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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Safety and Efficacy of Avacopan (CCX168) in Patients with C3 Glomerulopathy

    Summary
    EudraCT number
    2017-001821-42
    Trial protocol
    GB   BE   DE   NL   ES   DK   FR   IT   IE  
    Global end of trial date
    27 Oct 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Jul 2023
    First version publication date
    15 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL011_168
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND Number: 132 321
    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., +1 650 210 2900, clinicaltrials@chemocentryx.com
    Scientific contact
    Clinical trial disclosure, ChemoCentryx, Inc., +1 650 210 2900, clinicaltrials@chemocentryx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2021
    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 avacopan compared to placebo based on histologic changes in kidney biopsies taken before and during treatment.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and with all applicable laws and regulations of the locale and country where the study was conducted, and in compliance with Good Clinical Practice Guidelines. Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. The rationale of the study, procedural details, and investigational goals were explained to each subject, along with potential risks and benefits. Each subject was assured of his/her right to withdraw from the study at any time.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Sep 2017
    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: 6
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Ireland: 6
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    57
    EEA total number of subjects
    27
    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)
    2
    Adults (18-64 years)
    51
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 104 subjects screened.

    Period 1
    Period 1 title
    Blinded treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo Group
    Arm description
    Avacopan matching placebo Subjects with Elevated C5b-9 (> 244 ng/mL) and combined C5b-9 (elevated [> 244 ng/mL] and non-elevated C5b-9) in the ITT Population. ITT Population: included all randomized subjects who received at least one dose of study medication; subjects with a histologic activity score of 0 at baseline or who were ongoing and had not completed the Week 26 visit were not included in the ITT population.
    Arm type
    Placebo

    Investigational medicinal product name
    Avacopan Matching Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo capsules x 3 administered twice daily during the 26-week blinded treatment period

    Arm title
    Avacopan Group
    Arm description
    Avacopan (formerly CCX168) Subjects with Elevated C5b-9 (> 244 ng/mL) and combined C5b-9 (elevated [> 244 ng/mL] and non-elevated C5b-9) in the ITT Population. ITT Population: included all randomized subjects who received at least one dose of study medication; subjects with a histologic activity score of 0 at baseline or who were ongoing and had not completed the Week 26 visit were not included in the ITT population
    Arm type
    Experimental

    Investigational medicinal product name
    Avacopan
    Investigational medicinal product code
    Other name
    CCX168
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Avacopan (formerly CCX168) 10 mg capsules x 3 administered twice daily during the blinded 26-week blinded treatment period

    Number of subjects in period 1
    Placebo Group Avacopan Group
    Started
    29
    28
    Completed
    25
    22
    Not completed
    4
    6
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    1
    2
         Other
    2
    1
         Investigator Decision
    1
    -
         Lost to follow-up
    -
    1
         Sponsor decision
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo Group
    Reporting group description
    Avacopan matching placebo Subjects with Elevated C5b-9 (> 244 ng/mL) and combined C5b-9 (elevated [> 244 ng/mL] and non-elevated C5b-9) in the ITT Population. ITT Population: included all randomized subjects who received at least one dose of study medication; subjects with a histologic activity score of 0 at baseline or who were ongoing and had not completed the Week 26 visit were not included in the ITT population.

    Reporting group title
    Avacopan Group
    Reporting group description
    Avacopan (formerly CCX168) Subjects with Elevated C5b-9 (> 244 ng/mL) and combined C5b-9 (elevated [> 244 ng/mL] and non-elevated C5b-9) in the ITT Population. ITT Population: included all randomized subjects who received at least one dose of study medication; subjects with a histologic activity score of 0 at baseline or who were ongoing and had not completed the Week 26 visit were not included in the ITT population

    Reporting group values
    Placebo Group Avacopan Group Total
    Number of subjects
    29 28 57
    Age categorical
    Units: Subjects
        12-17 years
    2 0 2
        18-50 years
    20 23 43
        51-65 years
    4 4 8
        >65 years
    3 1 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    37.2 ± 17.53 32.2 ± 15.03 -
    Gender categorical
    Units: Subjects
        Female
    13 9 22
        Male
    16 19 35
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    4 2 6
        Not Hispanic or Latino
    25 26 51
    Race
    Units: Subjects
        Asian
    3 2 5
        Black or African American
    0 1 1
        White
    25 24 49
        Unknown or Not Reported
    1 1 2
    Region of Enrollment
    Units: Subjects
        Canada
    2 3 5
        Netherlands
    5 1 6
        Belgium
    1 2 3
        United States
    10 11 21
        Ireland
    3 3 6
        Denmark
    1 1 2
        Italy
    1 0 1
        United Kingdom
    2 2 4
        Germany
    2 1 3
        Spain
    2 4 6
    Geographic Region
    Units: Subjects
        North America
    12 14 26
        Rest of World
    17 14 31
    C3GN or DDD
    C3GN=C3 Glomerulonephritis; DDD=Dense Deposit Missing refers to one subject for whom disease type (C3GN vs DDD) could not be determined and subject was randomized in error.
    Units: Subjects
        C3GN
    25 23 48
        DDD
    4 4 8
        Missing
    0 1 1
    History of Kidney Transplant
    Missing refers to one subject for whom disease type (C3GN vs DDD) could not be determined and subject was randomized in error.
    Units: Subjects
        Yes
    2 1 3
        No
    27 26 53
        Missing
    0 1 1
    C5b-9 Stratum
    C5b-9 levels <= 244 ng/mL were normal according to the central laboratory used for the study. Defined by assay normal range.
    Units: Subjects
        > 244 ng/mL
    22 21 43
        <= 244 ng/mL
    7 7 14
    UPCR (g/g)
    UPCR=Urine Protein to Creatinine Ratio Urine protein-to-creatinine ratio (UPCR): UPCR was calculated by dividing the level of protein in a spot urine test by the creatinine level. UPCR estimates the 24-hour protein excretion in grams per day and is used in clinical practice and clinical trials to measure the severity of proteinuria in patients.
    Units: Subjects
        > 1 g/g
    21 22 43
        <= 1 g/g
    8 6 14
    Viral Test Results HIV-1/2 Antibody
    HIV=Human Immunodeficiency Virus
    Units: Subjects
        Reactive
    0 0 0
        Non-reactive
    29 28 57
    Viral Test Results - Hepatitis B Virus Surface Antigen
    Units: Subjects
        Reactive
    0 0 0
        Non-reactive
    29 28 57
    Viral Test Results - Hepatitis C Virus Antibody
    Units: Subjects
        Reactive
    0 1 1
        Non-reactive
    29 27 56
    Age at Diagnosis of C3G
    C3G=C3 Glomerulopathy
    Units: years
        arithmetic mean (standard deviation)
    33.3 ± 17.95 28.2 ± 17.08 -
    Duration of C3G
    Calculated from the time of first diagnosis based on renal biopsy. C3G=C3 glomerulopathy
    Units: months
        arithmetic mean (standard deviation)
    46.7 ± 43.78 48.2 ± 46.38 -
    eGFR
    eGFR=estimated Glomerular Filtration Rate
    Units: mL/ min/1.73m²
        arithmetic mean (standard deviation)
    72.34 ± 43.509 79.29 ± 39.751 -
    UPCR
    UPCR=Urine Protein to Creatinine Ratio Urine protein-to-creatinine ratio (UPCR): UPCR was calculated by dividing the level of protein in a spot urine test by the creatinine level. UPCR estimates the 24-hour protein excretion in grams per day and is used in clinical practice and clinical trials to measure the severity of proteinuria in patients.
    Units: g/g
        arithmetic mean (standard deviation)
    2.80 ± 2.435 4.11 ± 3.380 -
    Urinary MCP-1:Creatinine Ratio
    2 patients missed baseline Urinary MCP-1 data. Placebo group= 28 participants Avacopan group= 27 participants
    Units: pg/mg Creatinine
        arithmetic mean (standard deviation)
    750.29 ± 492.542 1215.88 ± 1303.35 -
    Body Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    72.65 ± 12.631 78.33 ± 19.229 -
    Height
    Units: centimetre(s)
        arithmetic mean (standard deviation)
    171.41 ± 8.773 173.82 ± 10.805 -
    BMI
    BMI=Body Mass Index
    Units: kilogram(s)/ square meter
        arithmetic mean (standard deviation)
    24.65 ± 3.410 26.05 ± 6.375 -
    EQ-5D-5L Index Score
    EQ-5D-5L=EuroQuality of Life-5 Domains-5 Levels The EQ-5D-5L consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The answers given can be converted into an Index Score ranging from 0 for death to 1 for perfect health.
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.88 ± 0.145 0.87 ± 0.116 -
    EQ-5D-5L VAS Score
    EQ-5D-5L=EuroQuality of Life-5 Domains-5 Levels VAS=Visual Analog Scale The EQ-5D-5L consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D questionnaire includes a Visual Analog Scale (VAS), by which respondents can report their perceived health status with a grade ranging from 0 (the worst imaginable health) to 100 (the best imaginable health).
    Units: units on a scale
        arithmetic mean (standard deviation)
    78.83 ± 20.604 73.61 ± 19.070 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo Group
    Reporting group description
    Avacopan matching placebo Subjects with Elevated C5b-9 (> 244 ng/mL) and combined C5b-9 (elevated [> 244 ng/mL] and non-elevated C5b-9) in the ITT Population. ITT Population: included all randomized subjects who received at least one dose of study medication; subjects with a histologic activity score of 0 at baseline or who were ongoing and had not completed the Week 26 visit were not included in the ITT population.

    Reporting group title
    Avacopan Group
    Reporting group description
    Avacopan (formerly CCX168) Subjects with Elevated C5b-9 (> 244 ng/mL) and combined C5b-9 (elevated [> 244 ng/mL] and non-elevated C5b-9) in the ITT Population. ITT Population: included all randomized subjects who received at least one dose of study medication; subjects with a histologic activity score of 0 at baseline or who were ongoing and had not completed the Week 26 visit were not included in the ITT population

    Primary: Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Subjects With Elevated C5b-9

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    End point title
    Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Subjects With Elevated C5b-9
    End point description
    Change from baseline to Week 26 in the biopsy-based C3G Histologic Index for disease activity - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. C3G Histological Index for Disease Activity Scores can range from 0 to 21. A decrease indicates improvement. C3G=C3 glomerulopathy
    End point type
    Primary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    21
    19
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -0.9 (-2.2 to 0.4)
    -1.0 (-2.3 to 0.4)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Statistical Analysis 1 for Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Subjects With Elevated C5b-9
    Comparison groups
    Placebo Group v Avacopan Group
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.967
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    1.8

    Primary: Percent Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Combined C5b-9 Strata

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    End point title
    Percent Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Combined C5b-9 Strata
    End point description
    Percent change from baseline to Week 26 in the biopsy-based C3G Histologic Index for disease activity - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. C3G Histological Index for Disease Activity Scores can range from 0 to 21. A decrease indicates improvement. C3G=C3 glomerulopathy * Multiple Imputation: Missing Week 26 values are imputed using the regression method to create 100 complete datasets.
    End point type
    Primary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    26
    26
    Units: Percentage change
        arithmetic mean (standard error)
    26.20 ± 47.302
    -5.77 ± 5.904
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Statistical Analysis 1 for Percent Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity -Combined C5b-9 Strata
    Comparison groups
    Avacopan Group v Placebo Group
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3083 [1]
    Method
    Van Elteren's Test
    Parameter type
    Mean difference (final values)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -108.83
         upper limit
    67.16
    Notes
    [1] - Test for normality showed that mean change and mean percent change were not normally distributed. Van Elteren's test was then applied to test mean percent change.

    Secondary: Proportion of Subjects Who Have a Histologic Response Defined as a Decrease (Improvement) in the Biopsy-based C3G Histologic Index for Activity of at Least 35% From Baseline to 26 Weeks - Subjects With Elevated C5b-9

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    End point title
    Proportion of Subjects Who Have a Histologic Response Defined as a Decrease (Improvement) in the Biopsy-based C3G Histologic Index for Activity of at Least 35% From Baseline to 26 Weeks - Subjects With Elevated C5b-9
    End point description
    Proportion of subjects who have a histologic response defined as a decrease (improvement) in the biopsy-based C3G Histologic Index for activity of at least 35% from baseline to 26 weeks - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. C3G Histological Index for Disease Activity Scores can range from 0 to 21. A decrease indicates improvement. C3G=C3 glomerulopathy
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    20
    18
    Units: Participants
        Responder
    4
    2
        Non-Responder
    16
    16
    No statistical analyses for this end point

    Secondary: Proportion of Subjects Who Have a Histologic Response Defined as a Decrease (Improvement) in the Biopsy-based C3G Histologic Index for Activity of at Least 35% From Baseline to 26 Weeks - Combined C5b-9 Strata

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    End point title
    Proportion of Subjects Who Have a Histologic Response Defined as a Decrease (Improvement) in the Biopsy-based C3G Histologic Index for Activity of at Least 35% From Baseline to 26 Weeks - Combined C5b-9 Strata
    End point description
    Proportion of subjects who have a histologic response defined as a decrease (improvement) in the biopsy-based C3G Histologic Index for activity of at least 35% from baseline to 26 weeks - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. C3G Histological Index for Disease Activity Scores can range from 0 to 21. A decrease indicates improvement. C3G=C3 glomerulopathy
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    25
    25
    Units: Participants
        Responder
    7
    4
        Non-Responder
    18
    21
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 26 in the C3G Histologic Index for Disease Chronicity - Subjects With Elevated C5b-9

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    End point title
    Change From Baseline to Week 26 in the C3G Histologic Index for Disease Chronicity - Subjects With Elevated C5b-9
    End point description
    Change from baseline to Week 26 in the biopsy-based C3G Histologic Index for disease chronicity over the placebo-controlled treatment period - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. C3G Histological Index for Disease Chronicity Scores can range from 0 to 10. A decrease indicates improvement. C3G=C3 glomerulopathy
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    21
    19
    Units: score on a scale
        least squares mean (confidence interval 95%)
    1.5 (0.9 to 2.2)
    1.1 (0.3 to 1.8)
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 26 in the C3G Histologic Index for Disease Chronicity - Combined C5b-9 Strata

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    End point title
    Change From Baseline to Week 26 in the C3G Histologic Index for Disease Chronicity - Combined C5b-9 Strata
    End point description
    Change from baseline to Week 26 in the biopsy-based C3G Histologic Index for disease chronicity over the placebo-controlled treatment period - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. C3G Histological Index for Disease Chronicity Scores can range from 0 to 10. A decrease indicates improvement. C3G=C3 glomerulopathy
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    26
    26
    Units: score on a scale
        least squares mean (confidence interval 95%)
    1.6 (1.1 to 2.2)
    0.8 (0.2 to 1.4)
    No statistical analyses for this end point

    Secondary: Renal Function as Assessed by Percent Change From Baseline Over 26 Weeks in eGFR - Subjects With Elevated C5b-9

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    End point title
    Renal Function as Assessed by Percent Change From Baseline Over 26 Weeks in eGFR - Subjects With Elevated C5b-9
    End point description
    The percent change from baseline over 26 weeks in estimated Glomerular Filtration Rate (eGFR) - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    20
    18
    Units: Percentage change
        least squares mean (confidence interval 95%)
    -4.73 (-12.29 to 2.83)
    6.11 (-1.86 to 14.08)
    No statistical analyses for this end point

    Secondary: Renal Function as Assessed by Percent Change From Baseline Over 26 Weeks in eGFR - Combined C5b-9 Strata

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    End point title
    Renal Function as Assessed by Percent Change From Baseline Over 26 Weeks in eGFR - Combined C5b-9 Strata
    End point description
    The percent change from baseline over 26 weeks in estimated Glomerular Filtration Rate (eGFR) - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    25
    25
    Units: Percentage change
        least squares mean (confidence interval 95%)
    -5.88 (-12.32 to 0.56)
    4.79 (-1.66 to 11.23)
    No statistical analyses for this end point

    Secondary: Renal Function as Assessed by Change From Baseline Over 26 Weeks in eGFR - Subjects With Elevated C5b-9

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    End point title
    Renal Function as Assessed by Change From Baseline Over 26 Weeks in eGFR - Subjects With Elevated C5b-9
    End point description
    The change from baseline over 26 weeks in estimated Glomerular Filtration Rate (eGFR) - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    20
    18
    Units: mL/min/1.73m²
        least squares mean (confidence interval 95%)
    -3.57 (-8.43 to 1.29)
    0.44 (-4.69 to 5.56)
    No statistical analyses for this end point

    Secondary: Renal Function as Assessed by Change From Baseline Over 26 Weeks in eGFR - Combined C5b-9 Strata

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    End point title
    Renal Function as Assessed by Change From Baseline Over 26 Weeks in eGFR - Combined C5b-9 Strata
    End point description
    The change from baseline over 26 weeks in estimated Glomerular Filtration Rate (eGFR) - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    25
    25
    Units: mL/min/1.73m²
        least squares mean (confidence interval 95%)
    -3.35 (-7.56 to 0.85)
    0.47 (-3.75 to 4.68)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline Over 26 Weeks in UPCR in Patients With Abnormal UPCR at Baseline - Subjects With Elevated C5b-9

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    End point title
    Percent Change From Baseline Over 26 Weeks in UPCR in Patients With Abnormal UPCR at Baseline - Subjects With Elevated C5b-9
    End point description
    Percent change from baseline Over 26 Weeks in UPCR in patients with Abnormal UPCR at Baseline (>= 0.15 g/g) - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. LSM=Least Squares Mean; UPCR = Urine Protein:Creatinine Ratio
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    20
    18
    Units: Percentage change
        least squares mean (confidence interval 95%)
    -14 (-34 to 12)
    -16 (-36 to 12)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline Over 26 Weeks in UPCR in Patients With Abnormal UPCR at Baseline - Combined C5b-9 Strata

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    End point title
    Percent Change From Baseline Over 26 Weeks in UPCR in Patients With Abnormal UPCR at Baseline - Combined C5b-9 Strata
    End point description
    Percent change from baseline Over 26 Weeks in UPCR in patients with Abnormal UPCR at Baseline (>= 0.15 g/g) - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. LSM=Least Squares Mean; UPCR = Urine Protein: Creatinine Ratio
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    25
    24
    Units: Percentage change
        least squares mean (confidence interval 95%)
    -14 (-33 to 10)
    -26 (-42 to -6)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline Over 26 Weeks in Urinary MCP-1 - Subjects With Elevated C5b-9

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    End point title
    Percent Change From Baseline Over 26 Weeks in Urinary MCP-1 - Subjects With Elevated C5b-9
    End point description
    Percent change from baseline over 26 weeks in urinary MCP-1: creatinine ratio - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. LSM=Least Squares Mean; MCP-1=Monocyte Chemoattractant Protein-1
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    19
    17
    Units: Percentage change
        least squares mean (confidence interval 95%)
    1 (-18 to 25)
    -23 (-39 to -4)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline Over 26 Weeks in Urinary MCP-1 - Combined C5b-9 Strata

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    End point title
    Percent Change From Baseline Over 26 Weeks in Urinary MCP-1 - Combined C5b-9 Strata
    End point description
    Percent change from baseline over 26 weeks in urinary MCP-1: creatinine ratio - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. LSM=Least Squares Mean; MCP-1=Monocyte Chemoattractant Protein-1
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    24
    23
    Units: Percentage change
        least squares mean (confidence interval 95%)
    1 (-17 to 23)
    -12 (-28 to 7)
    No statistical analyses for this end point

    Secondary: Change From Baseline Over 26 Weeks in EQ-5D-5L Health Scale VAS and Index Score - Subjects With Elevated C5b-9

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    End point title
    Change From Baseline Over 26 Weeks in EQ-5D-5L Health Scale VAS and Index Score - Subjects With Elevated C5b-9
    End point description
    Change from baseline over 26 weeks in EQ-5D-5L Health Scale VAS and Index Score - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. EQ-5D-5L: EuroQuality of Life-5 Domains-5 Levels. The EQ-5D-5L consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The answers given can be converted into an Index Score ranging from 0 for death to 1 for perfect health. The EQ-5D questionnaire also includes a Visual Analog Scale (VAS), by which respondents can report their perceived health status with a grade ranging from 0 (the worst imaginable health) to 100 (the best imaginable health).
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    20
    18
    Units: score on a scale
    least squares mean (confidence interval 95%)
        EQ-5D-5L VAS Score
    -3.5 (-7.8 to 0.8)
    -1.9 (-6.4 to 2.7)
        EQ-5D-5L Index Score
    0.0220 (-0.0206 to 0.0647)
    -0.0202 (-0.0653 to 0.0249)
    No statistical analyses for this end point

    Secondary: Change From Baseline Over 26 Weeks in EQ-5D-5L Health Scale VAS and Index Score - Combined C5b-9 Strata

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    End point title
    Change From Baseline Over 26 Weeks in EQ-5D-5L Health Scale VAS and Index Score - Combined C5b-9 Strata
    End point description
    Change from baseline over 26 weeks in EQ-5D-5L Health Scale VAS and Index Score - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. EQ-5D-5L: EuroQuality of Life-5 Domains-5 Levels. The EQ-5D-5L consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The answers given can be converted into an Index Score ranging from 0 for death to 1 for perfect health. The EQ-5D questionnaire also includes a Visual Analog Scale (VAS), by which respondents can report their perceived health status with a grade ranging from 0 (the worst imaginable health) to 100 (the best imaginable health).
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    25
    25
    Units: score on a scale
    least squares mean (confidence interval 95%)
        EQ-5D-5L VAS Score
    0.1 (-3.9 to 4.2)
    -1.9 (-6.0 to 2.2)
        EQ-5D-5L Index Score
    0.0060 (-0.0334 to 0.0454)
    -0.0138 (-0.0533 to 0.0256)
    No statistical analyses for this end point

    Secondary: Change From Baseline Over 26 Weeks in SF-36 v2 - Subjects With Elevated C5b-9

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    End point title
    Change From Baseline Over 26 Weeks in SF-36 v2 - Subjects With Elevated C5b-9
    End point description
    Change from baseline over 26 weeks in SF-36 v2 - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. SF-36v2: Medical Outcomes Survey Short Form-36 version 2. SF-36v2 measures each of the following eight health domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Scores on each item are summed and averaged. The SF-36v2 component domain scores range from 0 (worst health) to 100 (best health)
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    21 [2]
    19 [3]
    Units: score on a scale
    least squares mean (confidence interval 95%)
        SF-36v2: Physical Functioning
    2.8518 (-3.2409 to 8.9446)
    3.2197 (-3.3108 to 9.7502)
        SF-36v2: Role-Physical
    -4.2592 (-11.5984 to 3.0801)
    3.5162 (-4.2634 to 11.2958)
        SF-36v2: Bodily Pain
    3.6 (-4.2 to 11.4)
    -3.5 (-12.0 to 4.9)
        SF-36v2: General Health Perceptions
    -0.9 (-7.0 to 5.2)
    1.6 (-4.8 to 8.0)
        SF-36v2: Vitality
    -2.472 (-8.906 to 3.963)
    3.898 (-2.978 to 10.774)
        SF-36v2: Social Functioning
    4.58 (-2.30 to 11.47)
    0.34 (-7.20 to 7.88)
        SF-36v2: Role-Emotional
    0.6859 (-6.8507 to 8.2225)
    3.2461 (-4.6899 to 11.1821)
        SF-36v2: Mental Health
    2.423 (-3.684 to 8.530)
    2.730 (-3.791 to 9.251)
        SF-36v2: Mental Component
    0.7556 (-2.3560 to 3.8672)
    0.7608 (-2.6341 to 4.1558)
        SF-36v2: Physical Component
    -0.3257 (-2.6090 to 1.9576)
    0.0762 (-2.4423 to 2.5947)
    Notes
    [2] - All categories have 20 participants except SF-36v2: General Health Perceptions with 19.
    [3] - All categories have 18 participants except SF-36v2: Bodily Pain and Social Functioning with 17.
    No statistical analyses for this end point

    Secondary: Change From Baseline Over 26 Weeks in SF-36 v2 - Combined C5b-9 Strata

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    End point title
    Change From Baseline Over 26 Weeks in SF-36 v2 - Combined C5b-9 Strata
    End point description
    Change from baseline over 26 weeks in SF-36 v2 - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. SF-36v2: Medical Outcomes Survey Short Form-36 version 2. SF-36v2 measures each of the following eight health domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Scores on each item are summed and averaged. The SF-36v2 component domain scores range from 0 (worst health) to 100 (best health).
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    26 [4]
    26 [5]
    Units: score on a scale
    least squares mean (confidence interval 95%)
        SF-36v2: Physical Functioning
    2.9619 (-2.7150 to 8.6389)
    4.6532 (-1.1123 to 10.4187)
        SF-36v2: Role-Physical
    -2.4712 (-9.6179 to 4.6755)
    1.2077 (-5.9734 to 8.3887)
        SF-36v2: Bodily Pain
    1.5 (-5.7 to 8.7)
    -2.0 (-9.3 to 5.4)
        SF-36v2: General Health Perceptions
    -1.0 (-6.6 to 4.6)
    0.7 (-4.9 to 6.2)
        SF-36v2: Vitality
    -0.468 (-6.283 to 5.348)
    4.085 (-1.782 to 9.952)
        SF-36v2: Social Functioning
    4.66 (-1.41 to 10.73)
    1.55 (-4.66 to 7.76)
        SF-36v2: Role-Emotional
    4.3024 (-3.3147 to 11.9195)
    7.8375 (0.2129 to 15.4620)
        SF-36v2: Mental Health
    1.503 (-3.911 to 6.917)
    3.914 (-1.543 to 9.370)
        SF-36v2: Mental Component
    1.3591 (-1.7970 to 4.5153)
    2.3874 (-0.8529 to 5.6277)
        SF-36v2: Physical Component
    -0.3578 (-2.5452 to 1.8296)
    -0.5096 (-2.7680 to 1.7489)
    Notes
    [4] - All categories have 25 participants except SF-36v2: General Health Perceptions with 24 participants
    [5] - All categories have 25 participants except SF-36v2: Bodily Pain and Social Functioning with 24.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent SAEs, AEs, Relatedness to Study Medication and Withdrawals Due to AEs

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    End point title
    Number of Subjects With Treatment-emergent SAEs, AEs, Relatedness to Study Medication and Withdrawals Due to AEs
    End point description
    Number of Subjects with Treatment-emergent SAEs, AEs, relatedness to study medication and Withdrawals Due to AEs AEs=Adverse events SAEs=Serious adverse events TEAE=Treatment-emergent adverse events ‘Possibly related’ refers to the Investigators’ causality assessment Safety Population: The safety population included all subjects who were randomized and had received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From day 1 throughout the study period (day 182/week 26)
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    29
    28
    Units: Participants
        Number of subjects with at least one TEAE
    24
    25
        Number of subjects with SAEs
    3
    3
        Subjects with TEAEs related to Study Medication
    11
    10
        Subjects with TEAEs leading to discontinuation
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Treatment-emergent SAEs, AEs, Relatedness to Study Medication and Withdrawals Due to AEs

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    End point title
    Number of Treatment-emergent SAEs, AEs, Relatedness to Study Medication and Withdrawals Due to AEs
    End point description
    Number of Treatment-emergent SAEs, AEs, relatedness to study medication and Withdrawals Due to AEs AEs=Adverse events SAEs=Serious adverse events TEAE=Treatment-emergent adverse events ‘Possibly related’ refers to the Investigators’ causality assessment Safety Population: The safety population included all subjects who were randomized and had received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From day 1 throughout the study period (day 182/week 26)
    End point values
    Placebo Group Avacopan Group
    Number of subjects analysed
    29
    28
    Units: Participants
        Number of TEAEs
    107
    149
        Number of SAEs
    4
    6
        TEAEs possibly related to Study Medication
    24
    38
        Number of TEAEs leading to discontinuation
    2
    2
    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 182/week 26)
    Adverse event reporting additional description
    An adverse event is considered treatment-emergent if the start date/time of the event is on or after the date/ time of first study drug treatment up to the final observation in the double-blind treatment period (week 26).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo Group
    Reporting group description
    Avacopan-matching placebo capsules x 3 administered twice daily during the 26 week blinded treatment period Avacopan-matching placebo: Orally administered The safety population included all subjects who were randomized and had received at least one dose of study drug.

    Reporting group title
    Avacopan Group
    Reporting group description
    Avacopan (formerly CCX168) 10 mg capsules x 3 administered twice daily during the blinded 26 week blinded treatment period Avacopan: Orally administered The safety population included all subjects who were randomized and had received at least one dose of study drug.

    Serious adverse events
    Placebo Group Avacopan Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 28 (10.71%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Sjogren's syndrome
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial parotitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Group Avacopan Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 29 (82.76%)
    25 / 28 (89.29%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 28 (10.71%)
         occurrences all number
    3
    4
    Orthostatic hypotension
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    3
    Oedema peripheral
         subjects affected / exposed
    1 / 29 (3.45%)
    5 / 28 (17.86%)
         occurrences all number
    1
    6
    Pyrexia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    4
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 28 (10.71%)
         occurrences all number
    1
    4
    Blood creatine increased
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    3
    Lipase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Weight decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 29 (6.90%)
    5 / 28 (17.86%)
         occurrences all number
    4
    5
    Tremor
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 28 (10.71%)
         occurrences all number
    3
    3
    Lymphopenia
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 28 (3.57%)
         occurrences all number
    3
    1
    Diarrhoea
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 28 (7.14%)
         occurrences all number
    4
    2
    Dyspepsia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Mouth ulceration
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 28 (3.57%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    1 / 29 (3.45%)
    4 / 28 (14.29%)
         occurrences all number
    1
    4
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 28 (3.57%)
         occurrences all number
    3
    1
    Muscle spasms
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Pain in extremity
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 28 (3.57%)
         occurrences all number
    4
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 28 (7.14%)
         occurrences all number
    3
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    3
    Hyperkalaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
         occurrences all number
    2
    2
    Hypokalaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Sep 2017
    Protocol amendment 1 • added 12-lead ECG to screening and safety assessments • added urinary albumin:creatinine ratio (UACR) and protein: creatinine ratio (UPCR) to screening evaluations • clarified that the week 52 biopsy in adolescent subjects was optional and was not a protocol deviation if not collected • added active uncontrolled infection to the exclusion criteria • clarified that pharmacodynamic markers were exploratory endpoints • clarified albuminuria measurement • clarified that it was not necessary to use CTCAE grading for clinical events. CTCAE criteria could be used for severity assessment of lab values. If there was a clinical adverse event related to a lab abnormality, the adverse event was to be reported as the clinical event, where possible. • added a new section to accommodate reports of overdose, misuse and abuse of the investigational medicinal product. All associated adverse events were to be reported as adverse events or serious adverse events using the adverse events electronic case report form (eCRF) and/or the serious adverse event report form. • added instruction that subjects who terminated early from the trial would have serious adverse events recorded at follow-up visits or at least 30 days after last investigational product administration. • added instruction that serious adverse event information should be entered as soon as possible when EDC access is returned.
    16 Apr 2018
    Protocol Amendment 2 • added a secondary population with diagnosed C3G and lower levels of circulating C5b-9 levels which was previously excluded • expanded screening from 4 weeks to 6 weeks • clarified that adolescent subjects were enrolled only in regulatory territories where approval was received, and that the dose in adolescents depended on body weight and avacopan plasma exposure (AUC0-6hr) or avacopan trough concentrations • expanded the number of subjects enrolled in the study from 44 to 88 • added to inclusion criteria that the Investigator would provide assurance that adolescent subjects were willing and able to ingest the size “0” tablet • clarified that CT-scan or chest X-ray was not mandatory, if evidence of tuberculosis was excluded by other methods described • increase the number of lesions to be included in the C3G Histologic Index for disease activity from 4 to 7 • expanded description of the C3G Histologic Index for Activity scoring system using the glomerulopathy histologic score as described by Bomback et al (Bomback et al, 2018) • added text to the statistics methods to accommodate the new C5b-9 strata • added that missing data would be imputed with the last observation carried forward (LOCF). Multiple imputation using other statistical methods could also be performed. • added that the day 183 morning dose for adolescent subjects was to be taken in the clinic rather than at home • added that subjects were to be reminded through a telephone call that the week 52 dose should not be taken. • added that the final 4 PK samples (Weeks 52, 54, 57, 60) were for terminal PK evaluation • added exploratory endpoints around PK parameters and PK/PD relationship • added criteria for potential for early termination of the stratum with C5b 9 levels  244 ng/m • added that PK parameters would be calculated based on plasma concentration for samples collected on both day 1 and day 183 (week 26)
    02 Aug 2018
    Protocol Amendment 3 • added visits at week 23, 35, 41, and 48 per DMC recommendation to increase the frequency of liver testing; data on concomitant medications and Adverse events were to be collected for the added visits • added serum chemistries at week 2, 23, 35, 41, and 48 per DMC recommendation to increase the frequency of liver testing • added that any changes in concomitant medication use were to be recorded per DMC recommendation • added new safety information from an ongoing clinical trial in a different indication to coincide with updated Reference Safety Information in the Investigator’s Brochure • clarified that a follow-up renal biopsy was to be performed within 2 weeks before the week 26 visit and was to be completed before open-label medication was started • added scale to be used for crescent formation and fibrinoid necrosis involvement • clarified hepatic enzyme criteria under which dosing with investigational product would be suspended for that subject during investigation into the causality of abnormal liver tests and criteria for resumption of investigational product.
    20 Mar 2019
    Protocol Amendment 4 • clarified throughout that the investigational product was blinded • increased the duration of the study from 26 to 32 months to accommodate previous increase in sample size and slower than expected enrollment • updated the earliest time point for primary efficacy analysis • increase the frequency of hematology testing per DMC recommendation • clarified time allowed to differentiate between common fluctuations of renal function and true deterioration of renal function to prevent unnecessary discontinuation • clarified that investigational product dosing was paused during investigation of causality of abnormal liver tests, abnormal hematology, and serum chemistry tests and investigational product was to be discontinued, if applicable • updated clinical evaluation to include current clinical status, clarify patient safety information and to include the clinical safety information

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    02 Apr 2020
    Paused screening due to COVID-19
    25 Jun 2020
    02 Oct 2020
    Paused screening to any new participants with analysis of efficacy data and sent confirmation to sites on 12-Feb-2021 following the results of the analysis, no further subjects would be enrolled.
    -

    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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