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    Clinical Trial Results:
    AURORA: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adult Subjects With Nonalcoholic Steatohepatitis

    Summary
    EudraCT number
    		 2016-004566-26
    Trial protocol
    		 BE   PT   AT   ES   HU   GB   PL   SI   GR   LV   IT   RO  
    Global end of trial date
    09 Mar 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Apr 2022
    First version publication date
    20 Jan 2022
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Data added for two secondary endpoints.

    Trial information

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    Trial identification
    Sponsor protocol code
    3152-301-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03028740
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Registro Nacional Estudios Clinicos (RNEC): 1001
    Sponsors
    Sponsor organisation name
    Tobira Therapeutics, a subsidiary of Allergan plc
    Sponsor organisation address
    701 Gateway Blvd, Suite 300, South San Francisco, United States, CA 94080
    Public contact
    Therapeutic Area, Head, Allergan, 001 714-246-4500, IR-CTRegistration@Allergan.com
    Scientific contact
    Therapeutic Area, Head, Allergan, 001 714-246-4500, IR-CTRegistration@Allergan.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
    09 Mar 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The AURORA study was conducted to confirm the efficacy and safety of cenicriviroc (CVC) for the treatment of liver fibrosis in adult participants with Nonalcoholic Steatohepatitis (NASH).
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Apr 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
    Norway: 4
    Country: Number of subjects enrolled
    Poland: 101
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    United Kingdom: 42
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    France: 48
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Australia: 28
    Country: Number of subjects enrolled
    Brazil: 22
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    Hong Kong: 13
    Country: Number of subjects enrolled
    Israel: 29
    Country: Number of subjects enrolled
    Mexico: 25
    Country: Number of subjects enrolled
    New Zealand: 7
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    United States: 1285
    Worldwide total number of subjects
    1778
    EEA total number of subjects
    279
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    1373
    From 65 to 84 years
    405
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 1778 participants were randomized of which 1769 received treatment; 1293 participated in Part 1. The study was terminated early, and Part 2 did not enroll the planned number of participants. Therefore, Part 1 and Part 2 data were combined and reported as the Full Study Cohort for reporting of the Part 2 efficacy endpoints and the safety endpoints.

    Pre-assignment period milestones
    Number of subjects started
    		 1778
    Number of subjects completed
    		 1769

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did Not Receive Study Drug: 9
    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received cenicriviroc placebo-matching, tablet, orally, once daily for up to approximately 40 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cenicriviroc placebo-matching, tablet, orally, once daily for up to approximately 40 months.

    Arm title
    		 Cenicriviroc 150 mg
    Arm description
    		 Participants received cenicriviroc, 150 milligrams (mg), tablet, orally, once daily for up to approximately 40 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cenicriviroc
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cenicriviroc, 150 mg, tablet, orally, once daily for up to approximately 40 months.

    Number of subjects in period 1 [1]
    		Placebo Cenicriviroc 150 mg
    Started
    589
    1180
    Participated in Part 1
    432
    861
    Part 1: Received Study Drug
    429
    859
    Completed
    0
    0
    Not completed
    589
    1180
         Physician decision
    4
    11
         Non-compliance with Study Drug
    -
    2
         Adverse Event
    8
    26
         Protocol-specified Withdrawal Criteria Met
    27
    55
         Withdrawal by Subject
    48
    101
         Protocol Violation
    4
    8
         Study Terminated by Sponsor
    467
    917
         Lost to follow-up
    30
    54
         Reason not Specified
    1
    5
         Lack of efficacy
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline measures are based on the Safety Population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received cenicriviroc placebo-matching, tablet, orally, once daily for up to approximately 40 months.

    Reporting group title
    Cenicriviroc 150 mg
    Reporting group description
    		 Participants received cenicriviroc, 150 milligrams (mg), tablet, orally, once daily for up to approximately 40 months.

    Reporting group values
    		 Placebo Cenicriviroc 150 mg Total
    Number of subjects
    		 589 1180 1769
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 447 918 1365
        From 65-84 years
    		 142 262 404
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.8 ( 11.04 ) 55.2 ( 10.76 ) -
    Gender categorical
    Units: Subjects
        Female
    		 354 749 1103
        Male
    		 235 431 666
    Race
    Units: Subjects
        White
    		 539 1075 1614
        Black or African American
    		 14 38 52
        Asian
    		 22 45 67
        American Indian or Alaska Native
    		 7 8 15
        Native Hawaiian or Other Pacific Islander
    		 2 7 9
        More than one race
    		 3 6 9
        Unknown or Not Reported
    		 2 1 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 172 315 487
        Not Hispanic or Latino
    		 417 865 1282

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received cenicriviroc placebo-matching, tablet, orally, once daily for up to approximately 40 months.

    Reporting group title
    Cenicriviroc 150 mg
    Reporting group description
    		 Participants received cenicriviroc, 150 milligrams (mg), tablet, orally, once daily for up to approximately 40 months.

    Primary: Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages and No Worsening of Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort

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    End point title
    		 Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages and No Worsening of Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort [1]
    End point description
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal; 1A=mild, zone 3, perisinusoidal; 1B=moderate, zone 3, perisinusoidal; 1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant NAS categories. NAS is a semiquantitative scoring system based on the unweighted sum of: steatosis (0=<5% to 3=>66%), lobular inflammation (0=no foci to 3=>4 foci/200x), and hepatocellular ballooning (0=none to 2=many cells/prominent ballooning) scores. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage. mITT Population for the full study cohort included participants randomly assigned to a treatment group who received at least one dose of study drug for Parts 1 and 2 of the study combined.
    End point type
    Primary
    End point timeframe
    Month 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical analysis was planned to be reported for this endpoint.
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    589
    1180
    Units: percentage of participants
        number (confidence interval 95%)
    8.3 (5.9 to 11.1)
    6.8 (5.2 to 8.6)
    No statistical analyses for this end point

    Primary: Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages and No Worsening of Steatohepatitis on Liver Histology at Month 12

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    End point title
    		 Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages and No Worsening of Steatohepatitis on Liver Histology at Month 12
    End point description
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal; 1A=mild, zone 3, perisinusoidal; 1B=moderate, zone 3, perisinusoidal; 1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant NAS categories. NAS is a semiquantitative scoring system based on the unweighted sum of: steatosis (0=<5% to 3=>66%), lobular inflammation (0=no foci to 3=>4 foci/200x), and hepatocellular ballooning (0=none to 2=many cells/prominent ballooning) scores. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage. mITT Population for Part 1 included participants randomly assigned to a treatment group who received at least one dose of study drug in Part 1.
    End point type
    Primary
    End point timeframe
    Month 12
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    429
    859
    Units: percentage of participants
        number (confidence interval 95%)
    8.3 (6.0 to 11.3)
    6.6 (5.1 to 8.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Cenicriviroc 150 mg
    Number of subjects included in analysis
    1288
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2827 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 1.5
    Notes
    [2] - P-value was based on Cochran-Mantel-Haenszel general association test comparing Cenicriviroc vs Placebo, controlling for factors (randomization strata: fibrosis stage [2 vs 3] and presence or absence of T2DM at Baseline).
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Cenicriviroc 150 mg
    Number of subjects included in analysis
    1288
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.7844
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5032
         upper limit
    		 1.2229

    Secondary: Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage and No Worsening of Steatohepatitis on Liver Histology at Month 12

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    End point title
    		 Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage and No Worsening of Steatohepatitis on Liver Histology at Month 12
    End point description
    Fibrosis stage was evaluated using the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal;1A=mild, zone 3, perisinusoidal;1B=moderate, zone 3, perisinusoidal;1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. No worsening of steatohepatitis=no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant nonalcoholic fatty liver disease activity score (NAS) categories. NAS is a semiquantitative scoring system based on the unweighted sum of: steatosis (0=<5% to 3=>66%), lobular inflammation (0=no foci to 3=>4 foci/200x), and hepatocellular ballooning (0=none to 2=many cells/prominent ballooning) scores. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage. mITT Population for Part 1 included participants randomly assigned to a treatment group who received at least one dose of study drug in Part 1.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    429
    859
    Units: percentage of participants
        number (confidence interval 95%)
    25.5 (21.5 to 29.9)
    22.3 (19.6 to 25.2)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Cenicriviroc 150 mg
    Number of subjects included in analysis
    1288
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2067 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.2
         upper limit
    		 1.9
    Notes
    [3] - P-value was based on Cochran-Mantel-Haenszel general association test comparing Cenicriviroc vs Placebo, controlling for factors (randomization strata: fibrosis stage [2 vs 3] and presence or absence of Type 2 diabetes mellitus (T2DM) at Baseline).
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Cenicriviroc 150 mg
    Number of subjects included in analysis
    1288
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8369
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6341
         upper limit
    		 1.1044

    Secondary: Time to First Occurrence of Adjudicated Events in the Full Study Cohort

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    End point title
    		 Time to First Occurrence of Adjudicated Events in the Full Study Cohort
    End point description
    Time to first occurrence from Baseline=number of days from first dose of randomized investigational product to onset of first occurrence of any of following adjudicated events:death(all cause),histopathologic progression to cirrhosis,liver transplant,model for end stage liver disease(MELD)score≥15,ascites,hospitalization for onset of:variceal bleed,hepatic encephalopathy,spontaneous bacterial peritonitis.MELD:scoring system for assessing severity of chronic liver disease and uses participant’s values for total bilirubin,serum creatinine,international normalized ratio for prothrombin time to predict survival.MELD score ranges from 6(less ill) to 40(gravely ill)where score 40=71.3% mortality,9 or less=1.9% mortality. mITT Population for full study cohort: participants randomly assigned to a treatment group who received >=1 dose of study drug in Parts 1 and 2 of study combined. 99999=Median, lower and upper limit of 95% CI were not estimable due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to onset of first occurrence of the event (Up to approximately 42 months)
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    589
    1180
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage Regardless of Effect on Steatohepatitis at Month 12

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    End point title
    		 Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage Regardless of Effect on Steatohepatitis at Month 12
    End point description
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages 0=none, 1=perisinusoidal or periportal, 1A=mild, zone 3, perisinusoidal, 1B=moderate, zone 3, perisinusoidal, 1C=portal/periportal, 2=perisinusoidal and portal/periportal, 3=bridging fibrosis, 4=cirrhosis. mITT Population for Part 1 included participants randomly assigned to a treatment group who received at least one dose of study drug in Part 1. Overall number analyzed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    348
    692
    Units: percentage of participants
        number (confidence interval 95%)
    33.3 (28.6 to 38.4)
    30.6 (27.3 to 34.2)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Cenicriviroc 150 mg
    Number of subjects included in analysis
    1040
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4054 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 3.3
    Notes
    [4] - P-value was based on Cochran-Mantel-Haenszel general association test comparing Cenicriviroc vs Placebo, controlling for factors (randomization strata: fibrosis stage [2 vs 3] and presence or absence of T2DM at Baseline).
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Cenicriviroc 150 mg
    Number of subjects included in analysis
    1040
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8877
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6709
         upper limit
    		 1.1744

    Secondary: Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages Regardless of Effect on Steatohepatitis at Month 12

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    End point title
    		 Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages Regardless of Effect on Steatohepatitis at Month 12
    End point description
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages 0=none, 1=perisinusoidal or periportal, 1A=mild, zone 3, perisinusoidal, 1B=moderate, zone 3, perisinusoidal, 1C=portal/periportal, 2=perisinusoidal and portal/periportal, 3=bridging fibrosis, 4=cirrhosis. mITT Population for Part 1 included participants randomly assigned to a treatment group who received at least one dose of study drug in Part 1. Overall number analyzed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    348
    692
    Units: percentage of participants
        number (not applicable)
    10.3
    8.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage and No Worsening of Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort

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    End point title
    		 Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage and No Worsening of Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort
    End point description
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal; 1A=mild, zone 3, perisinusoidal; 1B=moderate, zone 3, perisinusoidal; 1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant NAS categories. NAS is a semiquantitative scoring system based on the unweighted sum of: steatosis (0=<5% to 3=>66%), lobular inflammation (0=no foci to 3=>4 foci/200x), and hepatocellular ballooning (0=none to 2=many cells/prominent ballooning) scores. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage. mITT Population for the full study cohort included participants randomly assigned to a treatment group who received at least one dose of study drug in Parts 1 and 2 of the study combined.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    589
    1180
    Units: percentage of participants
        number (confidence interval 95%)
    25.0 (21.2 to 29.2)
    22.0 (19.4 to 24.8)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort

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    End point title
    		 Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort
    End point description
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages 0=none, 1=perisinusoidal or periportal, 1A=mild, zone 3, perisinusoidal, 1B=moderate, zone 3, perisinusoidal, 1C=portal/periportal, 2=perisinusoidal and portal/periportal, 3=bridging fibrosis, 4=cirrhosis. mITT Population for the full study cohort included participants randomly assigned to a treatment group who received at least one dose of study drug in Parts 1 and 2 of the study combined. Overall number analyzed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    373
    741
    Units: percentage of participants
        number (confidence interval 95%)
    33.2 (28.7 to 38.2)
    30.5 (27.3 to 33.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort

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    End point title
    		 Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort
    End point description
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages 0=none, 1=perisinusoidal or periportal, 1A=mild, zone 3, perisinusoidal, 1B=moderate, zone 3, perisinusoidal, 1C=portal/periportal, 2=perisinusoidal and portal/periportal, 3=bridging fibrosis, 4=cirrhosis. mITT Population for the full study cohort included participants randomly assigned to a treatment group who received at least one dose of study drug in Parts 1 and 2 of the study combined. Overall number analyzed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    373
    741
    Units: percentage of participants
        number (not applicable)
    9.9
    8.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage and No Worsening of Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort

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    End point title
    		 Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage and No Worsening of Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort
    End point description
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal; 1A=mild, zone 3, perisinusoidal; 1B=moderate, zone 3, perisinusoidal; 1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant NAS categories. NAS is a semiquantitative scoring system based on the unweighted sum of: steatosis (0=<5% to 3=>66%), lobular inflammation (0=no foci to 3=>4 foci/200x), and hepatocellular ballooning (0=none to 2=many cells/prominent ballooning) scores. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage. No data was collected as the study was terminated and no participants reached the Month 60 timepoint.
    End point type
    Secondary
    End point timeframe
    Month 60
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [5] - No data was collected as study was terminated and no participants reached the Month 60 timepoint.
    [6] - No data was collected as study was terminated and no participants reached the Month 60 timepoint.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort

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    End point title
    		 Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort
    End point description
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages 0=none, 1=perisinusoidal or periportal, 1A=mild, zone 3, perisinusoidal, 1B=moderate, zone 3, perisinusoidal, 1C=portal/periportal, 2=perisinusoidal and portal/periportal, 3=bridging fibrosis, 4=cirrhosis. No data was collected as the study was terminated and no participants reached the Month 60 timepoint.
    End point type
    Secondary
    End point timeframe
    Month 60
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [7] - No data was collected as study was terminated and no participants reached the Month 60 timepoint.
    [8] - No data was collected as study was terminated and no participants reached the Month 60 timepoint.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages and No Worsening of Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort

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    End point title
    		 Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages and No Worsening of Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort
    End point description
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal; 1A=mild, zone 3, perisinusoidal; 1B=moderate, zone 3, perisinusoidal; 1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant NAS categories. NAS is a semiquantitative scoring system based on the unweighted sum of: steatosis (0=<5% to 3=>66%), lobular inflammation (0=no foci to 3=>4 foci/200x), and hepatocellular ballooning (0=none to 2=many cells/prominent ballooning) scores. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage. No data was collected as the study was terminated and no participants reached the Month 60 timepoint.
    End point type
    Secondary
    End point timeframe
    Month 60
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [9] - No data was collected as study was terminated and no participants reached the Month 60 timepoint.
    [10] - No data was collected as study was terminated and no participants reached the Month 60 timepoint
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort

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    End point title
    		 Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort
    End point description
    Fibrosis stage was evaluated using NASH CRN Fibrosis Staging System with stages 0=None, 1=Perisinusoidal or periportal, 1A=Mild, zone 3, perisinusoidal, 1B=Moderate, zone 3, perisinusoidal, 1C=Portal/periportal, 2=Perisinusoidal and portal/periportal, 3=Bridging fibrosis, 4=Cirrhosis. No data was collected as the study was terminated and no participants reached the Month 60 timepoint.
    End point type
    Secondary
    End point timeframe
    Month 60
    End point values
    		 Placebo Cenicriviroc 150 mg
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [11] - No data was collected as study was terminated and no participants reached the Month 60 timepoint.
    [12] - No data was collected as study was terminated and no participants reached the Month 60 timepoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose through 30 days after the last dose of study drug (Up to approximately 42 months)
    Adverse event reporting additional description
    Safety Population for the full study cohort included participants who received at least one dose of study drug in Parts 1 and 2 of the study combined.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Cenicriviroc 150 mg
    Reporting group description
    		 Participants received cenicriviroc, 150 milligrams (mg), tablet, orally, once daily for up to approximately 40 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received cenicriviroc placebo-matching, tablet, orally, once daily for up to approximately 40 months.

    Serious adverse events
    		 Cenicriviroc 150 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    159 / 1180 (13.47%)
    70 / 589 (11.88%)
         number of deaths (all causes)
    6
    2
         number of deaths resulting from adverse events
    4
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    3 / 1180 (0.25%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 1180 (0.17%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
    Additional description: Number of participants at risk (exposed) in each arm is based on the male population.
         subjects affected / exposed [1]
    2 / 431 (0.46%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acoustic neuroma
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basosquamous carcinoma
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct cancer
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm benign
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial neoplasm
    Additional description: Number of participants at risk (exposed) in each arm is based on the female population.
         subjects affected / exposed [2]
    1 / 749 (0.13%)
    0 / 354 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leiomyosarcoma
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma of eyelid
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic neuroendocrine tumour
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 1180 (0.00%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 1180 (0.00%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain neoplasm
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
    Additional description: Number of participants at risk (exposed) in each arm is based on the female population.
         subjects affected / exposed [3]
    0 / 749 (0.00%)
    1 / 354 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour of ampulla of Vater
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 1180 (0.08%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebolith
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ruptured ectopic pregnancy
    Additional description: Number of participants at risk (exposed) in each arm is based on the female population.
         subjects affected / exposed [4]
    0 / 749 (0.00%)
    1 / 534 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 1180 (0.34%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 1180 (0.17%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 1180 (0.08%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
    Additional description: Number of participants at risk (exposed) in each arm is based on the male population.
         subjects affected / exposed [5]
    1 / 431 (0.23%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
    Additional description: Number of participants at risk (exposed) in each arm is based on the female population.
         subjects affected / exposed [6]
    1 / 749 (0.13%)
    0 / 354 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polycystic ovaries
    Additional description: Number of participants at risk (exposed) in each arm is based on the female population.
         subjects affected / exposed [7]
    1 / 749 (0.13%)
    0 / 354 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hyperplasia
    Additional description: Number of participants at risk (exposed) in each arm is based on the female population.
         subjects affected / exposed [8]
    0 / 749 (0.00%)
    1 / 354 (0.28%)
         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 embolism
         subjects affected / exposed
    3 / 1180 (0.25%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    2 / 1180 (0.17%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 1180 (0.08%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (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 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 1180 (0.17%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 1180 (0.08%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric decompensation
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serum ferritin increased
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood uric acid increased
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         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 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 1180 (0.17%)
    5 / 589 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    2 / 1180 (0.17%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    2 / 1180 (0.17%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    2 / 1180 (0.17%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    2 / 1180 (0.17%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 1180 (0.08%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural contusion
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural hypotension
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 1180 (0.00%)
    3 / 589 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 1180 (0.00%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia postoperative
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural discomfort
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Snake bite
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
    Additional description: Number of participants at risk (exposed) in each arm is based on the male population.
         subjects affected / exposed [9]
    1 / 431 (0.23%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    4 / 1180 (0.34%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    4 / 1180 (0.34%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    3 / 1180 (0.25%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 1180 (0.25%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 1180 (0.17%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    2 / 1180 (0.17%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    2 / 1180 (0.17%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve disease mixed
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular hypertrophy
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery stenosis
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    3 / 1180 (0.25%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 1180 (0.25%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    2 / 1180 (0.17%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 1180 (0.08%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 1180 (0.08%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain stem infarction
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radial nerve palsy
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersomnia
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood loss anaemia
         subjects affected / exposed
    1 / 1180 (0.08%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenomegaly
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 1180 (0.34%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    6 / 1180 (0.51%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 1180 (0.17%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 1180 (0.17%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 1180 (0.08%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcoholic pancreatitis
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric panniculitis
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 1180 (0.00%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-alcoholic steatohepatitis
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash erythematous
         subjects affected / exposed
    1 / 1180 (0.08%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (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
    Nephrolithiasis
         subjects affected / exposed
    4 / 1180 (0.34%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    3 / 1180 (0.25%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 1180 (0.17%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    2 / 1180 (0.17%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypoparathyroidism
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid mass
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         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
    Back pain
         subjects affected / exposed
    4 / 1180 (0.34%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    2 / 1180 (0.17%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facet joint syndrome
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc displacement
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mixed connective tissue disease
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 1180 (0.00%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 1180 (0.00%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest wall haematoma
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    6 / 1180 (0.51%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 1180 (0.42%)
    4 / 589 (0.68%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    5 / 1180 (0.42%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 1180 (0.34%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 1180 (0.17%)
    5 / 589 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 1180 (0.17%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 1180 (0.08%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 1180 (0.08%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 1180 (0.08%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder empyema
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 1180 (0.00%)
    2 / 589 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster oticus
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval cellulitis
    Additional description: Number of participants at risk (exposed) in each arm is based on the female population.
         subjects affected / exposed [10]
    0 / 749 (0.00%)
    1 / 354 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    2 / 1180 (0.17%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alkalosis hypochloraemic
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alkalosis hypokalaemic
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (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
    1 / 1180 (0.08%)
    0 / 589 (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 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 1180 (0.08%)
    0 / 589 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         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 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    0 / 1180 (0.00%)
    1 / 589 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants exposed in each arm is based on the male population.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants exposed in each arm is based on the female population.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants exposed in each arm is based on the female population.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants exposed in each arm is based on the female population.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants exposed in each arm is based on the male population.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants exposed in each arm is based on the female population.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants exposed in each arm is based on the female population.
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants exposed in each arm is based on the female population.
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants exposed in each arm is based on the male population.
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants exposed in each arm is based on the female population.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cenicriviroc 150 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    425 / 1180 (36.02%)
    218 / 589 (37.01%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    64 / 1180 (5.42%)
    30 / 589 (5.09%)
         occurrences all number
    68
    33
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    74 / 1180 (6.27%)
    33 / 589 (5.60%)
         occurrences all number
    83
    34
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    104 / 1180 (8.81%)
    39 / 589 (6.62%)
         occurrences all number
    119
    44
    Diarrhoea
         subjects affected / exposed
    92 / 1180 (7.80%)
    56 / 589 (9.51%)
         occurrences all number
    121
    66
    Abdominal pain upper
         subjects affected / exposed
    64 / 1180 (5.42%)
    26 / 589 (4.41%)
         occurrences all number
    69
    27
    Abdominal pain
         subjects affected / exposed
    56 / 1180 (4.75%)
    30 / 589 (5.09%)
         occurrences all number
    71
    32
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    68 / 1180 (5.76%)
    35 / 589 (5.94%)
         occurrences all number
    84
    45
    Back pain
         subjects affected / exposed
    54 / 1180 (4.58%)
    36 / 589 (6.11%)
         occurrences all number
    55
    39
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    57 / 1180 (4.83%)
    33 / 589 (5.60%)
         occurrences all number
    64
    42
    Upper respiratory tract infection
         subjects affected / exposed
    41 / 1180 (3.47%)
    39 / 589 (6.62%)
         occurrences all number
    45
    43

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2017
    The following changes were implemented with Amendment 1: Revised program name from STELLARIS to AURORA. Modified Exclusion Criterion (aspartate aminotransferase [AST] criterion). Modified Exclusion Criterion (alanine aminotransferase [ALT] criterion). Revised timing of the Screening Visit relative to the Baseline Visit. Added hemoglobin A1c assessment to Screening Visit (Part 1 and Part 2). Added storage of plasma and serum samples to Screening Visit (Part 1 and Part 2). Added to study procedures the Short Form Healthy Survey—Version 2 (SF-36v2) questionnaire and its associated quality of life (QoL) evaluation. Removed from study procedures the Modified Medication Adherence Self-report Inventory (M-MASRI) questionnaire and clarified assessment of treatment adherence. Added fasting requirement prior to assessment of liver stiffness. Updated the number of subjects exposed to cenicriviroc (CVC). Modified concomitant use of p-glycoprotein (P-gp) inhibitors. Updated the list of allowed and disallowed concomitant medications. Updated the total blood volume collection. Clarified instructions for completion of all other study visits for subjects who permanently discontinue study drug. Clarified timing of study drug dosing. Added serum hepatic fibrosis indices and moderate end stage liver disease (MELD) score details to Appendix—Clinical Laboratory Tests. Added text for clarification and content-oriented changes were made.
    29 Jun 2017
    The following changes were implemented with Amendment 2: Correction made to disallowed supplementation with high-dose vitamin E. Removed requirement pertaining to counseling regarding prolonged ultraviolet (UV) exposure. Removed hepatitis B core antibody test from screening assessments. Added estimated glomerular filtration rate (eGFR) determinations to specified blood draw determinations. Revised Day 1 blood draw determinations to include hepatitis B core antibody (HBcAb) and hepatitis B surface antibody (HBsAb) titer. Clarified use of antiviral medications, opioids, and sedatives/hypnotics for disallowed medications. Provided updated version of the Work Productivity and Activity Impairment Questionnaire: Nonalcoholic Steatohepatitis for Fatty Liver questionnaire. Added text for clarification and content-oriented changes were made.
    10 Apr 2018
    The following changes were implemented with Amendment 3: Added adverse events of special interest (AESI) to types of reportable events. Added key secondary objective, secondary objectives, and exploratory objectives for Part 1. Revised the approximate number of participants to be randomized in Part 1 and participants randomized in Part 1 that will be included in Part 2 from 1000 participants to 1200. Increased the number of unique participants across Parts 1 and 2 from which adjudicated events were to be accrued before study termination from 240 to 367. Revised the number of participants to be randomized into Arms A and B of Part 1 from 667 to 800 and from 333 to 400, respectively and the number of participants to be newly randomized into Arms A and B of Part 2 from 667 to 534 and from 333 to 266, respectively. Increased the number of study centers from approximately 300 to up to 425. Revised the text to indicate that study drug (CVC or placebo) must be taken once daily with food. Added key secondary efficacy endpoint, secondary efficacy endpoint and exploratory efficacy endpoint for Part 1. Removed time to first occurrence of hepatocellular carcinoma (HCC) as a primary endpoint for Part 2. Safety analysis was updated to include major adverse cardiovascular events and new-onset type 2 diabetes mellitus (T2DM). Revised the definitions for intent-to-treat (ITT) and modified ITT (mITT) analysis sets. Revised the timing for the primary analysis of Part 1 to occur when approximately 1200 randomized participants had been followed for at least 12 months. Statistical significance levels for testing of the primary endpoints in Part 1 and 2 were updated. Statistical analysis was updated to reflect the testing hierarchy for the newly added key secondary endpoint. Testing methodology for the key secondary endpoint in Part 1 was added.
    10 Apr 2018
    Updated the number of participants exposed to CVC in the clinical development program. Added summaries of pharmacokinetic (PK) and safety data from studies 3152-101-002 and 3152-107-002. Updated the summary of data from the Phase 2b study (CENTAUR; Study 652-2-203 (NCT03059446)) based on the final Year 2 results. Added the definitions for treatment-emergent adverse events and for AESI. Changed the timing for collection of one sample for population PK analysis at Month 6 in Part 1. Revised the list of disallowed medications to allow for coadministration of P-gp inhibitors with CVC. Added text for clarification and content-oriented changes were made.
    25 Apr 2019
    The following changes were implemented with Amendment 4: Increased duration of 8 weeks for timing of Screening visit to 3 months to facilitate enrolment and all instances of “weeks” was changed to “months”. Updated emergency contact and serious adverse event (SAE) reporting information. Increased number of sites from 425 up to 600. Updated exposure data. Added details regarding Study 652-1-121 (NCT02120547) and 3152-102-002 (NCT03376841). Updated results for year 2 CENTAUR study 652-2-203 (NCT03059446) based on final clinical study report (CSR). Added details regarding newly randomized Stage 3 participants in Part 2. Redefined primary efficacy objective and endpoint for Part 1. Reorganized secondary efficacy objectives for Part 2. Modified inclusion/exclusion criterias. Added details regarding disallowed medication use and antidiabetic agents and washout period. Added details regarding newly randomized participants in Part 1 and 2. Added description of patient-reported outcomes (PRO) assessment via electronic tablet. Added subgroup analysis text regarding change from Baseline to Month 12 in Enhanced Liver Fibrosis (ELF) score. Added text relevant to European Union (EU) requirement: ...European Union Data Protection Directive 95/46/EC). Added text regarding role and responsibilities of the study monitor. Text was revised to address concerns from specific country health authorities but which the sponsor determined could be applicable to all countries. Added text for clarification and content-oriented changes were made.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    09 Mar 2021
    This study was terminated early due to lack of efficacy based on the results of the planned interim analysis of Part 1 data.
    -

    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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