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    Clinical Trial Results:
    A Multicentre, Interventional treatment, Randomised, Double-Blind, Single Group Assignment Placebo Controlled Study to Evaluate the Efficacy and Safety of Two Different Doses of Nefecon in primary IgA nephropathy patients at risk of developing end-stage renal disease

    Summary
    EudraCT number
    2012-001923-11
    Trial protocol
    FI   CZ   DE   BE   SE   DK   IT   GB   NL   ES  
    Global end of trial date
    25 Jun 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions
    Summary report(s)
    Study synopsis Nef-202, EudraCT no 2012-001923-11

    Trial information

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    Trial identification
    Sponsor protocol code
    Nef-202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01738035
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pharmalink AB
    Sponsor organisation address
    Wallingatan 26B, Stockholm, Sweden,
    Public contact
    Project Director (Alex Mercer), Pharmalink AB, 46 84113005, alex.mercer@pharmalink.se
    Scientific contact
    Project Director (Alex Mercer), Pharmalink AB, 46 84113005, alex.mercer@pharmalink.se
    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
    25 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the trial is to evaluate efficacy and safety of two different doses of Nefecon in the treatment of patients with primary IgA nephropathy (IgAN) at risk of developing end-stage renal disease, under rigorous blood pressure control with an angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin 2 receptor blocker (ARB).
    Protection of trial subjects
    Steroid related adverse reactions were specifically asked for and collected in addition to usual adverse event collection. This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. Essential documents are retained in accordance with ICH GCP. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited and no investigational medicinal product (IMP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Pharmalink received copies of these approvals. Safety assessments included several laboratory evaluations (clinical chemistry, haematology, urine analyses) as well as measurements of glomerular filtration rate, vital signs and physical examinations.
    Background therapy
    Patients remained on their angiotensin II type I receptor blockade (ARB) and/or angiotensin converting enzyme inhibitor (ACEI) treatment throughout the study treatment phase.
    Evidence for comparator
    Placebo-control
    Actual start date of recruitment
    11 Dec 2012
    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
    Netherlands: 5
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    Italy: 30
    Worldwide total number of subjects
    153
    EEA total number of subjects
    153
    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)
    150
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment started 11 December 2012 and was completed by 26 December 2013.

    Pre-assignment
    Screening details
    The study included a 6-months run-in period, 9-months treatment period and a 3-months follow-up period. During the run-in period the background anti-hypertensive medication was optimized.

    Period 1
    Period 1 title
    Treatment phase (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    To ensure blinding, placebo capsules without the active ingredient but with the same appearance and route of administration as the active capsules was used. All patients were given the same number of active and/or placebo capsules per day in order to keep the treatment (active or placebo) and dose blinded (16 mg, 8 mg or placebo).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Nefecon 8 mg/day
    Arm description
    Patients received 8 mg Nefecon daily for 9 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Nefecon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    8 mg/day Nefecon® (2 x 4 mg Nefecon capsules + 2 x “placebo” capsules) for 9 months, followed by Placebo (2 x “placebo” capsules) for 2 weeks (titration period). 16 mg/day Nefecon® (4 x 4 mg Nefecon capsules) for 9 months, followed by 8 mg/day Nefecon® (2 x 4 mg capsules) for 2 weeks (titration period).

    Arm title
    Nefecon 16 mg/day
    Arm description
    Patients received 16 mg Nefecon daily for 9 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Nefecon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    8 mg/day Nefecon® (2 x 4 mg Nefecon capsules + 2 x “placebo” capsules) for 9 months, followed by Placebo (2 x “placebo” capsules) for 2 weeks (titration period). 16 mg/day Nefecon® (4 x 4 mg Nefecon capsules) for 9 months, followed by 8 mg/day Nefecon® (2 x 4 mg capsules) for 2 weeks (titration period).

    Arm title
    Placebo
    Arm description
    Patients received placebo capsules daily for 9 months.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 placebo capsules daily

    Number of subjects in period 1
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Started
    51
    51
    51
    Interim analysis of primary end point
    30 [1]
    27 [2]
    33 [3]
    Completed
    51
    48
    50
    Not completed
    0
    3
    1
         Protocol deviation
    -
    2
    1
         Patient unable to swallow capsules
    -
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: There was a planned interim analysis of the primary efficacy end point at 9 months when 90 patients had completed their T5 visit.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: There was a planned interim analysis of the primary efficacy end point at 9 months when 90 patients had completed their T5 visit.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: There was a planned interim analysis of the primary efficacy end point at 9 months when 90 patients had completed their T5 visit.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nefecon 8 mg/day
    Reporting group description
    Patients received 8 mg Nefecon daily for 9 months.

    Reporting group title
    Nefecon 16 mg/day
    Reporting group description
    Patients received 16 mg Nefecon daily for 9 months.

    Reporting group title
    Placebo
    Reporting group description
    Patients received placebo capsules daily for 9 months.

    Reporting group values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo Total
    Number of subjects
    51 51 51 153
    Age categorical
    No additional details
    Units: Subjects
    Age continuous
    No additional information.
    Units: years
        arithmetic mean (full range (min-max))
    40.6 (20 to 82) 37.3 (18 to 64) 39.5 (18 to 73) -
    Gender categorical
    Units: Subjects
        Female
    14 15 15 44
        Male
    37 36 36 109

    End points

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    End points reporting groups
    Reporting group title
    Nefecon 8 mg/day
    Reporting group description
    Patients received 8 mg Nefecon daily for 9 months.

    Reporting group title
    Nefecon 16 mg/day
    Reporting group description
    Patients received 16 mg Nefecon daily for 9 months.

    Reporting group title
    Placebo
    Reporting group description
    Patients received placebo capsules daily for 9 months.

    Subject analysis set title
    Safety set Nefecon 8 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety analysis set consists of all patients who took at least one dose of the study medication.

    Subject analysis set title
    Safety set Nefecon 16 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety analysis set consists of all patients who took at least one dose of the study medication.

    Subject analysis set title
    Safety set Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety analysis set consists of all patients who took at least one dose of the study medication.

    Subject analysis set title
    Full analysis set Nefecon 8 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS for efficacy analysis is defined as all randomised patients who took at least one dose of the study medication and with at least one post dose efficacy measurements.

    Subject analysis set title
    Full analysis set Nefecon 16 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS for efficacy analysis is defined as all randomised patients who took at least one dose of the study medication and with at least one post dose efficacy measurements.

    Subject analysis set title
    Full analysis set Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS for efficacy analysis is defined as all randomised patients who took at least one dose of the study medication and with at least one post dose efficacy measurements.

    Subject analysis set title
    Per protocol analysis Nefecon 8 mg
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subset of the FAS and consists of patients who 1) have completed the 9 month treatment, 2) have sufficiently complied with the protocol and 3) have been compliant.

    Subject analysis set title
    Per protocol analysis 16 mg
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subset of the FAS and consists of patients who 1) have completed the 9 month treatment, 2) have sufficiently complied with the protocol and 3) have been compliant.

    Subject analysis set title
    Per protocol analysis Placebo
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subset of the FAS and consists of patients who 1) have completed the 9 month treatment, 2) have sufficiently complied with the protocol and 3) have been compliant.

    Primary: Mean reduction in UPCR

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    End point title
    Mean reduction in UPCR
    End point description
    The mean reduction in UPCR at 9 months compared to baseline UPCR values.
    End point type
    Primary
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    30
    27
    33
    Units: g/g
        least squares mean (confidence interval 95%)
    0.785 (0.638 to 0.965)
    0.727 (0.585 to 0.903)
    1.028 (0.841 to 1.256)
    Statistical analysis title
    Comparison of UPCR change from baseline
    Comparison groups
    Nefecon 8 mg/day v Nefecon 16 mg/day v Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0158 [1]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [1] - Interim analysis

    Secondary: Mean change in urine protein, UACR and urine albumin (urine protein)

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    End point title
    Mean change in urine protein, UACR and urine albumin (urine protein)
    End point description
    Mean change in urine protein from baseline at Month 9
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    34
    44
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.804 (0.657 to 0.983)
    0.7 (0.567 to 0.865)
    1.011 (0.833 to 1.226)
    No statistical analyses for this end point

    Secondary: Mean change in UPCR, urine protein, UACR and urine albumin from 9 to 12 months (UPCR)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin from 9 to 12 months (UPCR)
    End point description
    Mean change in UPCR from 9 to 12 months
    End point type
    Secondary
    End point timeframe
    From 9 to 12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    32
    44
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.959 (0.812 to 1.132)
    0.915 (0.767 to 1.091)
    1.045 (0.894 to 1.222)
    No statistical analyses for this end point

    Secondary: Mean change in serum creatinine, CKD-EPI eGFR, MDRD eGFR and creatinine clearance (serum creatinine)

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    End point title
    Mean change in serum creatinine, CKD-EPI eGFR, MDRD eGFR and creatinine clearance (serum creatinine)
    End point description
    Mean change in serum creatinine from baseline at 9 months.
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    42
    Units: milligram(s)/dL
        least squares mean (confidence interval 95%)
    0.989 (0.943 to 1.037)
    0.981 (0.933 to 1.032)
    1.072 (1.023 to 1.123)
    No statistical analyses for this end point

    Secondary: Mean change in urine protein, UACR and urine albumin (UACR)

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    End point title
    Mean change in urine protein, UACR and urine albumin (UACR)
    End point description
    Mean change in UACR from baseline at Month 9
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    44
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.864 (0.705 to 1.059)
    0.715 (0.573 to 0.892)
    1.057 (0.865 to 1.291)
    No statistical analyses for this end point

    Secondary: Mean change in urine protein, UACR and urine albumin (urine albumin)

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    End point title
    Mean change in urine protein, UACR and urine albumin (urine albumin)
    End point description
    Mean change in urine albumin from baseline at Month 9
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    44
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.815 (0.656 to 1.013)
    0.67 (0.531 to 0.846)
    1.022 (0.828 to 1.261)
    No statistical analyses for this end point

    Secondary: Mean change in UPCR, urine protein, UACR and urine albumin from 9 to 12 months (urine protein)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin from 9 to 12 months (urine protein)
    End point description
    Mean change in urine protein from 9 to 12 months
    End point type
    Secondary
    End point timeframe
    From 9 to 12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    32
    43
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.98 (0.817 to 1.177)
    0.862 (0.711 to 1.046)
    1.018 (0.858 to 1.209)
    No statistical analyses for this end point

    Secondary: Mean change in UPCR, urine protein, UACR and urine albumin from 9 to 12 months (UACR)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin from 9 to 12 months (UACR)
    End point description
    Mean change in UACR from 9 to 12 months
    End point type
    Secondary
    End point timeframe
    From 9 to 12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    32
    44
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.914 (0.758 to 1.101)
    0.867 (0.712 to 1.057)
    1.037 (0.87 to 1.235)
    No statistical analyses for this end point

    Secondary: Mean change in UPCR, urine protein, UACR and urine albumin from 9 to 12 months (urine albumin)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin from 9 to 12 months (urine albumin)
    End point description
    Mean change in urine albumin from 9 to 12 months
    End point type
    Secondary
    End point timeframe
    From 9 to 12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    32
    43
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.934 (0.763 to 1.144)
    0.819 (0.66 to 1.015)
    1.021 (0.844 to 1.235)
    No statistical analyses for this end point

    Secondary: Mean change in serum creatinine, CKD EPI eGFR, MDRD eGFR and creatinine clearance (CKD EPI)

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    End point title
    Mean change in serum creatinine, CKD EPI eGFR, MDRD eGFR and creatinine clearance (CKD EPI)
    End point description
    Mean change in chronic kidney disease epidemiology collaboration equation (CKD EPI) estimated GFR (eGFR) from baseline at 9 months.
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    42
    Units: millilitre(s)/min/1.73m2
        least squares mean (confidence interval 95%)
    0.991 (0.934 to 1.052)
    1.006 (0.946 to 1.07)
    0.902 (0.85 to 0.956)
    No statistical analyses for this end point

    Secondary: Mean change in serum creatinine, CKD EPI eGFR, MDRD eGFR and creatinine clearance (MDRD)

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    End point title
    Mean change in serum creatinine, CKD EPI eGFR, MDRD eGFR and creatinine clearance (MDRD)
    End point description
    Mean change in MDRD eGFR from baseline at 9 months
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    42
    Units: millilitre(s)/min/1.73m2
        least squares mean (confidence interval 95%)
    0.995 (0.937 to 1.056)
    1.022 (0.96 to 1.088)
    0.906 (0.854 to 0.961)
    No statistical analyses for this end point

    Secondary: Mean change in serum creatinine, CKD EPI eGFR, MDRD eGFR and creatinine clearance (creatinine clearance)

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    End point title
    Mean change in serum creatinine, CKD EPI eGFR, MDRD eGFR and creatinine clearance (creatinine clearance)
    End point description
    Mean change in creatinine clearance from baseline at month 9
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    42
    Units: millilitre(s)/min/1.73*m2
        least squares mean (confidence interval 95%)
    0.952 (0.851 to 1.065)
    0.985 (0.877 to 1.107)
    0.906 (0.813 to 1.01)
    No statistical analyses for this end point

    Other pre-specified: Defined reduction in UPCR (≥30%)

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    End point title
    Defined reduction in UPCR (≥30%)
    End point description
    Achieving defined reductions (≥30%, ≥40%, ≥50%) in UPCR, urine protein, UACR and urine albumin at Month 9 compared to baseline
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    34
    44
    Units: number of patients
    14
    16
    12
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (UPCR, Month 1)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (UPCR, Month 1)
    End point description
    Mean change in UPCR, urine protein, UACR and urine albumin from baseline at 1, 3, 6, 10.5 and 12 months
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    49
    48
    49
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.946 (0.831 to 1.077)
    1.045 (0.918 to 1.189)
    1.046 (0.918 to 1.192)
    No statistical analyses for this end point

    Other pre-specified: Mean change in CDK-EPI at 1 month

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    End point title
    Mean change in CDK-EPI at 1 month
    End point description
    Mean change in CKD-EPI eGFR from baseline at 1, 3, 6, 10.5, and 12 months
    End point type
    Other pre-specified
    End point timeframe
    1 month
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    47
    47
    48
    Units: millilitre(s)/min/1.73m2
        least squares mean (confidence interval 95%)
    0.964 (0.917 to 1.014)
    0.989 (0.941 to 1.04)
    0.959 (0.912 to 1.008)
    No statistical analyses for this end point

    Other pre-specified: Mean change in cystatin C-based eGFR

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    End point title
    Mean change in cystatin C-based eGFR
    End point description
    Mean change in cystatin C-based eGFR CKD-EPI from baseline at Month 9
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    42
    Units: millilitre(s)/min/1.73m2
        least squares mean (confidence interval 95%)
    0.941 (0.869 to 1.019)
    0.93 (0.856 to 1.01)
    0.925 (0.857 to 0.999)
    No statistical analyses for this end point

    Other pre-specified: Proportion of patients with microhaematuria at 9 months

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    End point title
    Proportion of patients with microhaematuria at 9 months
    End point description
    Proportion of patients with microhaematuria at Month 9
    End point type
    Other pre-specified
    End point timeframe
    Month 9
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    39
    33
    43
    Units: patients with haematuria
    32
    21
    37
    No statistical analyses for this end point

    Other pre-specified: Proportion of patients with microhaematuria at 12 months

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    End point title
    Proportion of patients with microhaematuria at 12 months
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Month 12
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    38
    34
    41
    Units: patients with haematuria
    27
    24
    34
    No statistical analyses for this end point

    Other pre-specified: Mean change in EPI-CDK at 3 months

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    End point title
    Mean change in EPI-CDK at 3 months
    End point description
    End point type
    Other pre-specified
    End point timeframe
    3 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    48
    42
    50
    Units: millilitre(s)/min/1.73m2
        least squares mean (confidence interval 95%)
    0.974 (0.924 to 1.026)
    0.988 (0.937 to 1.042)
    0.93 (0.884 to 0.979)
    No statistical analyses for this end point

    Other pre-specified: Mean change in CDK-EPI at 6 months

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    End point title
    Mean change in CDK-EPI at 6 months
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    44
    37
    46
    Units: millilitre(s)/min/1.73m2
        least squares mean (confidence interval 95%)
    0.994 (0.93 to 1.063)
    0.968 (0.903 to 1.039)
    0.917 (0.859 to 0.979)
    No statistical analyses for this end point

    Other pre-specified: Mean change in CDK-EPI at 10.5 months

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    End point title
    Mean change in CDK-EPI at 10.5 months
    End point description
    End point type
    Other pre-specified
    End point timeframe
    10.5 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    42
    Units: millilitre(s)/min/1.73m2
        least squares mean (confidence interval 95%)
    0.933 (0.878 to 0.992)
    0.991 (0.93 to 1.056)
    0.891 (0.839 to 0.946)
    No statistical analyses for this end point

    Other pre-specified: Mean change in CDK-EPI at 12 months

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    End point title
    Mean change in CDK-EPI at 12 months
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    38
    34
    46
    Units: millilitre(s)/min/1.73m2
        least squares mean (confidence interval 95%)
    0.92 (0.857 to 0.988)
    0.993 (0.921 to 1.069)
    0.891 (0.832 to 0.954)
    No statistical analyses for this end point

    Other pre-specified: Defined reduction in UPCR (≥40%)

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    End point title
    Defined reduction in UPCR (≥40%)
    End point description
    Achieving defined reductions (≥30%, ≥40%, ≥50%) in UPCR, urine protein, UACR and urine albumin at Month 9 compared to baseline
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    34
    44
    Units: number of patients
    9
    10
    8
    No statistical analyses for this end point

    Other pre-specified: Defined reduction in UPCR (≥50%)

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    End point title
    Defined reduction in UPCR (≥50%)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    34
    44
    Units: number of patients
    6
    8
    5
    No statistical analyses for this end point

    Other pre-specified: Defined reduction in urine protein (≥30%)

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    End point title
    Defined reduction in urine protein (≥30%)
    End point description
    Achieving defined reductions (≥30%, ≥40%, ≥50%) in UPCR, urine protein, UACR and urine albumin at Month 9 compared to baseline
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    34
    44
    Units: number of patients
    16
    15
    12
    No statistical analyses for this end point

    Other pre-specified: Defined reduction in urine protein (≥40%)

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    End point title
    Defined reduction in urine protein (≥40%)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    34
    44
    Units: patients
    13
    11
    9
    No statistical analyses for this end point

    Other pre-specified: Defined reduction in urine protein (≥50%)

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    End point title
    Defined reduction in urine protein (≥50%)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    34
    44
    Units: patients
    7
    10
    8
    No statistical analyses for this end point

    Other pre-specified: Defined reduction in UACR (≥30%)

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    End point title
    Defined reduction in UACR (≥30%)
    End point description
    Achieving defined reductions (≥30%, ≥40%, ≥50%) in UPCR, urine protein, UACR and urine albumin at Month 9 compared to baseline
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    44
    Units: patients
    14
    16
    12
    No statistical analyses for this end point

    Other pre-specified: Defined reduction in UACR (≥40%)

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    End point title
    Defined reduction in UACR (≥40%)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    44
    Units: patients
    13
    15
    7
    No statistical analyses for this end point

    Other pre-specified: Defined reduction in UACR (≥50%)

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    End point title
    Defined reduction in UACR (≥50%)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    44
    Units: patients
    6
    10
    5
    No statistical analyses for this end point

    Other pre-specified: Defined reduction in urine albumin (≥30%)

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    End point title
    Defined reduction in urine albumin (≥30%)
    End point description
    Achieving defined reductions (≥30%, ≥40%, ≥50%) in UPCR, urine protein, UACR and urine albumin at Month 9 compared to baseline
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    44
    Units: patients
    16
    17
    13
    No statistical analyses for this end point

    Other pre-specified: Defined reduction in urine albumin (≥40%)

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    End point title
    Defined reduction in urine albumin (≥40%)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    44
    Units: patients
    11
    16
    9
    No statistical analyses for this end point

    Other pre-specified: Defined reduction in urine albumin (≥50%)

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    End point title
    Defined reduction in urine albumin (≥50%)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    9 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    34
    44
    Units: patients
    9
    10
    7
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (UPCR, Month 3)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (UPCR, Month 3)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    48
    42
    50
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.874 (0.744 to 1.027)
    0.868 (0.735 to 1.025)
    1.023 (0.872 to 1.2)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (UPCR, Month 6)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (UPCR, Month 6)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    45
    38
    46
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.815 (0.692 to 0.959)
    0.966 (0.814 to 1.147)
    1.074 (0.913 to 1.262)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (UPCR, Month 10.5)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (UPCR, Month 10.5)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    33
    43
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.737 (0.608 to 0.893)
    0.646 (0.525 to 0.795)
    0.995 (0.826 to 1.199)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (UPCR, Month 12)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (UPCR, Month 12)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    32
    46
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.774 (0.656 to 0.914)
    0.68 (0.568 to 0.815)
    1.005 (0.857 to 1.178)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (urine protein, Month 1)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (urine protein, Month 1)
    End point description
    Mean change in UPCR, urine protein, UACR and urine albumin from baseline at 1, 3, 6, 10.5 and 12 months
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    48
    47
    49
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.917 (0.784 to 1.072)
    0.967 (0.828 to 1.128)
    1.017 (0.871 to 1.188)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (urine protein, Month 3)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (urine protein, Month 3)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    47
    42
    50
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.817 (0.68 to 0.981)
    0.81 (0.672 to 0.977)
    0.999 (0.835 to 1.195)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (urine protein, Month 6)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (urine protein, Month 6)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    44
    38
    46
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.804 (0.666 to 0.97)
    0.925 (0.761 to 1.125)
    1.021 (0.85 to 1.227)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (urine protein, Month 10.5)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (urine protein, Month 10.5)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    33
    43
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.602 (0.464 to 0.78)
    0.585 (0.442 to 0.774)
    0.896 (0.697 to 1.15)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (urine protein, Month 12)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (urine protein, Month 12)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    32
    45
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.738 (0.618 to 0.882)
    0.599 (0.495 to 0.724)
    0.967 (0.815 to 1.147)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (UACR, Month 1)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (UACR, Month 1)
    End point description
    Mean change in UPCR, urine protein, UACR and urine albumin from baseline at 1, 3, 6, 10.5 and 12 months
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    49
    48
    49
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.988 (0.864 to 1.129)
    1.031 (0.9 to 1.18)
    1.008 (0.879 to 1.156)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (UACR, Month 3)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (UACR, Month 3)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    48
    41
    50
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.888 (0.747 to 1.055)
    0.834 (0.694 to 1.002)
    1.011 (0.85 to 1.202)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (UACR, Month 6)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (UACR, Month 6)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    45
    38
    46
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.828 (0.695 to 0.987)
    0.952 (0.787 to 1.151)
    1.072 (0.899 to 1.279)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (UACR, Month 10.5)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (UACR, Month 10.5)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    33
    43
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.709 (0.567 to 0.886)
    0.556 (0.435 to 0.71)
    0.991 (0.798 to 1.232)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (UACR, Month 12)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (UACR, Month 12)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    32
    46
    Units: gram(s)/gram
        least squares mean (confidence interval 95%)
    0.723 (0.6 to 0.871)
    0.624 (0.508 to 0.768)
    1.003 (0.838 to 1.202)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (urine albumin, Month 1)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (urine albumin, Month 1)
    End point description
    Mean change in UPCR, urine protein, UACR and urine albumin from baseline at 1, 3, 6, 10.5 and 12 months
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    48
    47
    49
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.955 (0.81 to 1.125)
    0.949 (0.806 to 1.118)
    0.973 (0.827 to 1.146)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (urine albumin, Month 3)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (urine albumin, Month 3)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    47
    41
    50
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.827 (0.678 to 1.01)
    0.771 (0.626 to 0.948)
    0.98 (0.806 to 1.191)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (urine albumin, Month 6)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (urine albumin, Month 6)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    44
    38
    46
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.815 (0.664 to 1)
    0.905 (0.731 to 1.121)
    1.012 (0.829 to 1.236)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (urine albumin, Month 10.5)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (urine albumin, Month 10.5)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    40
    33
    43
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.574 (0.43 to 0.766)
    0.502 (0.367 to 0.686)
    0.885 (0.671 to 1.169)
    No statistical analyses for this end point

    Other pre-specified: Mean change in UPCR, urine protein, UACR and urine albumin (urine albumin, Month 12)

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    End point title
    Mean change in UPCR, urine protein, UACR and urine albumin (urine albumin, Month 12)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Number of subjects analysed
    41
    32
    45
    Units: gram(s)
        least squares mean (confidence interval 95%)
    0.685 (0.559 to 0.838)
    0.544 (0.437 to 0.678)
    0.956 (0.788 to 1.161)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of signing the informed consent to the completion of the clinical trial (including the second follow up visit) or premature patient discontinuation from the trial.
    Adverse event reporting additional description
    An ongoing AE is followed up if patient is withdrawn. The reporting period for SAEs ends at the final follow-up visit 12 months after the first administration of study medication.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0E
    Reporting groups
    Reporting group title
    Nefecon 8 mg/day
    Reporting group description
    Patients received 8 mg Nefecon daily for 9 months.

    Reporting group title
    Nefecon 16 mg/day
    Reporting group description
    Patients received 16 mg Nefecon daily for 9 months.

    Reporting group title
    Placebo
    Reporting group description
    Patients received placebo capsules daily for 9 months.

    Serious adverse events
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 51 (1.96%)
    7 / 49 (14.29%)
    3 / 50 (6.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 49 (2.04%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 49 (2.04%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Nefecon 8 mg/day Nefecon 16 mg/day Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 51 (94.12%)
    43 / 49 (87.76%)
    42 / 50 (84.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 49 (10.20%)
    1 / 50 (2.00%)
         occurrences all number
    3
    5
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    2 / 51 (3.92%)
    6 / 49 (12.24%)
    2 / 50 (4.00%)
         occurrences all number
    3
    9
    3
    Fatigue
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 49 (4.08%)
    3 / 50 (6.00%)
         occurrences all number
    2
    2
    3
    Psychiatric disorders
    Insomnia
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 51 (11.76%)
    8 / 49 (16.33%)
    2 / 50 (4.00%)
         occurrences all number
    6
    9
    2
    Mood swings
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 49 (10.20%)
    2 / 50 (4.00%)
         occurrences all number
    3
    5
    2
    Depression
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 49 (6.12%)
    0 / 50 (0.00%)
         occurrences all number
    2
    3
    0
    Investigations
    Glycosylated haemoglobin increased
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 49 (8.16%)
    0 / 50 (0.00%)
         occurrences all number
    5
    4
    0
    Weight increased
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 49 (8.16%)
    0 / 50 (0.00%)
         occurrences all number
    2
    4
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 49 (6.12%)
    3 / 50 (6.00%)
         occurrences all number
    4
    3
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 49 (8.16%)
    1 / 50 (2.00%)
         occurrences all number
    2
    5
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences all number
    3
    1
    0
    Blood and lymphatic system disorders
    Increased tendency to bruise
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 49 (6.12%)
    0 / 50 (0.00%)
         occurrences all number
    4
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 51 (5.88%)
    6 / 49 (12.24%)
    3 / 50 (6.00%)
         occurrences all number
    3
    6
    4
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    4
    0
    1
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    2 / 51 (3.92%)
    7 / 49 (14.29%)
    4 / 50 (8.00%)
         occurrences all number
    2
    9
    5
    Diarrhoea
         subjects affected / exposed
    1 / 51 (1.96%)
    5 / 49 (10.20%)
    7 / 50 (14.00%)
         occurrences all number
    1
    5
    9
    Abdominal pain upper
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 49 (8.16%)
    1 / 50 (2.00%)
         occurrences all number
    1
    7
    1
    Abdominal pain
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 49 (6.12%)
    1 / 50 (2.00%)
         occurrences all number
    4
    4
    1
    Nausea
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 49 (6.12%)
    1 / 50 (2.00%)
         occurrences all number
    4
    5
    1
    Vomiting
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 49 (6.12%)
    2 / 50 (4.00%)
         occurrences all number
    2
    3
    2
    Dry mouth
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 49 (6.12%)
    0 / 50 (0.00%)
         occurrences all number
    1
    3
    0
    Constipation
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 49 (6.12%)
    0 / 50 (0.00%)
         occurrences all number
    0
    4
    0
    Abdominal distension
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 49 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    0
    4
    Skin and subcutaneous tissue disorders
    Acne
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 51 (15.69%)
    9 / 49 (18.37%)
    3 / 50 (6.00%)
         occurrences all number
    9
    10
    3
    Hirsutism
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 49 (10.20%)
    1 / 50 (2.00%)
         occurrences all number
    3
    5
    1
    Pruritus
         subjects affected / exposed
    2 / 51 (3.92%)
    5 / 49 (10.20%)
    0 / 50 (0.00%)
         occurrences all number
    2
    6
    0
    Alopecia
         subjects affected / exposed
    4 / 51 (7.84%)
    4 / 49 (8.16%)
    2 / 50 (4.00%)
         occurrences all number
    5
    4
    2
    Lipohypertrophy
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 49 (8.16%)
    0 / 50 (0.00%)
         occurrences all number
    2
    4
    0
    Skin striae
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 49 (8.16%)
    0 / 50 (0.00%)
         occurrences all number
    2
    4
    0
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    8 / 51 (15.69%)
    9 / 49 (18.37%)
    2 / 50 (4.00%)
         occurrences all number
    8
    14
    2
    Back pain
         subjects affected / exposed
    6 / 51 (11.76%)
    3 / 49 (6.12%)
    1 / 50 (2.00%)
         occurrences all number
    8
    3
    1
    Muscle spasms
         subjects affected / exposed
    5 / 51 (9.80%)
    2 / 49 (4.08%)
    2 / 50 (4.00%)
         occurrences all number
    5
    2
    3
    Arthralgia
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 49 (6.12%)
    2 / 50 (4.00%)
         occurrences all number
    5
    5
    3
    Myalgia
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 49 (6.12%)
    2 / 50 (4.00%)
         occurrences all number
    0
    3
    2
    Pain in extremity
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 49 (4.08%)
    2 / 50 (4.00%)
         occurrences all number
    3
    2
    2
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    5 / 51 (9.80%)
    8 / 49 (16.33%)
    3 / 50 (6.00%)
         occurrences all number
    5
    8
    3
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 51 (15.69%)
    10 / 49 (20.41%)
    10 / 50 (20.00%)
         occurrences all number
    16
    16
    14
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 49 (6.12%)
    3 / 50 (6.00%)
         occurrences all number
    3
    3
    3
    Influenza
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 49 (6.12%)
    1 / 50 (2.00%)
         occurrences all number
    4
    3
    1
    Bronchitis
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    4
    0
    1
    Pharyngitis
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    3
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2013
    To implement a series of measures to improve patient recruitment without compromising the scientific value of the study, the protocol was amended as follows: • The exclusion criterion for patients previously treated with a course of immunosuppressive agents or systemic steroids for IgAN was removed • Number of site visits was reduced • The alternative of using measured GFR to determine a patient’s eligibility for the study was added if the Investigator believed that an eGFR calculation would not be likely to reflect a given patient’s actual level of renal function. • Minor protocol inconsistencies were corrected
    03 Mar 2014
    The protocol was amended to: • Enable all patients enrolled in the 6-month run-in phase of the study to enter the treatment phase, provided they were eligible for randomisation, they continued to consent and that sufficient study drug was available. Study drug kits were available for a maximum of 160 patients • Perform an interim analysis on the primary endpoint and selected secondary and tertiary endpoints once 90 patients had completed the 9 month treatment phase of the study. This interim analysis provided early data on whether NEFECON treatment resulted in a clinical benefit compared with placebo, thereby establishing the potential risk/benefit for the remaining patients in the study and addressing the validity of continuing the study • Introduce statistical methodology to provide more reliable analyses. The primary endpoint, log change from baseline in UPCR values at 9 months, was planned to be assessed by analysis of covariance. Mixed model repeated measures (MMRM) was considered to provide more reliable analyses
    06 Nov 2014
    The protocol was amended as follows: • The statistical analysis of mean change in UPCR, urine protein, UACR, urine albumin and CKD-EPI eGFR from baseline to post treatment time-points (1, 3, 6, 9, 10.5 and 12 months) was achieved using a single MMRM analysis for each of these variables • The proportion of patients with microhaematuria at 9 and 12 months were assessed using a single generalised linear mixed model taking into account all data collected post randomisation with treatment effects estimated for the 9 and 12 month time points of interest • Mean change in serum creatinine, MDRD eGFR, cystatin C-based eGFR and creatinine clearance levels from baseline to 9 months as well as specified reductions (≥30%, ≥40%, ≥50%) in UPCR, urine protein, UACR, and urine albumin at 9 months compared with baseline were also evaluated using similar methodology In addition, a subgroup analysis was planned for the primary endpoint, as described in the SAP (Appendix 16.1.9) and in Section 9.7.1.6. Region was based on country but for a few small countries, there was a need to combine into larger geographical regions. All tests were one sided at the 2.5% significance level. These changes were made before the first formal interim analysis. No changes were made to the planned conduct of the study.

    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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