according to local practice, but this is not a mandatory requirement.

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Prednisone / Methylprednisolone
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.05-0.075 mg/kg by 9 months (36 weeks) and until trial end at 18 months (72 weeks).

    Arm title
    Intravenous Cyclophosphamide (CYC)
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Azathioprine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose is 2 mg/kg/day, maximum 200 mg/day, rounded to the nearest 25 mg. Weight at time of commencing azathioprine to be used for dose calculation. - Check FBC and alanine transaminase (ALT) or aspartate transaminase (AST) (for hepatotoxicity): a. Every two weeks for one month (4 weeks) b. Every two months (8 weeks) for the first 12 months (48 weeks) c. Then three-monthly (every 12 weeks) - Stop if leukocytes <4.0 x 109 cells/l. Restart when leukocytes ≥ 4.0 x109 cells/l with AZA dose reduced by at least 25%. Monitor weekly for one month (4 weeks). - If liver transaminases are over twice upper limit of normal level then Azathioprine should be temporarily discontinued. - Thiopurine s-methyltransferase (TPMT) activity or polymorphism assessment to be used according to local practice, but this is not a mandatory requirement.

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Prednisone / Methylprednisolone
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.05-0.075 mg/kg by 9 months (36 weeks) and until trial end at 18 months (72 weeks).

    Number of subjects in period 3
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Started
    6
    5
    Completed
    5
    5
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Mycophenolate mofetil (MMF)
    Reporting group description
    -

    Reporting group title
    Intravenous Cyclophosphamide (CYC)
    Reporting group description
    -

    Reporting group values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC) Total
    Number of subjects
    6 5 11
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    4 4 8
        Adolescents (12-17 years)
    2 1 3
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    10.8 (7.0 to 12.1) 7.9 (6.7 to 9.4) -
    Gender categorical
    Units: Subjects
        Female
    3 3 6
        Male
    3 2 5

    End points

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    End points reporting groups
    Reporting group title
    Mycophenolate mofetil (MMF)
    Reporting group description
    -

    Reporting group title
    Intravenous Cyclophosphamide (CYC)
    Reporting group description
    -
    Reporting group title
    Mycophenolate mofetil (MMF)
    Reporting group description
    3-6 months (12-24 weeks) induction therapy with oral MMF

    Reporting group title
    Intravenous Cyclophosphamide (CYC)
    Reporting group description
    3-6 months (12-24 weeks) induction therapy with intravenous CYC regimen
    Reporting group title
    Mycophenolate mofetil (MMF)
    Reporting group description
    -

    Reporting group title
    Intravenous Cyclophosphamide (CYC)
    Reporting group description
    -

    Primary: Remission within 24 weeks with adherence to protocolised corticosteroid taper

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    End point title
    Remission within 24 weeks with adherence to protocolised corticosteroid taper
    End point description
    Remission within six months (24 weeks) of randomisation defined as a paediatric vasculitis activity score (PVAS) of zero on two consecutive readings (both within 6 months (24 weeks) of randomisation ≥ one month (4 weeks) apart, with adherence to the protocolised corticosteroid taper.
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Subjects
    4
    4
    Statistical analysis title
    Bayesian analysis
    Statistical analysis description
    Calculation of a posterior distribution for the probability of remission within 6-months of randomisation to MMF
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Parameter type
    Probability
    Point estimate
    0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    0.85
    Notes
    [1] - Presentation of summary statistics for the posterior distribution (mode and 95% credible interval)
    Statistical analysis title
    Bayesian analysis
    Statistical analysis description
    Calculation of a posterior distribution for the probability of remission within 6-months of randomisation to CYC
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Parameter type
    Probability
    Point estimate
    0.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    0.87
    Notes
    [2] - Presentation of summary statistics for the posterior distribution (mode and 95% credible interval)
    Statistical analysis title
    Bayesian analysis
    Statistical analysis description
    Calculation of a posterior distribution for the odds-ratio of remission within 6-months of randomisation to MMF vs CYC
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    Method
    Parameter type
    Probability
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    1.88
    Notes
    [3] - Presentation of summary statistics for the posterior distribution (mode and 95% credible interval)

    Secondary: Remission within 24 weeks irrespective of adherence to protocolised corticosteroid taper

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    End point title
    Remission within 24 weeks irrespective of adherence to protocolised corticosteroid taper
    End point description
    Remission within six months (24 weeks) of randomisation defined as paediatric vasculitis activity score (PVAS) of zero on two consecutive readings ≥ one month (4 weeks) apart, irrespective of adherence to a protocolised corticosteroid taper
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Subjects
    4
    4
    Statistical analysis title
    Fisher's exact test
    Statistical analysis description
    Does treatment arm have a significant effect on remission rates
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1
    Method
    Fisher exact
    Parameter type
    Relative Risk
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    2.5

    Secondary: Time to remission, with adherence to a protocolised corticosteroid taper

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    End point title
    Time to remission, with adherence to a protocolised corticosteroid taper
    End point description
    Time to remission defined as PVAS of zero on two consecutive readings ≥ one month (4 weeks) apart, with adherence to a protocolised corticosteroid taper, measured from randomisation
    End point type
    Secondary
    End point timeframe
    From randomisation to 72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Weeks
        median (confidence interval 95%)
    7.1 (4.0 to 999)
    17.6 (4.4 to 35.3)
    Attachments
    Kaplan-Meier curve showing time to remission
    No statistical analyses for this end point

    Secondary: Paediatric vasculitis damage index (PVDI) at 24 weeks

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    End point title
    Paediatric vasculitis damage index (PVDI) at 24 weeks
    End point description
    Paediatric vasculitis damage index (PVDI – modified from the adult VDI) at 6, 12 and 18 months (24, 48 and 72 weeks) after randomisation
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0.5 (0 to 1)
    2 (0 to 2)
    No statistical analyses for this end point

    Secondary: Paediatric vasculitis damage index (PVDI) at 48 weeks

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    End point title
    Paediatric vasculitis damage index (PVDI) at 48 weeks
    End point description
    Paediatric vasculitis damage index (PVDI – modified from the adult VDI) at 6, 12 and 18 months (24, 48 and 72 weeks) after randomisation
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    5
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0 (0 to 1)
    2 (0 to 3)
    No statistical analyses for this end point

    Secondary: Paediatric vasculitis damage index (PVDI) at 72 weeks

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    End point title
    Paediatric vasculitis damage index (PVDI) at 72 weeks
    End point description
    Paediatric vasculitis damage index (PVDI – modified from the adult VDI) at 6, 12 and 18 months (24, 48 and 72 weeks) after randomisation
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    5
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0 (0 to 1)
    2 (0 to 3)
    Attachments
    MMF PVDI over time
    CYC PVDI over time
    No statistical analyses for this end point

    Secondary: CHAQ Disability Index at Baseline

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    End point title
    CHAQ Disability Index at Baseline
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general health.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Units
        median (inter-quartile range (Q1-Q3))
    1.5 (0.6 to 2.4)
    1.5 (0.3 to 1.5)
    No statistical analyses for this end point

    Secondary: CHAQ Disability Index at 16 weeks

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    End point title
    CHAQ Disability Index at 16 weeks
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general health.
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0.3 (0 to 0.6)
    1.0 (0 to 1.9)
    No statistical analyses for this end point

    Secondary: CHAQ Disability Index at 24 weeks

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    End point title
    CHAQ Disability Index at 24 weeks
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general health.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0.1 (0 to 0.1)
    0.5 (0 to 1.9)
    No statistical analyses for this end point

    Secondary: CHAQ Disability Index at 48 weeks

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    End point title
    CHAQ Disability Index at 48 weeks
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general health.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    4
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0.1)
    0.8 (0.1 to 1.7)
    No statistical analyses for this end point

    Secondary: CHAQ Disability Index at 72 weeks

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    End point title
    CHAQ Disability Index at 72 weeks
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general health.
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    4
    4
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    1.0 (0.2 to 1.8)
    Attachments
    MMF CHAQ disability Patient Profiles
    CYC CHAQ Disability: Patient Profiles
    No statistical analyses for this end point

    Secondary: CHAQ Pain at Baseline

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    End point title
    CHAQ Pain at Baseline
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general health.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    4
    4
    Units: Units
        median (inter-quartile range (Q1-Q3))
    40.5 (6.0 to 70.5)
    30.5 (5.5 to 56.0)
    No statistical analyses for this end point

    Secondary: CHAQ Pain at 16 weeks

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    End point title
    CHAQ Pain at 16 weeks
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general health.
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    4
    4
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0.5 (0 to 20.5)
    2.5 (0 to 27.5)
    No statistical analyses for this end point

    Secondary: CHAQ Pain at 24 weeks

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    End point title
    CHAQ Pain at 24 weeks
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general health.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    4
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    4.5 (1.0 to 34.5)
    No statistical analyses for this end point

    Secondary: CHAQ Pain at 48 weeks

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    End point title
    CHAQ Pain at 48 weeks
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general health.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    5
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0 (0 to 1)
    2 (0 to 12)
    No statistical analyses for this end point

    Secondary: CHAQ Pain at 72 weeks

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    End point title
    CHAQ Pain at 72 weeks
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general health.
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    4
    2
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    2 (0 to 4)
    Attachments
    MMF CHAQ Pain: Patient Profiles
    CYC CHAQ Pain: Patient Profiles
    No statistical analyses for this end point

    Secondary: CHAQ General Evaluation at Baseline

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    End point title
    CHAQ General Evaluation at Baseline
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    4
    3
    Units: Units
        median (inter-quartile range (Q1-Q3))
    35 (6 to 68.5)
    15 (0 to 79)
    No statistical analyses for this end point

    Secondary: CHAQ General Evaluation at 16 weeks

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    End point title
    CHAQ General Evaluation at 16 weeks
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general evaluation.
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    4
    4
    Units: Units
        median (inter-quartile range (Q1-Q3))
    8.5 (2.5 to 16)
    10 (6 to 11)
    No statistical analyses for this end point

    Secondary: CHAQ General Evaluation at 24 weeks

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    End point title
    CHAQ General Evaluation at 24 weeks
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general evaluation.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    4
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    8 (1 to 29.5)
    No statistical analyses for this end point

    Secondary: CHAQ General Evaluation at 48 weeks

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    End point title
    CHAQ General Evaluation at 48 weeks
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general evaluation.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    3
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0 (0 to 1)
    5 (0 to 22)
    No statistical analyses for this end point

    Secondary: CHAQ General Evaluation at 72 weeks

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    End point title
    CHAQ General Evaluation at 72 weeks
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is a functional outcome score measuring disability, pain, and general evaluation.
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    4
    2
    Units: Units
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    2 (0 to 4)
    Attachments
    MMF CHAQ General Evaluation: Patient Profiles
    CYC CHAQ General Evaluation: Patient Profiles
    No statistical analyses for this end point

    Secondary: CHQ Physical Summary Score (PhS) at Baseline

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    End point title
    CHQ Physical Summary Score (PhS) at Baseline
    End point description
    The Child Health Questionnaire™ (CHQ) is a family of generic person-reported outcomes measures to assess health-related quality of life for children and adolescents from 5-to-18 years of age. Two sub-scores are derived: Physical Summary Score (PhS); and Psychosocial Summary Score (PsS)
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Units
        median (inter-quartile range (Q1-Q3))
    8.3 (-0.4 to 18.0)
    9.0 (1.8 to 14.0)
    No statistical analyses for this end point

    Secondary: CHQ Physical Summary Score (PhS) at 16 weeks

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    End point title
    CHQ Physical Summary Score (PhS) at 16 weeks
    End point description
    The Child Health Questionnaire™ (CHQ) is a family of generic person-reported outcomes measures to assess health-related quality of life for children and adolescents from 5-to-18 years of age. Two sub-scores are derived: Physical Summary Score (PhS); and Psychosocial Summary Score (PsS)
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Units
        median (inter-quartile range (Q1-Q3))
    42.9 (32.1 to 50.5)
    12.8 (6.3 to 35.0)
    No statistical analyses for this end point

    Secondary: CHQ Physical Summary Score (PhS) at 24 weeks

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    End point title
    CHQ Physical Summary Score (PhS) at 24 weeks
    End point description
    The Child Health Questionnaire™ (CHQ) is a family of generic person-reported outcomes measures to assess health-related quality of life for children and adolescents from 5-to-18 years of age. Two sub-scores are derived: Physical Summary Score (PhS); and Psychosocial Summary Score (PsS)
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    4
    Units: Units
        median (inter-quartile range (Q1-Q3))
    50.8 (46.8 to 51.8)
    26.6 (7.8 to 41.6)
    No statistical analyses for this end point

    Secondary: CHQ Physical Summary Score (PhS) at 48 weeks

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    End point title
    CHQ Physical Summary Score (PhS) at 48 weeks
    End point description
    The Child Health Questionnaire™ (CHQ) is a family of generic person-reported outcomes measures to assess health-related quality of life for children and adolescents from 5-to-18 years of age. Two sub-scores are derived: Physical Summary Score (PhS); and Psychosocial Summary Score (PsS)
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    2
    Units: Units
        median (inter-quartile range (Q1-Q3))
    54.3 (52.4 to 55.9)
    16.8 (12.8 to 20.7)
    No statistical analyses for this end point

    Secondary: CHQ Physical Summary Score (PhS) at 72 weeks

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    End point title
    CHQ Physical Summary Score (PhS) at 72 weeks
    End point description
    The Child Health Questionnaire™ (CHQ) is a family of generic person-reported outcomes measures to assess health-related quality of life for children and adolescents from 5-to-18 years of age. Two sub-scores are derived: Physical Summary Score (PhS); and Psychosocial Summary Score (PsS)
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    4
    Units: Units
        median (inter-quartile range (Q1-Q3))
    48.7 (48.2 to 55.4)
    38.7 (18.3 to 51.9)
    No statistical analyses for this end point

    Secondary: CHQ Psychosocial Summary Score (PsS) at Baseline

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    End point title
    CHQ Psychosocial Summary Score (PsS) at Baseline
    End point description
    The Child Health Questionnaire™ (CHQ) is a family of generic person-reported outcomes measures to assess health-related quality of life for children and adolescents from 5-to-18 years of age. Two sub-scores are derived: Physical Summary Score (PhS); and Psychosocial Summary Score (PsS)
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: unit(s)s
        median (inter-quartile range (Q1-Q3))
    34.9 (32.5 to 48.1)
    28.9 (25.0 to 32.7)
    No statistical analyses for this end point

    Secondary: CHQ Psychosocial Summary Score (PsS) at 16 weeks

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    End point title
    CHQ Psychosocial Summary Score (PsS) at 16 weeks
    End point description
    The Child Health Questionnaire™ (CHQ) is a family of generic person-reported outcomes measures to assess health-related quality of life for children and adolescents from 5-to-18 years of age. Two sub-scores are derived: Physical Summary Score (PhS); and Psychosocial Summary Score (PsS)
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Units
        median (inter-quartile range (Q1-Q3))
    52.0 (48.4 to 60.1)
    42.8 (39.9 to 43.6)
    No statistical analyses for this end point

    Secondary: CHQ Psychosocial Summary Score (PsS) at 24 weeks

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    End point title
    CHQ Psychosocial Summary Score (PsS) at 24 weeks
    End point description
    The Child Health Questionnaire™ (CHQ) is a family of generic person-reported outcomes measures to assess health-related quality of life for children and adolescents from 5-to-18 years of age. Two sub-scores are derived: Physical Summary Score (PhS); and Psychosocial Summary Score (PsS)
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    4
    Units: Units
        median (inter-quartile range (Q1-Q3))
    60.7 (58.2 to 65.5)
    39.1 (25.7 to 52.9)
    No statistical analyses for this end point

    Secondary: CHQ Psychosocial Summary Score (PsS) at 48 weeks

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    End point title
    CHQ Psychosocial Summary Score (PsS) at 48 weeks
    End point description
    The Child Health Questionnaire™ (CHQ) is a family of generic person-reported outcomes measures to assess health-related quality of life for children and adolescents from 5-to-18 years of age. Two sub-scores are derived: Physical Summary Score (PhS); and Psychosocial Summary Score (PsS)
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    2
    Units: Units
        median (inter-quartile range (Q1-Q3))
    54.3 (53.5 to 56.5)
    24.8 (15.3 to 34.4)
    No statistical analyses for this end point

    Secondary: CHQ Psychosocial Summary Score (PsS) at 72 weeks

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    End point title
    CHQ Psychosocial Summary Score (PsS) at 72 weeks
    End point description
    The Child Health Questionnaire™ (CHQ) is a family of generic person-reported outcomes measures to assess health-related quality of life for children and adolescents from 5-to-18 years of age. Two sub-scores are derived: Physical Summary Score (PhS); and Psychosocial Summary Score (PsS)
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    4
    Units: Units
        median (inter-quartile range (Q1-Q3))
    59.0 (57.8 to 60.2)
    52.4 (38.5 to 58.6)
    No statistical analyses for this end point

    Secondary: Cumulative Oral Corticosteroid dose at 24 weeks

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    End point title
    Cumulative Oral Corticosteroid dose at 24 weeks
    End point description
    Total oral corticosteroid prescribed from randomisation to 24 weeks
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: mg/kg
        median (inter-quartile range (Q1-Q3))
    51.6 (51.0 to 52.0)
    50.7 (50.3 to 50.8)
    No statistical analyses for this end point

    Secondary: Cumulative Oral Corticosteroid dose at 72 weeks

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    End point title
    Cumulative Oral Corticosteroid dose at 72 weeks
    End point description
    Total oral corticosteroid prescribed from randomisation to 72 weeks
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    5
    Units: mg/kg
        median (inter-quartile range (Q1-Q3))
    74.0 (73.9 to 77.6)
    73.1 (72.7 to 73.6)
    No statistical analyses for this end point

    Secondary: Height z-score at 72 weeks

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    End point title
    Height z-score at 72 weeks
    End point description
    Age and sex adjusted z-scores for height. A score of 0 means average height for that age/sex. Scores below -2 and above 2 indicate very unusual heights for age/sex.
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    5
    Units: z-score
        median (inter-quartile range (Q1-Q3))
    -1.0 (-1.1 to 1.0)
    0.0 (-0.2 to 0.1)
    Attachments
    MMF Height Z-scores: Profile plots
    CYC Height Z-scores: Profile plots
    No statistical analyses for this end point

    Secondary: Weight z-score at 72 weeks

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    End point title
    Weight z-score at 72 weeks
    End point description
    Age and sex adjusted z-scores for weight. A score of 0 means average weight for that age/sex. Scores below -2 and above 2 indicate very unusual weights for age/sex.
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    5
    Units: Z-score
        median (inter-quartile range (Q1-Q3))
    -0.5 (-0.5 to -0.5)
    1.6 (1.0 to 2.3)
    Attachments
    MMF Weight Z-scores: Profile plots
    CYC Weight Z-scores: Profile plots
    No statistical analyses for this end point

    Secondary: BMI z-score at 72 weeks

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    End point title
    BMI z-score at 72 weeks
    End point description
    Age and sex adjusted z-scores for BMIt. A score of 0 means average BMI for that age/sex. Scores below -2 and above 2 indicate very unusual BMI for age/sex.
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    5
    Units: z-score
        median (inter-quartile range (Q1-Q3))
    -0.3 (-0.4 to 0.0)
    1.5 (1.3 to 2.4)
    Attachments
    MMF BMI Z-scores: Profile plots
    CYC BMI Z-scores: Profile plots
    No statistical analyses for this end point

    Secondary: Relapse rate

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    End point title
    Relapse rate
    End point description
    A relapse is defined as a PVAS score > 0 occurring after remission. In addition to the remission rate, it was also planned to report time-to-relapse, and rates of major/minor relapses. However, as no relapses were observed, we simply report the relapse rate.
    End point type
    Secondary
    End point timeframe
    From point of remission to 72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    5
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Secondary: At least one adverse event, which may including drug toxicity

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    End point title
    At least one adverse event, which may including drug toxicity
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to 72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Subjects
    5
    5
    No statistical analyses for this end point

    Secondary: Time from randomisation to death

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    End point title
    Time from randomisation to death
    End point description
    The endpoint was planned as a time-to-event. However, as no subjects died, we report this as a rate.
    End point type
    Secondary
    End point timeframe
    From randomisation to 72 weeks
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Quality-adjusted life years (QALYs)

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    End point title
    Quality-adjusted life years (QALYs)
    End point description
    Measure of utility of treatments
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: QALY
        arithmetic mean (confidence interval 95%)
    1.13 (0.58 to 1.44)
    1.18 (1.07 to 1.48)
    Statistical analysis title
    Mean difference
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.575
         upper limit
    0.48

    Secondary: Probability of cost-effectiveness at £20,000 per QALY threshold

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    End point title
    Probability of cost-effectiveness at £20,000 per QALY threshold
    End point description
    Cost-effectiveness acceptability
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Probability
        number (not applicable)
    0.32
    0.68
    No statistical analyses for this end point

    Secondary: Probability of cost-effectiveness at £30,000 per QALY threshold

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    End point title
    Probability of cost-effectiveness at £30,000 per QALY threshold
    End point description
    Probability of cost-effectiveness at £30,000 per QALY threshold
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: Probability
        number (not applicable)
    0.34
    0.66
    No statistical analyses for this end point

    Secondary: Disaggregated 18-month costs: Day-case admittance

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    End point title
    Disaggregated 18-month costs: Day-case admittance
    End point description
    Total costs associated with admission to hospital where an overnight stay was not required
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: GBP(£)
        arithmetic mean (confidence interval 95%)
    4261 (-2842 to 11365)
    1053 (-612 to 2718)
    Statistical analysis title
    Mean difference
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    3208
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1786
         upper limit
    12112

    Secondary: Disaggregated 18-month costs: Out-patient clinic

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    End point title
    Disaggregated 18-month costs: Out-patient clinic
    End point description
    Costs associated with out-patient clinic attendance
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: GBP(£)
        arithmetic mean (confidence interval 95%)
    74 (-67 to 215)
    1036 (296 to 1998)
    Statistical analysis title
    Mean difference
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -962
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1835
         upper limit
    -83

    Secondary: Disagreggated 18 month costs: General ward visit

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    End point title
    Disagreggated 18 month costs: General ward visit
    End point description
    Cost arising from general ward visits
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: GBP(£)
        arithmetic mean (confidence interval 95%)
    341 (-68 to 852)
    272 (-99 to 644)
    Statistical analysis title
    Mean difference
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -486
         upper limit
    623

    Secondary: Disagreggated 18 month costs: Concomitant medications

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    End point title
    Disagreggated 18 month costs: Concomitant medications
    End point description
    Costs arising from concomitant medications
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: GBP(£)
        arithmetic mean (confidence interval 95%)
    281 (108 to 505)
    682 (96 to 1933)
    Statistical analysis title
    Mean difference
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -401
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1670
         upper limit
    255

    Secondary: Disagreggated 18 month costs: Azathioprine

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    End point title
    Disagreggated 18 month costs: Azathioprine
    End point description
    Costs associated with the medication Azathioprine
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: GBP(£)
        arithmetic mean (confidence interval 95%)
    30 (21 to 41)
    1542 (27 to 6047)
    Statistical analysis title
    Mean difference
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -1512
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6015
         upper limit
    3

    Secondary: Disagreggated 18 month costs: Cyclophosphamide

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    End point title
    Disagreggated 18 month costs: Cyclophosphamide
    End point description
    Costs associated with the treatment Cyclophosphamide (CYC treatment arm only)
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    5
    Units: GBP(£)
        arithmetic mean (confidence interval 95%)
    380 (297 to 468)
    No statistical analyses for this end point

    Secondary: Disagreggated 18 month costs: Mycophenolate mofetil

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    End point title
    Disagreggated 18 month costs: Mycophenolate mofetil
    End point description
    Costs associated with the treatment Mycophenolate mofetil (MMF treatment arm only)
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF)
    Number of subjects analysed
    6
    Units: GBP(£)
        arithmetic mean (confidence interval 95%)
    976 (98 to 3204)
    No statistical analyses for this end point

    Secondary: Disagreggated 18 month costs: Corticosteroids

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    End point title
    Disagreggated 18 month costs: Corticosteroids
    End point description
    Costs associated with corticosteroids
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: GBP(£)
        arithmetic mean (confidence interval 95%)
    52 (42 to 60)
    57 (41 to 67)
    Statistical analysis title
    Mean difference
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18
         upper limit
    12

    Secondary: Mean total discounted costs

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    End point title
    Mean total discounted costs
    End point description
    Total costs associated with each treatment group
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: GBP(£)
        arithmetic mean (confidence interval 95%)
    6071 (640 to 15555)
    4725 (1480 to 7157)
    Statistical analysis title
    Mean difference
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1346
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4709
         upper limit
    11175

    Secondary: Incremental net health benefit (INHB): Cost effectiveness threshold £20,000 per QALY

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    End point title
    Incremental net health benefit (INHB): Cost effectiveness threshold £20,000 per QALY
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: GBP per QALY
        arithmetic mean (confidence interval 95%)
    0.826 (0.327 to 1.297)
    0.944 (0.465 to 1.406)
    Statistical analysis title
    Incremental analysis
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.114
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    0.574
    Notes
    [4] - Incremental analysis

    Secondary: Incremental net health benefit (INHB): Cost effectiveness threshold £30,000 per QALY

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    End point title
    Incremental net health benefit (INHB): Cost effectiveness threshold £30,000 per QALY
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to 18 months
    End point values
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Number of subjects analysed
    6
    5
    Units: GBP per QALY
        arithmetic mean (confidence interval 95%)
    0.931 (0.482 to 1.363)
    1.020 (0.622 to 1.414)
    Statistical analysis title
    Incremental analysis
    Comparison groups
    Mycophenolate mofetil (MMF) v Intravenous Cyclophosphamide (CYC)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.092
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.695
         upper limit
    0.5
    Notes
    [5] - Incremental analysis

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomisation to 72 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Mycophenolate mofetil (MMF)
    Reporting group description
    -

    Reporting group title
    Intravenous Cyclophosphamide (CYC)
    Reporting group description
    -

    Serious adverse events
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Mycophenolate mofetil (MMF) Intravenous Cyclophosphamide (CYC)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 6 (83.33%)
    5 / 5 (100.00%)
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Mood altered
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Avulsion fracture
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Back injury
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Skin injury
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    7
    Blood iron decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Laboratory test abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Red blood cell sedimentation rate increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Migraine
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    1
    3
    Diarrhoea
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 5 (20.00%)
         occurrences all number
    2
    1
    Abdominal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Supernumerary teeth
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Alopecia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Dermatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Skin striae
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Iron deficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 5 (40.00%)
         occurrences all number
    4
    2
    Fungal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    Gastroenteritis viral
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Helicobacter infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2014
    Changes to Protocol. Documents submitted: Protocol V2.0. Protocol section 10.2.3 amended so that the reference to 48 weeks as been deleted as advised. Protocol section 5.2, exclusion criteria revised to state that sexually active females are excluded if they are not prepared to use two reliable means of contraception for the complete duration of the trial and for 12 months after study drug therapy is discontinued. Protocol section 7.10.1 amended to state that “For patients of reproductive potential (males and females), use of reliable means of contraception as stated in Exclusion Criteria is required throughout study participation and for 12 months after study drug therapy is discontinued.” Abstinence is acceptable in the trial and section 5.2, exclusion criteria 15 has been amended to show abstinence is acceptable only if it is the preferred and usual lifestyle of the patient. Protocol section 7.3.2 has been updated to state that protection from UV-light exposure is mandatory and patients should wear sunscreen SPF 50+ when exposed to UV-light. Protocol section 2.4 has also been updated to add UV-light exposure as a potential trial risk. Protocol section 7.10.2 has been updated to state that live vaccinations are not permitted for the duration of the trial period. The protocol has been updated following the telephone conversation with Farhat Gilani Pharmacovigilance Manager, University College London, to show that SAE’s which are not related to disease progression will be reported within 24 hours of becoming aware of the event. SAE’s that are symptoms due to disease progression will be reported on the adverse event forms which are submitted within fourteen days of the patient visit. A MYPAN website will be created at the address www.mypantrial.org.uk. The website will display information about the trial, including a summary, location of the sites involved, links to collaborators, methods of contacting the trial team and updates on recruitment figures.
    26 Oct 2015
    Addition of UK site – Addenbrookes Hospital Removal of UK Site – Queens Medical Centre, Nottingham
    17 Dec 2015
    Changes to Protocol. Documents submitted: Protocol V3.0, Amendment assessment form, Notification of substantial amendment, Cover letter, SmPC Cellcept oral suspension, SmPC Cellcept 250mg, SmPC Cellcept 500mg
    29 Feb 2016
    Addition of two UK sites: University College London University Hospital and Royal Free Hospital Removal of UK Site – Bristol University Hospital
    04 May 2016
    Substantial changes have been made to the contraceptive advice in the SmPC for Mycophenolate Mofetil. This advice is now reflected in the updated PISCs for the adults and parents.
    26 Oct 2016
    The IRAS form has been updated to declare the use of X-Rays as a screening tool to rule out infections prior to commencement in the study. The patient information sheets and consent forms have been updated to give participants more information about the use of X-Rays as part of the study and the risks involved.
    17 Jul 2017
    Documents submitted: Protocol V4.0. Recruitment period extended from 30th January 2018 to 0th June 2018 Section 5.1: Inclusion criteria. Text updated to clarify that if the patient was not adequately treated at the time of diagnosis then they may still be eligible for the study. Section 9: Removal of interim monitoring and analysis Section 10.9.2: Clarification of urgent safety measures reporting procedures
    24 May 2018
    GDPR information letter sent out to patient and parents, including information correctly notifying them about the way their consent forms have been handled. Section 4.4. and 4.8 amended with new RSI information
    28 Nov 2019
    Update to the Reference Safety Information (section 4.4 and 4.8) for the trial after an update to the SmPC for Cellcept.

    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.
    None reported
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