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    Clinical Trial Results:
    A Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Safety and Efficacy of CCX168 (Avacopan) in Patients with Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis Treated Concomitantly with Rituximab or Cyclophosphamide/Azathioprine

    Summary
    EudraCT number
    2016-001121-14
    Trial protocol
    IE   SE   DE   GB   AT   CZ   NL   ES   HU   DK   BE   NO   FR   IT  
    Global end of trial date
    01 Nov 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    14 Mar 2024
    First version publication date
    13 Dec 2021
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Following receipt of ClinicalTrials.gov Protocol Registration and Results System (PRS) comments, the Sponsor would like to make some updates to be consistent across both databases.

    Trial information

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    Trial identification
    Sponsor protocol code
    CL010_168
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    ChemoCentryx, Inc
    Sponsor organisation address
    850 Maude Avenue, Mountain View, California, United States, 94043
    Public contact
    Clinical trial disclosure, ChemoCentryx, Inc., clinicaltrials@chemocentryx.com
    Scientific contact
    Clinical trial disclosure, ChemoCentryx, Inc., clinicaltrials@chemocentryx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002023-PIP01-16
    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
    01 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the efficacy of CCX168 (avacopan) to induce and sustain remission in patients with active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), when used in combination with cyclophosphamide followed by azathioprine, or in combination with rituximab.
    Protection of trial subjects
    This study was carried out in compliance with the protocol and its amendments, and in accordance with Good Clinical Practice (GCP), as described in the International Conference on Harmonisation (ICH) Harmonised Tripartite Guidelines for Good Clinical Practice 2000 and the United States (US) Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR including parts 50 and 56 concerning informed consent and IRB regulations). The study was conducted in accordance with local and national regulatory requirements and the Declaration of Helsinki. Prior to the initiation of any study procedures, each subject or his/her legal guardian read, signed and dated an IEC or IRB approved ICF. The ICF was reviewed and approved by the Sponsor and the Investigator’s IEC / IRB prior to initiation of the study and was in compliance with the Declaration of Helsinki, ICH GCP, and US Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR Part 46, Subpart A). Sample ICFs and sample subject information are retained in the Trial Master File. The original signed ICF was kept on file by the Investigator with the subject’s records, and a copy was given to each subject.
    Background therapy
    Subjects in both groups (Prednisone and Avacopan) also received either IV or oral cyclophosphamide followed by oral azathioprine, or IV rituximab, as follows: • IV cyclophosphamide 15 mg/kg IV up to 1.2 g maximum was given on Day 1 and also at the Week 2, 4, 7, 10, and 13 study visits. - The cyclophosphamide dose was adjusted based on the subject’s age, eGFR, and WBC count according to protocol-specified criteria • Oral cyclophosphamide 2 mg/kg/day (maximum 200 mg/day) was given orally starting on Day 1 and continuing up to the day before Week 15. - The cyclophosphamide dose was adjusted based on the subject’s age, eGFR, and WBC count according to protocol-specified criteria • IV rituximab on Day 1, and then Weeks 1, 2, and 3 at a dose of 375 mg/m2 at each visit for a total of 4 weekly infusions - Glucocorticoid pre-medication for the rituximab IV infusions was allowed
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Dec 2016
    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: 6
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    United Kingdom: 40
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Czechia: 9
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    France: 40
    Country: Number of subjects enrolled
    Germany: 54
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    New Zealand: 4
    Country: Number of subjects enrolled
    Switzerland: 10
    Country: Number of subjects enrolled
    United States: 47
    Worldwide total number of subjects
    331
    EEA total number of subjects
    182
    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)
    3
    Adults (18-64 years)
    167
    From 65 to 84 years
    158
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    Overall, demographic characteristics were well balanced between treatment groups. Most subjects were White and not Hispanic or Latino. Geographically, most subjects were enrolled at sites in Europe (70.1%), North America (18.1%) and Japan (6.3%). A total of 143 study centers randomized at least 1 subject. The target enrollment was 300 subjects.

    Pre-assignment
    Screening details
    Of 386 subjects screened, 331 were enrolled in the study and randomized to treatment. Reasons for subjects failing screening included not meeting inclusion/exclusion criteria, withdrawal by subject, AE and other.

    Period 1
    Period 1 title
    Overall Study (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
    This study was double-blind, double-dummy, i.e., placebo capsules were identical in appearance to the avacopan capsules, and prednisone capsules also had matching placebo capsules. To maintain the blind, multiple measures were taken (i.e., randomization code was not accessible to study personnel who had contact with study centers or who were involved in data management and analysis for the duration of the study).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Prednisone group
    Arm description
    Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone In the Prednisone group, one subject was randomized but withdrawn for not meeting disease criteria prior to dosing.
    Arm type
    Active comparator

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    • Avacopan-matching placebo twice daily orally for 52 weeks (364 days) - Three avacopan-matching placebo capsules in the morning, preferably with food, and three in the evening, preferably with food, approximately 12 hours after the morning dose • Oral prednisone tapering regimen over 20 weeks (140 days) - Prednisone 60 mg per day if the subject's body weight was ≥55 kg, or 45 mg per day if the subject's body weight was <55 kg, starting on Day 1 with tapering according to the protocol-specified schedule - Adolescents who weighed ≤37 kg started at a prednisone dose of 30 mg per day

    Arm title
    Avacopan group
    Arm description
    Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo
    Arm type
    Experimental

    Investigational medicinal product name
    Avacopan
    Investigational medicinal product code
    CCX168
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    • Avacopan 30 mg twice daily orally for 52 weeks (364 days) - Three 10 mg avacopan capsules in the morning, preferably with food, and three in the evening, preferably with food, approximately 12 hours after the morning dose • Oral prednisone-matching placebo tapering regimen over 20 weeks (140 days) - Prednisone-matching placebo capsules equivalent to 60 mg per day if the subject's body weight was ≥55 kg, or 45 mg per day if the subject's body weight was <55 kg, starting on Day 1 with tapering according to a protocol-specified schedule - Adolescents who weighed ≤37 kg started at a prednisone-matching placebo dose of 30 mg per day

    Number of subjects in period 1
    Prednisone group Avacopan group
    Started
    165
    166
    Completed
    150
    151
    Not completed
    15
    15
         Adverse event, serious fatal
    4
    2
         Consent withdrawn by subject
    3
    6
         Physician decision
    4
    3
         Adverse event, non-fatal
    2
    1
         Other
    -
    1
         Lost to follow-up
    2
    1
         Withdrawal by parent/guardian
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Prednisone group
    Reporting group description
    Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone In the Prednisone group, one subject was randomized but withdrawn for not meeting disease criteria prior to dosing.

    Reporting group title
    Avacopan group
    Reporting group description
    Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo

    Reporting group values
    Prednisone group Avacopan group Total
    Number of subjects
    165 166 331
    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)
    1 2 3
        Adults (18-50 years)
    28 30 58
        Adults (51-64 years)
    61 48 109
        Adults (65-75 years)
    52 62 114
        Adults (>75 years)
    22 24 46
        Not recorded
    1 0 1
    Gender categorical
    Units: Subjects
        Female
    76 68 144
        Male
    88 98 186
        Not recorded
    1 0 1
    Race
    Units: Subjects
        Asian
    15 17 32
        Black or African American
    2 3 5
        White
    140 138 278
        Other
    6 8 14
        Multiple
    1 0 1
        Not recorded
    1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    5 7 12
        Not Hispanic or Latino
    157 151 308
        Unknown
    1 1 2
        Not Reported
    1 7 8
        Not recorded
    1 0 1
    Country
    Units: Subjects
        Australia
    4 10 14
        Austria
    3 3 6
        Belgium
    4 6 10
        Canada
    5 8 13
        Czech Republic
    7 2 9
        Denmark
    10 6 16
        France
    18 22 40
        Germany
    32 22 54
        Italy
    2 9 11
        Japan
    10 11 21
        Netherlands
    5 1 6
        New Zealand
    2 2 4
        Republic of Ireland
    4 4 8
        Spain
    7 8 15
        Sweden
    2 5 7
        Switzerland
    6 4 10
        United Kingdom
    23 17 40
        United States of America
    20 26 46
        Not recorded
    1 0 1
    Geographic Region
    Units: Subjects
        North America
    25 34 59
        Europe and Rest of World excluding Japan
    129 121 250
        Japan
    10 11 21
        Not recorded
    1 0 1
    ANCA-associated vasculitis Status
    ANCA=anti-neutrophil cytoplasmic autoantibody
    Units: Subjects
        Newly diagnosed
    114 115 229
        Relapsed
    50 51 101
        Not recorded
    1 0 1
    ANCA Positivity
    ANCA=anti-neutrophil cytoplasmic autoantibody
    Units: Subjects
        PR3
    70 72 142
        MPO
    94 94 188
        Not recorded
    1 0 1
    Standard of Care Treatment
    IV=intravenous
    Units: Subjects
        Rituximab
    107 107 214
        IV Cyclophosphamide
    51 51 102
        Oral Cyclophosphamide
    6 8 14
        Not recorded
    1 0 1
    Type of ANCA-associated vasculitis
    ANCA=anti-neutrophil cytoplasmic autoantibody
    Units: Subjects
        Granulomatosis with polyangiitis (GPA)
    90 91 181
        Microscopic polyangiitis (MPA)
    74 75 149
        Not recorded
    1 0 1
    Age at screening
    In the Prednisone group, one subject was randomized but withdrawn for not meeting disease criteria prior to dosing. Thus, the figure reported in this group is for a total number of subjects of 164.
    Units: year
        arithmetic mean (standard deviation)
    60.5 ± 14.50 61.2 ± 14.56 -
    Age at diagnosis of ANCA-associated Vasculitis
    ANCA=anti-neutrophil cytoplasmic autoantibody In the Prednisone group, one subject was randomized but withdrawn for not meeting disease criteria prior to dosing. Thus, the figure reported in this group is for a total number of subjects of 164.
    Units: year
        arithmetic mean (standard deviation)
    59.4 ± 15.19 59.8 ± 15.60 -
    Duration of ANCA-Associated Vasculitis
    ANCA=anti-neutrophil cytoplasmic autoantibody In the Prednisone group, one subject was randomized but withdrawn for not meeting disease criteria prior to dosing. Thus, the figure reported in this group is for a total number of subjects of 164.
    Units: month
        arithmetic mean (standard deviation)
    20.13 ± 40.473 22.93 ± 52.464 -
    Body Weight
    In the Prednisone group, one subject was randomized but withdrawn for not meeting disease criteria prior to dosing. Thus, the figure reported in this group is for a total number of subjects of 164.
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    77.71 ± 19.335 76.43 ± 20.254 -
    BMI
    BMI=Body Mass Index In the Prednisone group, one subject was randomized but withdrawn for not meeting disease criteria prior to dosing. Thus, the figure reported in this group is for a total number of subjects of 164.
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    26.78 ± 5.212 26.72 ± 5.997 -
    BVAS Score
    BVAS=Birmingham Vasculitis Activity Score BVAS Entry Criteria (N)*: 1 or more major item: 102/104 3 or more minor items: 142/146 2 renal items of proteinuria and hematuria: 57/60 BVAS Components (N)*: General: 114/111 Cutaneous: 23/24 Mucous Membranes/Eyes: 40/26 Ear Nose and Throat:69/75 Chest: 71/71 Cardiovascular: 3/6 Abdominal: 1/4 Renal + Other (RBC Casts and/or Glomerulonephritis): 134/134 Nervous System: 31/38 *Subjects can appear in more than one category; Prednisone/Avacopan Prednisone group - 1 subject withdrawn for not meeting disease criteria prior to dosing. N=164.
    Units: Number
        arithmetic mean (standard deviation)
    16.2 ± 5.69 16.3 ± 5.87 -
    VDI Score
    VDI=Vasculitis Damage Index In the Prednisone group, one subject was randomized but withdrawn for not meeting disease criteria prior to dosing. In addition, two subjects did not have a baseline VDI Score (one in each treatment group). Thus, the figures reported in the Prednisone and Avacopan groups are for a total number of subjects of 163 and 165, respectively.
    Units: Number
        arithmetic mean (standard deviation)
    0.7 ± 1.39 0.7 ± 1.54 -

    End points

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    End points reporting groups
    Reporting group title
    Prednisone group
    Reporting group description
    Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone In the Prednisone group, one subject was randomized but withdrawn for not meeting disease criteria prior to dosing.

    Reporting group title
    Avacopan group
    Reporting group description
    Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo

    Primary: Percentage of subjects achieving disease remission at Week 26

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    End point title
    Percentage of subjects achieving disease remission at Week 26
    End point description
    Disease remission at Week 26 was defined as: • Achieving a BVAS of 0 as determined by the Adjudication Committee; • No administration of glucocorticoids given for ANCA-associated vasculitis within 4 weeks prior to Week 26; • No BVAS >0 during the 4 weeks prior to Week 26 (if collected for an unscheduled assessment).
    End point type
    Primary
    End point timeframe
    Week 26
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    164
    166
    Units: percentage of subjects
        number (confidence interval 95%)
    70.1 (62.5 to 77.0)
    72.3 (64.8 to 78.9)
    Statistical analysis title
    Comparison between groups
    Statistical analysis description
    The proportion of subjects achieving disease remission at Week 26 and the two-sided 95% confidence intervals (CIs) for the difference in proportions was estimated for the comparison between the avacopan group and the prednisone group. For both the noninferiority and superiority tests, the one-sided P-values are presented. Statistical significance was claimed based on the one-sided type-I error of 0.025.
    Comparison groups
    Prednisone group v Avacopan group
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    < 0.0001 [2]
    Method
    Summary Score test
    Parameter type
    Common difference in remission rates
    Point estimate
    3.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6
         upper limit
    12.8
    Notes
    [1] - Summary Score estimate of the common difference and Miettinen-Nurminen (score) confidence limits for the common difference.
    [2] - The non-inferiority null hypothesis (H0) for the primary endpoint was rejected and the alternative hypothesis (H1) that the avacopan group was not inferior to the prednisone group when comparing the remission rate at Week 26 was accepted.
    Statistical analysis title
    Comparison between groups
    Statistical analysis description
    The proportion of subjects achieving disease remission at Week 26 and the two-sided 95% confidence intervals (CIs) for the difference in proportions was estimated for the comparison between the avacopan group and the prednisone group. For both the noninferiority and superiority tests, the one-sided P-values are presented. Statistical significance was claimed based on the one-sided type-I error of 0.025.
    Comparison groups
    Prednisone group v Avacopan group
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.2387 [4]
    Method
    Summary Score test
    Parameter type
    Common difference in remission rates
    Point estimate
    3.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6
         upper limit
    12.8
    Notes
    [3] - Summary Score estimate of the common difference and Miettinen-Nurminen (score) confidence limits for the common difference.
    [4] - The superiority null hypothesis (H0) that the avacopan group was not different from the prednisone group when comparing the remission rate at Week 26 was accepted.

    Primary: Percentage of subjects achieving sustained disease remission at Week 52

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    End point title
    Percentage of subjects achieving sustained disease remission at Week 52
    End point description
    Sustained remission at Week 52 was defined as: • Disease remission at Week 26 as defined above; • Disease remission at Week 52 defined as a BVAS of 0 at Week 52 as determined by the Adjudication Committee and no administration of glucocorticoids for treatment of ANCA-associated vasculitis within 4 weeks prior to Week 52; • No disease relapse between Week 26 and Week 52 as determined by the Adjudication Committee.
    End point type
    Primary
    End point timeframe
    Week 52
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    164
    166
    Units: percentage of subjects
        number (confidence interval 95%)
    54.9 (46.9 to 62.6)
    65.7 (57.9 to 72.8)
    Statistical analysis title
    Comparison between groups
    Statistical analysis description
    The proportion of subjects achieving sustained disease remission at Week 52, and the two-sided 95% confidence intervals (CIs) for the difference in proportions (avacopan minus prednisone) was estimated for the comparison between the avacopan group and the prednisone group. For both the noninferiority and superiority tests, the one-sided P-values are presented. Statistical significance was claimed based on the one-sided type-I error of 0.025.
    Comparison groups
    Prednisone group v Avacopan group
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    P-value
    < 0.0001 [6]
    Method
    Summary Score test
    Parameter type
    Common difference in remission rates
    Point estimate
    12.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.6
         upper limit
    22.3
    Notes
    [5] - Summary Score estimate of the common difference and Miettinen-Nurminen (score) confidence limits for the common difference.
    [6] - The non-inferiority null hypothesis (H0) for the efficacy endpoint was rejected and the alternative hypothesis (H1) that the avacopan group was not inferior to the prednisone group when comparing the sustained remission rate at Week 52 was accepted.
    Statistical analysis title
    Comparison between groups
    Statistical analysis description
    The proportion of subjects achieving sustained disease remission at Week 52, and the two-sided 95% confidence intervals (CIs) for the difference in proportions (avacopan minus prednisone) was estimated for the comparison between the avacopan group and the prednisone group. For both the noninferiority and superiority tests, the one-sided P-values are presented. Statistical significance was claimed based on the one-sided type-I error of 0.025.
    Comparison groups
    Prednisone group v Avacopan group
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.0066 [8]
    Method
    Summary Score test
    Parameter type
    Common difference in remission rates
    Point estimate
    12.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.6
         upper limit
    22.3
    Notes
    [7] - Summary Score estimate of the common difference and Miettinen-Nurminen (score) confidence limits for the common difference.
    [8] - The superiority alternative hypothesis (H1) that the avacopan group was superior to the prednisone group when comparing the sustained remission rate at Week 52 was accepted.

    Secondary: Glucocorticoid-induced toxicity as measured by change from baseline over the first 26 weeks in the GTI

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    End point title
    Glucocorticoid-induced toxicity as measured by change from baseline over the first 26 weeks in the GTI
    End point description
    GTI-CWS=Glucocorticoid Toxicity Index Cumulative Worsening Score GTI-AIS=Glucocorticoid Toxicity Index Aggregate Improvement Score The Glucocorticoid Toxicity Index (GTI) was developed to score glucocorticoid toxicity. The GTI includes: the Cumulative Worsening Score (CWS) that captures cumulative toxicity, both permanent and transient, over the course of time (serves as a cumulative record of toxicity); and the Aggregate Improvement Score that captures both improvement and worsening of toxicity over time (serves as a record of both improving and worsening toxicity). Both scores range from 0 (best health) to 100 (worst health).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 13 and 26
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    161 [9]
    160 [10]
    Units: Glucocorticoid Toxicity Index
    least squares mean (standard error)
        GTI-CWS (Week 13)
    36.6 ± 3.41
    25.7 ± 3.40
        GTI-CWS (Week 26)
    56.6 ± 3.45
    39.7 ± 3.43
        GTI-AIS (Week 13)
    23.2 ± 3.46
    9.9 ± 3.45
        GTI-AIS (Week 26)
    23.4 ± 3.50
    11.2 ± 3.48
    Notes
    [9] - Number of subjects analysed at Week 26 was 153.
    [10] - Number of subjects analysed at Week 26 was 154.
    No statistical analyses for this end point

    Secondary: Percentage of subjects with BVAS of 0 at Week 4, regardless of whether the subjects received glucocorticoids during this period of time and based on assessment by the blinded AC

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    End point title
    Percentage of subjects with BVAS of 0 at Week 4, regardless of whether the subjects received glucocorticoids during this period of time and based on assessment by the blinded AC
    End point description
    BVAS=Birmingham Vasculitis Activity Score AC=Adjudication Committee The BVAS form is divided into 9 organ-based systems, with each section including symptoms/signs that are typical of that particular organ involvement in systemic vasculitis. The clinician only scores features believed to be due to active vasculitis. Completion of the form provides a numerical score, which ranges from 0 (best health) to 63 (worst health).
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    164
    166
    Units: Percentage of subjects
        number (confidence interval 95%)
    68.9 (61.2 to 75.9)
    62.7 (54.8 to 70.0)
    No statistical analyses for this end point

    Secondary: Change from baseline over 52 weeks in health-related quality of life as measured by the domains and component scores of the SF-36v2 and EQ-5D-5L VAS and Index

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    End point title
    Change from baseline over 52 weeks in health-related quality of life as measured by the domains and component scores of the SF-36v2 and EQ-5D-5L VAS and Index
    End point description
    SF-36v2: Medical Outcomes Survey Short Form-36 version 2; EQ-5D-5L: EuroQuality of Life-5 Domains-5 Levels The SF-36v2 component scores and the EQ-5D-5L VAS score range from 0 (worst health) to 100 (best health). The EQ-5D-5L Index Score ranges from 0 (worst health) to 1 (best health).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 and 52
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    150 [11]
    154 [12]
    Units: Change from baseline
    least squares mean (standard error)
        SF-36v2: Physical Component Score (Week 26)
    1.344 ± 0.7432
    4.445 ± 0.7332
        SF-36v2: Physical Component Score (Week 52)
    2.626 ± 0.7505
    4.980 ± 0.7435
        SF-36v2: Physical Functioning (Week 26)
    1.88 ± 1.787
    7.31 ± 1.773
        SF-36v2: Physical Functioning (Week 52)
    4.82 ± 1.809
    9.55 ± 1.790
        SF-36v2: Role Physical (Week 26)
    7.52 ± 2.198
    16.78 ± 2.173
        SF-36v2: Role Physical (Week 52)
    12.27 ± 2.228
    17.12 ± 2.198
        SF-36v2: Bodily Pain (Week 26)
    9.82 ± 2.197
    14.75 ± 2.164
        SF-36v2: Bodily Pain (Week 52)
    11.87 ± 2.220
    16.12 ± 2.185
        SF-36v2: General Health Perception (Week 26)
    -2.89 ± 1.428
    3.12 ± 1.405
        SF-36v2: General Health Perception (Week 52)
    -0.17 ± 1.442
    5.84 ± 1.420
        SF-36v2: Mental Component Score (Week 26)
    3.271 ± 0.8403
    4.849 ± 0.8273
        SF-36v2: Mental Component Score (Week 52)
    4.694 ± 0.8491
    6.394 ± 0.8406
        SF-36v2: Mental Health (Week 26)
    6.84 ± 1.331
    8.29 ± 1.318
        SF-36v2: Mental Health (Week 52)
    9.66 ± 1.347
    10.89 ± 1.337
        SF-36v2: Role Emotional (Week 26)
    1.40 ± 2.183
    7.32 ± 2.158
        SF-36v2: Role Emotional (Week 52)
    4.14 ± 2.212
    9.38 ± 2.181
        SF-36v2: Social Functioning (Week 26)
    11.09 ± 2.037
    14.50 ± 2.002
        SF-36v2: Social Functioning (Week 52)
    13.56 ± 2.059
    18.06 ± 2.030
        SF-36v2: Vitality (Week 26)
    6.42 ± 1.751
    12.03 ± 1.727
        SF-36v2: Vitality (Week 52)
    10.48 ± 1.770
    14.36 ± 1.750
        EQ-5D-5L VAS Score (Week 26)
    5.5 ± 1.39
    9.1 ± 1.38
        EQ-5D-5L VAS Score (Week 52)
    7.1 ± 1.41
    13.0 ± 1.39
        EQ-5D-5L Index Score (Week 26)
    -0.0010 ± 0.01462
    0.0229 ± 0.01438
        EQ-5D-5L Index Score (Week 52)
    -0.0038 ± 0.01471
    0.0474 ± 0.01451
    Notes
    [11] - The number of subjects analysed varied from 144 to 150 amongst the subcategories specified.
    [12] - The number of subjects analysed varied from 147 to 154 amongst the subcategories specified.
    No statistical analyses for this end point

    Secondary: Percentage of subjects and time to experiencing a relapse after previously achieving remission at Week 26 in the study

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    End point title
    Percentage of subjects and time to experiencing a relapse after previously achieving remission at Week 26 in the study
    End point description
    A relapse was defined as occurrence of at least one major item in the BVAS, or three or more minor items in the BVAS, or one or two minor items in the BVAS recorded at two consecutive visits, after: (a) having achieved remission at Week 26 (BVAS=0 and no glucocorticoids for ANCA-associated vasculitis within 4 weeks) or (b) having achieved BVAS=0 at any time during the treatment period The median time to relapse was not estimable because of small number of relapsed subjects.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    115
    120
    Units: percentage of subjects
        number (confidence interval 95%)
    12.2 (6.8 to 19.6)
    7.5 (3.5 to 13.8)
    No statistical analyses for this end point

    Secondary: In subjects with renal disease at baseline (based in the BVAS renal component), the change in eGFR from baseline over 52 weeks

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    End point title
    In subjects with renal disease at baseline (based in the BVAS renal component), the change in eGFR from baseline over 52 weeks
    End point description
    Change from baseline in kidney function, as measured by eGFR (based on the MDRD equation), was measured in subjects with renal disease based on the BVAS renal component. eGFR=estimated glomerular filtration rate; BVAS=Birmingham Vasculitis Activity Score; MDRD=Modification of Diet in Renal Disease
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 and 52
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    127 [13]
    121 [14]
    Units: Change in eGFR (mL/min/1.73 m2)
    least squares mean (confidence interval 95%)
        Week 26
    2.9 (0.9 to 4.9)
    5.8 (3.7 to 7.8)
        Week 52
    4.1 (2.1 to 6.1)
    7.3 (5.2 to 9.4)
    Notes
    [13] - Number of subjects analysed at Week 52 was 125
    [14] - Number of subjects analysed at Week 52 was 119
    No statistical analyses for this end point

    Secondary: In subjects with renal disease and albuminuria at baseline (based in the BVAS renal component), the percent change in UACR from baseline over 52 weeks

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    End point title
    In subjects with renal disease and albuminuria at baseline (based in the BVAS renal component), the percent change in UACR from baseline over 52 weeks
    End point description
    BVAS=Birmingham Vasculitis Activity Score; UACR=Urinary albumin:creatinine ratio
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 26 and 52
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    124 [15]
    121 [16]
    Units: percent change
    least squares mean (confidence interval 95%)
        Week 4
    0 (-16 to 19)
    -40 (-50 to -28)
        Week 26
    -70 (-75 to -65)
    -63 (-69 to -56)
        Week 52
    -77 (-81 to -72)
    -74 (-78 to -69)
    Notes
    [15] - Number of subjects analysed at Week 26 was 118. Number of subjects analysed at Week 52 was 114.
    [16] - Number of subjects analysed at Week 26 was 113. Number of subjects analysed at Week 52 was 109
    No statistical analyses for this end point

    Secondary: In subjects with renal disease at baseline (based in the BVAS renal component), the percent change in urinary MCP-1:creatinine ratio from baseline over 52 weeks

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    End point title
    In subjects with renal disease at baseline (based in the BVAS renal component), the percent change in urinary MCP-1:creatinine ratio from baseline over 52 weeks
    End point description
    BVAS=Birmingham Vasculitis Activity Score; MCP-1=monocyte chemoattractant protein-1
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 and 52
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    117 [17]
    106 [18]
    Units: percent change
    least squares mean (confidence interval 95%)
        Week 26
    -64 (-67 to -59)
    -67 (-70 to -63)
        Week 52
    -71 (-74 to -67)
    -73 (-76 to -70)
    Notes
    [17] - Number of subjects analysed at Week 52 was 108.
    [18] - Number of subjects analysed at Week 52 was 106.
    No statistical analyses for this end point

    Secondary: Change in the VDI from baseline over 52 weeks, including the Week 26 and Week 52 time points

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    End point title
    Change in the VDI from baseline over 52 weeks, including the Week 26 and Week 52 time points
    End point description
    VDI=Vasculitis Damage Index The VDI is comprised of 64 items of damage, grouped into 11 organ-based systems or categorizations. Damage is defined as the presence of non-healing scars and does not give any indication of current disease activity. Damage is also defined as having been present or currently present for at least 3 months. Completion of the form provides a numerical score, which ranges from 0 (best health) to 64 (worst health).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 and 52
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    155 [19]
    161 [20]
    Units: score on a scale
    least squares mean (standard error)
        Week 26
    0.97 ± 0.092
    1.06 ± 0.090
        Week 52
    1.15 ± 0.093
    1.17 ± 0.091
    Notes
    [19] - Number of subjects analysed at Week 52 was 151.
    [20] - Number of subjects analysed at Week 52 was 150.
    No statistical analyses for this end point

    Secondary: Subject incidence of treatment-emergent SAEs, AEs, and withdrawals due to AEs

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    End point title
    Subject incidence of treatment-emergent SAEs, AEs, and withdrawals due to AEs
    End point description
    AEs=Adverse events; SAEs=Serious adverse events; TEAE=Treatment-emergent adverse event
    End point type
    Secondary
    End point timeframe
    From day 1 throughout the study period (day 421/week 60)
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    164
    166
    Units: Number
        Number of subjects with at least one TEAE
    161
    164
        Number of TEAEs
    2139
    1779
        Number of subjects with SAEs
    74
    70
        Number of SAEs
    166
    116
        Subjects with TEAE leading to discontinuation
    28
    27
    No statistical analyses for this end point

    Secondary: Number of subjects with clinically significant ECG changes from baseline

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    End point title
    Number of subjects with clinically significant ECG changes from baseline
    End point description
    Clinical significance was assessed by the individual reading of the ECGs. ECG=Electrocardiogram
    End point type
    Secondary
    End point timeframe
    From day 1 throughout the study period (day 421/week 60)
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    164
    166
    Units: Subjects
    8
    12
    No statistical analyses for this end point

    Secondary: Number of subjects where a relationship between Avacopan/Placebo, glucocorticoid use, cyclophosphamide, rituximab, and azathioprine or mycophenolate use to an AE as determined by the investigator

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    End point title
    Number of subjects where a relationship between Avacopan/Placebo, glucocorticoid use, cyclophosphamide, rituximab, and azathioprine or mycophenolate use to an AE as determined by the investigator
    End point description
    AE=Adverse Event
    End point type
    Secondary
    End point timeframe
    From day 1 throughout the study period (day 421/week 60)
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    164
    166
    Units: Subjects
        Relationship of avacopan/placebo to an AE
    103
    100
        Relationship of glucocorticoid use to an AE
    131
    107
        Relationship of cyclophosphamide IV use to an AE
    30
    31
        Relationship of oral cyclophosphamide use to an AE
    4
    8
        Relationship of rituximab use to an AE
    61
    50
        Relationship of azathioprine use to an AE
    35
    28
        Relationship of mycophenolate use to an AE
    9
    6
    No statistical analyses for this end point

    Secondary: Certain safety endpoints of interest: infections, hepatic system abnormalities, WBC count decreases, and hypersensitivity.

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    End point title
    Certain safety endpoints of interest: infections, hepatic system abnormalities, WBC count decreases, and hypersensitivity.
    End point description
    WBC=White Blood Cell; TEAE=Treatment-Emergent Adverse Event TE = Treatment-Emergent
    End point type
    Secondary
    End point timeframe
    From day 1 throughout the study period (day 421/week 60)
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    164
    166
    Units: Subjects
        Any Treatment-Emergent Infection
    124
    113
        Any Serious Treatment-Emergent Infection
    25
    22
        Any Severe Treatment-Emergent Infection
    10
    12
        Any Treatment-Emergent Life-threatening Infection
    2
    1
        Any Treatment-Emergent Infection Leading to Death
    2
    1
        Any TEAE Associated with Hepatic Abnormalities
    19
    22
        Any TEAE Associated with Low WBC Counts
    39
    31
        Any TEAE Associated with hypersensitivity
    70
    68
        Any TE Infection Leading to Study Withdrawal
    5
    4
    No statistical analyses for this end point

    Secondary: Change from baseline and shifts from baseline in all safety laboratory parameters - hematology

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    End point title
    Change from baseline and shifts from baseline in all safety laboratory parameters - hematology
    End point description
    Units differ for categories as follows: Leukocytes/Neutrophils/Lymphocytes - 10^3 cells/μL Eosinophils/Basophils/Monocytes/Platelets - 10^9 cells/L Erythrocytes - 10^12 cells/L Hemoglobin - g/dL Hematocrit - percentage of red blood cells
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 and 52
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    151 [21]
    147 [22]
    Units: Specified in end point description
    arithmetic mean (standard error)
        Leukocytes (Week 26)
    -5.69 ± 0.338
    -5.94 ± 0.387
        Leukocytes (Week 52)
    -5.54 ± 0.365
    -5.62 ± 0.395
        Neutrophils (Week 26)
    -5.10 ± 0.338
    -5.24 ± 0.380
        Neutrophils (Week 52)
    -4.89 ± 0.361
    -4.95 ± 0.372
        Lymphocytes (Week 26)
    -0.62 ± 0.090
    -0.84 ± 0.099
        Lymphocytes (Week 52)
    -0.67 ± 0.090
    -0.82 ± 0.100
        Eosinophils (Week 26)
    0.07 ± 0.016
    0.07 ± 0.018
        Eosinophils (Week 52)
    0.05 ± 0.013
    0.07 ± 0.019
        Basophils (Week 26)
    -0.01 ± 0.004
    -0.00 ± 0.004
        Basophils (Week 52)
    -0.01 ± 0.004
    -0.01 ± 0.004
        Monocytes (Week 26)
    0.01 ± 0.022
    -0.04 ± 0.024
        Monocytes (Week 52)
    0.01 ± 0.024
    -0.01 ± 0.026
        Platelets (Week 26)
    -73.9 ± 8.49
    -77.1 ± 9.30
        Platelets (Week 52)
    -75.5 ± 8.01
    -73.8 ± 9.31
        Erythrocytes (Week 26)
    0.226 ± 0.0450
    0.252 ± 0.0432
        Erythrocytes (Week 52)
    0.244 ± 0.0410
    0.279 ± 0.0432
        Hemoglobin (Week 26)
    1.07 ± 0.129
    1.10 ± 0.120
        Hemoglobin (Week 52)
    1.20 ± 0.126
    1.27 ± 0.125
        Hematocrit (Week 26)
    2.6 ± 0.38
    2.7 ± 0.38
        Hematocrit (Week 52)
    3.0 ± 0.37
    3.2 ± 0.38
    Notes
    [21] - The number of subjects analysed varied from 147 to 152 amongst the subcategories
    [22] - The number of subjects analysed varied from 143 to 147 amongst the subcategories specified
    No statistical analyses for this end point

    Secondary: Change from baseline and shifts from baseline in all safety laboratory parameters - serum chemistry

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    End point title
    Change from baseline and shifts from baseline in all safety laboratory parameters - serum chemistry
    End point description
    Units differ for categories as follows: Lactate Dehydrogenase/Alkaline Phosphatase/Creatine Kinase/ Alanine Aminotransferase/ Aspartate Aminotransferase - U/L Creatinine/ Urea Nitrogen/ Protein/ Cholesterol/ LDL Cholesterol/ Bilirubin - mg/dL
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 and 52
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    154 [23]
    150 [24]
    Units: Specified in the end point description
    arithmetic mean (standard error)
        Lactate Dehydrogenase (Week 26)
    2.3 ± 5.68
    -6.1 ± 5.40
        Lactate Dehydrogenase (Week 52)
    -8.6 ± 5.33
    -10.7 ± 4.80
        Alkaline Phosphatase (Week 26)
    -0.6 ± 2.47
    -3.9 ± 2.84
        Alkaline Phosphatase (Week 52)
    0.8 ± 1.77
    -4.0 ± 2.34
        Creatine Kinase (Week 26)
    47.6 ± 5.27
    76.8 ± 10.34
        Creatine Kinase (Week 52)
    57.6 ± 5.67
    76.3 ± 9.68
        Alanine Aminotransferase (Week 26)
    -6.8 ± 1.77
    -6.1 ± 1.54
        Alanine Aminotransferase (Week 52)
    -8.2 ± 1.57
    -7.2 ± 1.46
        Aspartate Aminotransferase (Week 26)
    1.9 ± 0.98
    2.5 ± 0.72
        Aspartate Aminotransferase (Week 52)
    0.5 ± 0.85
    2.0 ± 0.69
        Creatinine (Week 26)
    -0.105 ± 0.0569
    -0.195 ± 0.0508
        Creatinine (Week 52)
    -0.200 ± 0.0416
    -0.244 ± 0.0627
        Urea Nitrogen (Week 26)
    -9.4 ± 1.16
    -11.0 ± 1.32
        Urea Nitrogen (Week 52)
    -7.8 ± 1.11
    -11.9 ± 1.32
        Protein (Week 26)
    50 ± 50
    220 ± 47
        Protein (Week 52)
    160 ± 48
    250 ± 41
        Cholesterol (Week 26)
    19.0 ± 4.27
    7.4 ± 3.99
        Cholesterol (Week 52)
    13.8 ± 4.28
    9.3 ± 4.05
        LDL Cholesterol (Week 26)
    22.7 ± 3.66
    12.0 ± 3.47
        LDL Cholesterol (Week 52)
    21.7 ± 3.48
    11.9 ± 3.41
        Bilirubin (Week 26)
    0.065 ± 0.0182
    0.078 ± 0.0250
        Bilirubin (Week 52)
    0.053 ± 0.0185
    0.057 ± 0.0201
    Notes
    [23] - The number of subjects analysed varied from 146 to 154 amongst the subcategories
    [24] - The number of subjects analysed varied from 141 to 162 amongst the subcategories
    No statistical analyses for this end point

    Secondary: Change from baseline in vital signs

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    End point title
    Change from baseline in vital signs
    End point description
    Units differ for categories as follows: Systolic Blood Pressure/ Diastolic Blood Pressure - mmHg Pulse Rate - beats/min Temperature - degree Celsius Weight - kilogram(s) BMI - kilogram(s)/ square meter
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 and 52
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    154 [25]
    154 [26]
    Units: Specified in the end point description
    arithmetic mean (standard error)
        Systolic Blood Pressure (Week 26)
    -2.5 ± 1.70
    -2.6 ± 1.54
        Systolic Blood Pressure (Week 52)
    -2.4 ± 1.64
    -1.0 ± 1.60
        Diastolic Blood Pressure (Week 26)
    2.7 ± 0.98
    0.5 ± 0.92
        Diastolic Blood Pressure (Week 52)
    1.4 ± 1.01
    1.4 ± 1.00
        Pulse Rate (Week 26)
    2.2 ± 1.12
    0.9 ± 1.25
        Pulse Rate (Week 52)
    -1.3 ± 1.07
    -0.3 ± 1.21
        Temperature (Week 26)
    -0.03 ± 0.043
    -0.11 ± 0.046
        Temperature (Week 52)
    0.04 ± 0.044
    -0.11 ± 0.048
        Weight (Week 26)
    3.33 ± 0.397
    1.93 ± 0.369
        Weight (Week 52)
    3.27 ± 0.477
    2.59 ± 0.487
        BMI (Week 26)
    1.13 ± 0.135
    0.67 ± 0.132
        BMI (Week 52)
    1.12 ± 0.164
    0.94 ± 0.179
    Notes
    [25] - The number of subjects analysed varied from 148 to 154 amongst the subcategories specified
    [26] - The number of subjects analysed varied from 148 to 154 amongst the subcategories specified
    No statistical analyses for this end point

    Secondary: Number of subjects experiencing a relapse after previously achieving BVAS=0 during the study

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    End point title
    Number of subjects experiencing a relapse after previously achieving BVAS=0 during the study
    End point description
    BVAS=Birmingham Vasculitis Activity Score; A relapse was defined as occurrence of at least one major item in the BVAS, or three or more minor items in the BVAS, or one or two minor items in the BVAS recorded at two consecutive visits, after: a. having achieved remission at Week 26 (BVAS=0 and no glucocorticoids for ANCA-associated vasculitis within 4 weeks) or b. having achieved BVAS=0 at any time during the treatment period The BVAS form is divided into 9 organ-based systems, with each section including symptoms/signs that are typical of that particular organ involvement in systemic vasculitis. The clinician only scores features believed to be due to active vasculitis. Completion of the form provides a numerical score, which ranges from 0 (best health) to 63 (worst health).
    End point type
    Secondary
    End point timeframe
    From day 1 throughout the study period (day 421/week 60)
    End point values
    Prednisone group Avacopan group
    Number of subjects analysed
    157
    158
    Units: Participants
    33
    16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From day 1 throughout the study period (day 421/week 60)
    Adverse event reporting additional description
    An AE was considered treatment-emergent if the start date/time of the event was on or after the date/time of first dose of study drug through 56 days following the last dose administered during the randomized treatment period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Avacopan group
    Reporting group description
    Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo. The safety population included all subjects who were randomized and had received at least one dose of study drug.

    Reporting group title
    Prednisone group
    Reporting group description
    Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone. The safety population included all subjects who were randomized and had received at least one dose of study drug.

    Serious adverse events
    Avacopan group Prednisone group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    70 / 166 (42.17%)
    74 / 164 (45.12%)
         number of deaths (all causes)
    2
    4
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ of skin
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Granulomatosis with polyangiitis
         subjects affected / exposed
    5 / 166 (3.01%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Microscopic polyangiitis
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Arteriovenous fistula operation
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 166 (1.20%)
    3 / 164 (1.83%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hernia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anti-neutrophil cytoplasmic antibody positive vasculitis
         subjects affected / exposed
    12 / 166 (7.23%)
    20 / 164 (12.20%)
         occurrences causally related to treatment / all
    0 / 12
    1 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    2 / 166 (1.20%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Antineutrophil cytoplasmic antibody increased
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 166 (0.60%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 166 (0.00%)
    3 / 164 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthopnoea
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal ulcer
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal ulceration
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somatic symptom disorder
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 166 (1.20%)
    3 / 164 (1.83%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 166 (0.60%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical observation
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural vomiting
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 166 (1.20%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 166 (1.20%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 166 (0.60%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Mononeuropathy multiplex
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 166 (0.60%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    1 / 166 (0.60%)
    3 / 164 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow toxicity
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granulomatous lymphadenitis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Episcleritis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         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
    0 / 166 (0.00%)
    3 / 164 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Large intestine polyp
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Abdominal hernia
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis gastrointestinal
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    2 / 166 (1.20%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis cholestatic
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Purpura
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 166 (1.81%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    8 / 166 (4.82%)
    6 / 164 (3.66%)
         occurrences causally related to treatment / all
    2 / 9
    3 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 166 (1.81%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 166 (1.20%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 166 (1.20%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cryptococcosis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes simplex
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 166 (1.20%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 166 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         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
    Avacopan group Prednisone group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    164 / 166 (98.80%)
    161 / 164 (98.17%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    30 / 166 (18.07%)
    29 / 164 (17.68%)
         occurrences all number
    36
    31
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    35 / 166 (21.08%)
    40 / 164 (24.39%)
         occurrences all number
    39
    56
    Fatigue
         subjects affected / exposed
    17 / 166 (10.24%)
    15 / 164 (9.15%)
         occurrences all number
    19
    15
    Pyrexia
         subjects affected / exposed
    15 / 166 (9.04%)
    19 / 164 (11.59%)
         occurrences all number
    18
    25
    Immune system disorders
    Anti-neutrophil cytoplasmic antibody positive vasculitis
    Additional description: Worsening of vasculitis is reported as the Preferred Term of "anti-neutrophil cytoplasmic antibody-positive vasculitis".
         subjects affected / exposed
    26 / 166 (15.66%)
    34 / 164 (20.73%)
         occurrences all number
    30
    46
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 166 (15.66%)
    26 / 164 (15.85%)
         occurrences all number
    31
    29
    Epistaxis
         subjects affected / exposed
    14 / 166 (8.43%)
    21 / 164 (12.80%)
         occurrences all number
    21
    30
    Dyspnoea
         subjects affected / exposed
    8 / 166 (4.82%)
    11 / 164 (6.71%)
         occurrences all number
    11
    14
    Oropharyngeal pain
         subjects affected / exposed
    6 / 166 (3.61%)
    12 / 164 (7.32%)
         occurrences all number
    7
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    13 / 166 (7.83%)
    25 / 164 (15.24%)
         occurrences all number
    13
    27
    Investigations
    Weight increased
         subjects affected / exposed
    1 / 166 (0.60%)
    17 / 164 (10.37%)
         occurrences all number
    1
    19
    Blood creatinine increased
         subjects affected / exposed
    10 / 166 (6.02%)
    8 / 164 (4.88%)
         occurrences all number
    10
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    34 / 166 (20.48%)
    23 / 164 (14.02%)
         occurrences all number
    43
    30
    Dizziness
         subjects affected / exposed
    11 / 166 (6.63%)
    10 / 164 (6.10%)
         occurrences all number
    14
    10
    Tremor
         subjects affected / exposed
    2 / 166 (1.20%)
    10 / 164 (6.10%)
         occurrences all number
    2
    11
    Paraesthesia
         subjects affected / exposed
    9 / 166 (5.42%)
    7 / 164 (4.27%)
         occurrences all number
    10
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 166 (7.83%)
    18 / 164 (10.98%)
         occurrences all number
    13
    19
    Leukopenia
         subjects affected / exposed
    12 / 166 (7.23%)
    14 / 164 (8.54%)
         occurrences all number
    15
    20
    Increased tendency to bruise
         subjects affected / exposed
    7 / 166 (4.22%)
    10 / 164 (6.10%)
         occurrences all number
    7
    11
    Lymphopenia
         subjects affected / exposed
    6 / 166 (3.61%)
    18 / 164 (10.98%)
         occurrences all number
    7
    27
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    39 / 166 (23.49%)
    34 / 164 (20.73%)
         occurrences all number
    54
    46
    Diarrhoea
         subjects affected / exposed
    25 / 166 (15.06%)
    24 / 164 (14.63%)
         occurrences all number
    33
    31
    Vomiting
         subjects affected / exposed
    25 / 166 (15.06%)
    21 / 164 (12.80%)
         occurrences all number
    29
    27
    Abdominal pain upper
         subjects affected / exposed
    11 / 166 (6.63%)
    10 / 164 (6.10%)
         occurrences all number
    12
    13
    Constipation
         subjects affected / exposed
    11 / 166 (6.63%)
    11 / 164 (6.71%)
         occurrences all number
    11
    11
    Dyspepsia
         subjects affected / exposed
    5 / 166 (3.01%)
    10 / 164 (6.10%)
         occurrences all number
    6
    12
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    19 / 166 (11.45%)
    13 / 164 (7.93%)
         occurrences all number
    26
    17
    Pruritus
         subjects affected / exposed
    10 / 166 (6.02%)
    10 / 164 (6.10%)
         occurrences all number
    15
    11
    Alopecia
         subjects affected / exposed
    7 / 166 (4.22%)
    12 / 164 (7.32%)
         occurrences all number
    7
    12
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    3 / 166 (1.81%)
    9 / 164 (5.49%)
         occurrences all number
    3
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    31 / 166 (18.67%)
    36 / 164 (21.95%)
         occurrences all number
    42
    48
    Muscle spasms
         subjects affected / exposed
    18 / 166 (10.84%)
    37 / 164 (22.56%)
         occurrences all number
    23
    47
    Back pain
         subjects affected / exposed
    16 / 166 (9.64%)
    22 / 164 (13.41%)
         occurrences all number
    16
    22
    Myalgia
         subjects affected / exposed
    16 / 166 (9.64%)
    22 / 164 (13.41%)
         occurrences all number
    17
    25
    Pain in extremity
         subjects affected / exposed
    13 / 166 (7.83%)
    13 / 164 (7.93%)
         occurrences all number
    13
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    25 / 166 (15.06%)
    30 / 164 (18.29%)
         occurrences all number
    38
    46
    Upper respiratory tract infection
         subjects affected / exposed
    24 / 166 (14.46%)
    24 / 164 (14.63%)
         occurrences all number
    28
    33
    Urinary tract infection
         subjects affected / exposed
    12 / 166 (7.23%)
    23 / 164 (14.02%)
         occurrences all number
    19
    33
    Pneumonia
         subjects affected / exposed
    11 / 166 (6.63%)
    11 / 164 (6.71%)
         occurrences all number
    12
    11
    Sinusitis
         subjects affected / exposed
    10 / 166 (6.02%)
    12 / 164 (7.32%)
         occurrences all number
    10
    12
    Bronchitis
         subjects affected / exposed
    5 / 166 (3.01%)
    10 / 164 (6.10%)
         occurrences all number
    7
    11
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    12 / 166 (7.23%)
    20 / 164 (12.20%)
         occurrences all number
    13
    21

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jun 2017
    Administrative and editorial changes were made throughout. Relevant sections were revised to: • Indicate some changes regarding eligibility assessment • Indicate that the modified Schwartz equation is used to calculate eGFR for adolescents • Clarify that subjects may receive oral glucocorticoids if required • Indicate that enteric coated mycophenolate sodium would be allowed if mycophenolate mofetil was not tolerated/not available for use • Indicate that atovaquone may also be used for prophylaxis against Pneumocystis jirovecii infections • Update to be consistent with the guidance in the IB regarding laboratory abnormalities • Add that oral cyclophosphamide doses would be rounded down to the nearest 25 mg (or 50 mg if not available) Multiple changes were made to comply with requests from Regulatory agencies and Ethics Committees globally: • Indicated stratification factors were used as factors for the minimization algorithm • Definitions added for “women of childbearing potential” and “postmenopausal” • Inclusion criteria #2 and #19 were revised • Added urine pregnancy tests at Weeks 20, 32, and 45 • Referred Investigators to the side effect profile of prednisone and to the prescribing information for prednisone • Added a benefit and risk assessment section • Serious infections were added to the list of SAEs/AEs leading to withdrawal • Statements were added to indicate that: - Subjects who relapsed might require additional immunosuppressive therapy, and subjects who had a Grade 3< AE possibly related to study medication needed to be suspended until the event has resolved - Dosing regimens of prednisone, cyclophosphamide, rituximab, azathioprine, and mycophenolate were in line with current SOC - Lab reports indicating abnormalities for all subjects would be provided to Investigators - Clarify early study termination - All substantial protocol amendments had to be approved by the Competent Authorities prior to implementation
    15 Jun 2018
    • Study center visits were increased to implement additional monitoring for potential hepatotoxicity, as recommended by the DMC. • Instruction provided for actions to be taken if a subject develops a Grade 3 or higher AE considered possibly related to study medication to allow additional monitoring for potential hepatotoxicity, as recommended by the DMC. • Clarified that a relapse does not comprise treatment failure prior to Week 26. • Included guidance to the Investigators that in addition to events needing to be clearly documented in the EDC, that all local and national vaccination recommendations should be followed. • Clinical evaluations updated to include AEs and potential risks identified by the DMC based on review of unblinded safety data.
    06 Dec 2018
    Amended to include an open-label extension study; however, the sponsor decided not to proceed with the open-label extension study.
    18 Jan 2019
    • Deleted “first morning” in First morning UACR, random void was acceptable and first morning void was not necessary. • The definition of ITT population and treatment failures were amended to align with definition in the Statistical Analysis Plan. • Added hematology for study weeks 23, 29, 35, 42, and 48 and that the blood samples were to be collected for shipment to the central laboratory. • Section 4.4 Removal of Subjects from Therapy of Assessment was updated to add language on pausing for Grade 2 neutropenia and also provided further details on transaminase elevations that were in the previously issued (June 2018) safety notification letter. • Section 7.2.4.6 Laboratory Abnormalities was updated to incorporate recommendations of the DMC and rules for pausing administration of blinded study drug. • Clinical Evaluation was updated based on DMC review of unblinded safety data from all completed and ongoing studies of avacopan.

    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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