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    Clinical Trial Results:
    mycophenylate mofetil and tacrolimus vs tacrolimus alone for the treatment of nephrotic syndrome secondary to idiopathic membranous glomerulonephritis

    Summary
    EudraCT number
    		 2008-001009-41
    Trial protocol
    		 GB  
    Global end of trial date
    19 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2019
    First version publication date
    04 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    grim1001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00843856
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ImperialCollegeNHSTrust
    Sponsor organisation address
    Du Cane Road, London, United Kingdom,
    Public contact
    Megan Griffith, Imperial College NHS Trust, +44 0208383527, megan.griffith1@nhs.net
    Scientific contact
    Megan Griffith, ImperialCollegeNHSTrust, +44 0208383527, megan.griffith1@nhs.net
    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
    14 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate if the addition of mycophenylate mofetil to standard therapy with tacrolimus prevents relapse of nephrotic syndrome in patients with idiopathic membranous glomerulonephritis
    Protection of trial subjects
    All patients were regularly seen and monitored in the renal clinic at Hammersmith Hospital London.
    Background therapy
    		 All patients were given supportive therapy which included ace inhibitors angiotensin receptor blockers diuretics, statins and anticoagulation as clinically indicated.
    Evidence for comparator
    		 Calcineurin inhibitors (CNIs) such as cyclosporin and tacrolimus (TAC) are commonly used for the treatment of Membranous Glomerulonephritis (MGN) and are effective in inducing remission. Their antiproteinuric effect has been clearly documented; however relapses after discontinuation are common and there is a concern about nephrotoxicity after prolonged use. Although their main mode of action is immunomodulatory they also have a significant antiproteinuric effect which is attributed to their haemodynamic effect on glomerular perfusion as well as to their direct effect on podocytes. A study comparing tacrolimus to placebo showed that TAC alone is effective in achieving remission but patients often relapse after treatment withdrawal . A recent trial comparing rituximab to cyclosporine also showed a high relapse rate of the cyclosporine arm after treatment withdrawal. Mycophenolate mofetil (MMF) has been used for the treatment of MGN in regimens of variable dosing and duration, either alone or in combination with steroids. MMF monotherapy is not effective in inducing remission; however it has been successfully used in combination with steroids. MMF has a long history of use in combination with CNIs in transplantation with a good safety profile and this combination has also been used in nephrotic syndrome secondary to other glomerulonephritides such as lupus nephritis. The presence of anti-PLA2R auto-antibodies in a significant number of patients with MGN suggests that an immunosuppressive agent such as MMF, that suppresses B lymphocyte proliferation and antibody formation, may be particularly effective in inducing and maintaining immunological and clinical remission in MGN. We therefore compared the efficacy of combination treatment with tacrolimus and mycophenolate mofetil versus tacrolimus alone for achieving sustained remission in patients with Idiopathic Membranous Glomerulonephritis.
    Actual start date of recruitment
    03 Mar 2009
    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
    United Kingdom: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    34
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from the glomerulonephritis clinic at Hammersmith Hospital, London from march 2009 to December 2014.

    Pre-assignment
    Screening details
    		 Patients with Membranous Glomerulonephritis, diagnosed on renal biopsy, with nephrotic syndrome after 3 months of ace inhibitors or angiotensin receptor blockers.

    Period 1
    Period 1 title
    tacrolimus vs mycophenylate mofetil (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 tacrolimus
    Arm description
    		 2mg twice daily tacrolimus titrated to archive whole blood levels of 5-12ng/ml
    Arm type
    		 Active comparator

    Investigational medicinal product name
    tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2mg twice daily

    Arm title
    		 tacrolimus and mycophenylate mofetil
    Arm description
    		 tacrolimus and mycophenylate mofetil
    Arm type
    		 Experimental

    Investigational medicinal product name
    tacrolimus
    Investigational medicinal product code
    Other name
    prograff
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg twice a day titrated to achieve blood levels of 5-12ng/L

    Investigational medicinal product name
    mycophenylate mofetil
    Investigational medicinal product code
    Other name
    cellcept
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500mg twice a day titrated to achieve blood mycophenylate acid levels of 1.5-3 mg/L

    Number of subjects in period 1
    		tacrolimus tacrolimus and mycophenylate mofetil
    Started
    20
    20
    Completed
    19
    18
    Not completed
    1
    2
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    tacrolimus
    Reporting group description
    		 2mg twice daily tacrolimus titrated to archive whole blood levels of 5-12ng/ml

    Reporting group title
    tacrolimus and mycophenylate mofetil
    Reporting group description
    		 tacrolimus and mycophenylate mofetil

    Reporting group values
    		 tacrolimus tacrolimus and mycophenylate mofetil Total
    Number of subjects
    		 20 20 40
    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)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 19 15 34
        From 65-84 years
    		 1 5 6
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 55 (24 to 68) 48 (28 to 66) -
    Gender categorical
    Units: Subjects
        Female
    		 9 7 16
        Male
    		 11 13 24
    Serum albumin
    Units: g/L
        median (full range (min-max))
    		 17 (8 to 30) 18 (11 to 27) -
    Estimated glomerus filtration rate (GRF)
    Units: mls/min/1.73m2
        median (full range (min-max))
    		 109 (44 to 142) 121 (63 to 201) -

    End points

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    End points reporting groups
    Reporting group title
    tacrolimus
    Reporting group description
    		 2mg twice daily tacrolimus titrated to archive whole blood levels of 5-12ng/ml

    Reporting group title
    tacrolimus and mycophenylate mofetil
    Reporting group description
    		 tacrolimus and mycophenylate mofetil

    Primary: number of patients who gained remission from the nephrotic syndrome who subsequently relapsed

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    End point title
    		 number of patients who gained remission from the nephrotic syndrome who subsequently relapsed
    End point description
    In the TAC group 16/20 achieved remission compared to 19/20 (95%) in the TAC/MMF group (p=0.34). There was no difference between the groups in the number of patients who subsequently relapsed. In the TAC group 8/16 patient(50%) relapsed and in the TAC/MMF group 8/19 patients (42%) relapsed (p=0.7).
    End point type
    Primary
    End point timeframe
    Initially measured at 6 months after stopping treatment and monitored until the end of the trial.
    End point values
    		 tacrolimus tacrolimus and mycophenylate mofetil
    Number of subjects analysed
    16 [1]
    19 [2]
    Units: patients
    8
    8
    Notes
    [1] - number of patients who achieved remission
    [2] - number of patients who achieved remission
    Statistical analysis title
    		 Relapsed
    Comparison groups
    tacrolimus v tacrolimus and mycophenylate mofetil
    Number of subjects included in analysis
    35
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.7
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Number of patient archieved remission

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    End point title
    		 Number of patient archieved remission
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 tacrolimus tacrolimus and mycophenylate mofetil
    Number of subjects analysed
    20
    20
    Units: patient
    16
    19
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Reported throughout the trial, 10 years
    Adverse event reporting additional description
    Review of patients in OP and reporting of all admissions
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    tacrolimus
    Reporting group description
    		 -

    Reporting group title
    tacrolimus and mycophenolate mofetil
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: None serious adverse event occurred.
    Serious adverse events
    		 tacrolimus tacrolimus and mycophenolate mofetil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 20 (35.00%)
    3 / 20 (15.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidectomy
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 20 (15.00%)
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    acut kidney injury
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestatic jaundice
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 tacrolimus tacrolimus and mycophenolate mofetil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31492152
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