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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-center Study to Evaluate the Safety and Efficacy of GS-9620 for the Treatment of Virally-Suppressed Subjects with Chronic Hepatitis B

    Summary
    EudraCT number
    		 2014-001400-22
    Trial protocol
    		 IT   NL  
    Global end of trial date
    20 Oct 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 Sep 2020
    First version publication date
    03 Nov 2017
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Updated the global end of trial date and date of interim/final analysis to 20 October 2016.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-283-1059
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02166047
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ACTRN12614000628640 : ANZCTR
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trials Mailbox , Gilead Sciences International Ltd , ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trials Mailbox , Gilead Sciences International Ltd , ClinicalTrialDisclosures@gilead.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
    20 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to evaluate the safety and tolerability of vesatolimod (GS-9620) in participants with chronic hepatitis B (CHB) infection currently being treated with oral antivirals (OAV) and to evaluate the efficacy of vesatolimod at Week 24 measured by the change from baseline in serum hepatitis B surface antigen (HBsAg) (log10 IU/ml) levels.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 All participants continued their approved HBV oral antiviral therapy (tenofovir disoproxil fumarate (TDF), entecavir (ETV), adefovir, lamivudine, or telbivudine, either as single agents or in combination) throughout the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    United States: 43
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    Korea, Republic of: 28
    Country: Number of subjects enrolled
    New Zealand: 24
    Worldwide total number of subjects
    162
    EEA total number of subjects
    34
    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)
    159
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in the United States, Canada, Italy, South Korea, The Netherlands, and New Zealand. The first participant was screened on 30 June 2014. The last study visit occurred on 19 October 2016.

    Pre-assignment
    Screening details
    		 200 participants were screened.

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vesatolimod 1 mg 4 Weeks (Cohort A)
    Arm description
    		 Vesatolimod 1 mg tablet once a week for 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vesatolimod
    Investigational medicinal product code
    Other name
    GS-9620
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 mg once a week

    Arm title
    		 Vesatolimod 2 mg 4 Weeks (Cohort A)
    Arm description
    		 Vesatolimod 2 mg tablet once a week for 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vesatolimod
    Investigational medicinal product code
    Other name
    GS-9620
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg once a week

    Arm title
    		 Vesatolimod 4 mg 4 Weeks (Cohort A)
    Arm description
    		 Vesatolimod 4 mg tablet once a week for 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vesatolimod
    Investigational medicinal product code
    Other name
    GS-9620
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg once a week

    Arm title
    		 Placebo 4 Weeks (Cohort A)
    Arm description
    		 Placebo tablet once a week for 4 weeks
    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
    Placebo once a week

    Arm title
    		 Vesatolimod 1 mg 8 Weeks (Cohort B)
    Arm description
    		 Vesatolimod 1 mg tablet once a week for 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vesatolimod
    Investigational medicinal product code
    Other name
    GS-9620
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 mg once a week

    Arm title
    		 Vesatolimod 2 mg 8 Weeks (Cohort B)
    Arm description
    		 Vesatolimod 2 mg tablet once a week for 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vesatolimod
    Investigational medicinal product code
    Other name
    GS-9620
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg once a week

    Arm title
    		 Vesatolimod 4 mg 8 Weeks (Cohort B)
    Arm description
    		 Vesatolimod 4 mg tablet once a week for 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vesatolimod
    Investigational medicinal product code
    Other name
    GS-9620
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg once a week

    Arm title
    		 Placebo 8 Weeks (Cohort B)
    Arm description
    		 Placebo tablet once a week for 8 weeks
    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
    Placebo once a week

    Arm title
    		 Vesatolimod 1 mg 12 Weeks (Cohort C)
    Arm description
    		 Vesatolimod 1 mg tablet once a week for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vesatolimod
    Investigational medicinal product code
    Other name
    GS-9620
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 mg once a week

    Arm title
    		 Vesatolimod 2 mg 12 Weeks (Cohort C)
    Arm description
    		 Vesatolimod 2 mg tablet once a week for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vesatolimod
    Investigational medicinal product code
    Other name
    GS-9620
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg once a week

    Arm title
    		 Vesatolimod 4 mg 12 Weeks (Cohort C)
    Arm description
    		 Vesatolimod 4 mg tablet once a week for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vesatolimod
    Investigational medicinal product code
    Other name
    GS-9620
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg once a week

    Arm title
    		 Placebo 12 Weeks (Cohort C)
    Arm description
    		 Placebo tablet once a week for 12 weeks
    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
    Placebo once a week

    Number of subjects in period 1
    		Vesatolimod 1 mg 4 Weeks (Cohort A) Vesatolimod 2 mg 4 Weeks (Cohort A) Vesatolimod 4 mg 4 Weeks (Cohort A) Placebo 4 Weeks (Cohort A) Vesatolimod 1 mg 8 Weeks (Cohort B) Vesatolimod 2 mg 8 Weeks (Cohort B) Vesatolimod 4 mg 8 Weeks (Cohort B) Placebo 8 Weeks (Cohort B) Vesatolimod 1 mg 12 Weeks (Cohort C) Vesatolimod 2 mg 12 Weeks (Cohort C) Vesatolimod 4 mg 12 Weeks (Cohort C) Placebo 12 Weeks (Cohort C)
    Started
    16
    15
    16
    5
    18
    17
    17
    5
    16
    17
    14
    6
    Completed
    16
    14
    14
    5
    17
    17
    15
    5
    16
    17
    12
    6
    Not completed
    0
    1
    2
    0
    1
    0
    2
    0
    0
    0
    2
    0
         Withdrawal By Subject
    -
    1
    2
    -
    -
    -
    1
    -
    -
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    -
    -
    1
    -
    1
    -
    -
    -
    2
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Vesatolimod 1 mg 4 Weeks (Cohort A)
    Reporting group description
    		 Vesatolimod 1 mg tablet once a week for 4 weeks

    Reporting group title
    Vesatolimod 2 mg 4 Weeks (Cohort A)
    Reporting group description
    		 Vesatolimod 2 mg tablet once a week for 4 weeks

    Reporting group title
    Vesatolimod 4 mg 4 Weeks (Cohort A)
    Reporting group description
    		 Vesatolimod 4 mg tablet once a week for 4 weeks

    Reporting group title
    Placebo 4 Weeks (Cohort A)
    Reporting group description
    		 Placebo tablet once a week for 4 weeks

    Reporting group title
    Vesatolimod 1 mg 8 Weeks (Cohort B)
    Reporting group description
    		 Vesatolimod 1 mg tablet once a week for 8 weeks

    Reporting group title
    Vesatolimod 2 mg 8 Weeks (Cohort B)
    Reporting group description
    		 Vesatolimod 2 mg tablet once a week for 8 weeks

    Reporting group title
    Vesatolimod 4 mg 8 Weeks (Cohort B)
    Reporting group description
    		 Vesatolimod 4 mg tablet once a week for 8 weeks

    Reporting group title
    Placebo 8 Weeks (Cohort B)
    Reporting group description
    		 Placebo tablet once a week for 8 weeks

    Reporting group title
    Vesatolimod 1 mg 12 Weeks (Cohort C)
    Reporting group description
    		 Vesatolimod 1 mg tablet once a week for 12 weeks

    Reporting group title
    Vesatolimod 2 mg 12 Weeks (Cohort C)
    Reporting group description
    		 Vesatolimod 2 mg tablet once a week for 12 weeks

    Reporting group title
    Vesatolimod 4 mg 12 Weeks (Cohort C)
    Reporting group description
    		 Vesatolimod 4 mg tablet once a week for 12 weeks

    Reporting group title
    Placebo 12 Weeks (Cohort C)
    Reporting group description
    		 Placebo tablet once a week for 12 weeks

    Reporting group values
    		 Vesatolimod 1 mg 4 Weeks (Cohort A) Vesatolimod 2 mg 4 Weeks (Cohort A) Vesatolimod 4 mg 4 Weeks (Cohort A) Placebo 4 Weeks (Cohort A) Vesatolimod 1 mg 8 Weeks (Cohort B) Vesatolimod 2 mg 8 Weeks (Cohort B) Vesatolimod 4 mg 8 Weeks (Cohort B) Placebo 8 Weeks (Cohort B) Vesatolimod 1 mg 12 Weeks (Cohort C) Vesatolimod 2 mg 12 Weeks (Cohort C) Vesatolimod 4 mg 12 Weeks (Cohort C) Placebo 12 Weeks (Cohort C) Total
    Number of subjects
    		 16 15 16 5 18 17 17 5 16 17 14 6 162
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47 ( 7.3 ) 50 ( 11.2 ) 47 ( 10.0 ) 53 ( 5.3 ) 51 ( 8.2 ) 44 ( 9.0 ) 44 ( 11.1 ) 53 ( 5.4 ) 48 ( 9.8 ) 48 ( 9.7 ) 50 ( 11.6 ) 46 ( 10.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1 5 4 1 9 4 4 1 5 2 3 0 39
        Male
    		 15 10 12 4 9 13 13 4 11 15 11 6 123
    HBsAg Level
    Units: Subjects
        ≤ 5000 IU/mL
    		 13 13 13 4 15 15 14 5 14 15 13 5 139
        > 5000 IU/mL
    		 3 2 3 1 3 2 3 0 2 2 1 1 23
    Hepatitis B envelope antigen (HBeAg) Status
    Units: Subjects
        Negative
    		 12 11 12 4 13 14 14 5 13 14 12 4 128
        Positive
    		 4 4 4 1 5 3 3 0 3 3 2 2 34
    Hepatitis B surface antigen (HBsAg)
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    		 2.8 ( 0.88 ) 3.1 ( 0.59 ) 3.0 ( 0.70 ) 3.1 ( 0.69 ) 3.1 ( 0.62 ) 3.0 ( 0.69 ) 3.1 ( 0.90 ) 2.7 ( 0.73 ) 3.3 ( 0.45 ) 3.0 ( 0.54 ) 3.0 ( 0.69 ) 2.4 ( 1.01 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Vesatolimod 1 mg 4 Weeks (Cohort A)
    Reporting group description
    		 Vesatolimod 1 mg tablet once a week for 4 weeks

    Reporting group title
    Vesatolimod 2 mg 4 Weeks (Cohort A)
    Reporting group description
    		 Vesatolimod 2 mg tablet once a week for 4 weeks

    Reporting group title
    Vesatolimod 4 mg 4 Weeks (Cohort A)
    Reporting group description
    		 Vesatolimod 4 mg tablet once a week for 4 weeks

    Reporting group title
    Placebo 4 Weeks (Cohort A)
    Reporting group description
    		 Placebo tablet once a week for 4 weeks

    Reporting group title
    Vesatolimod 1 mg 8 Weeks (Cohort B)
    Reporting group description
    		 Vesatolimod 1 mg tablet once a week for 8 weeks

    Reporting group title
    Vesatolimod 2 mg 8 Weeks (Cohort B)
    Reporting group description
    		 Vesatolimod 2 mg tablet once a week for 8 weeks

    Reporting group title
    Vesatolimod 4 mg 8 Weeks (Cohort B)
    Reporting group description
    		 Vesatolimod 4 mg tablet once a week for 8 weeks

    Reporting group title
    Placebo 8 Weeks (Cohort B)
    Reporting group description
    		 Placebo tablet once a week for 8 weeks

    Reporting group title
    Vesatolimod 1 mg 12 Weeks (Cohort C)
    Reporting group description
    		 Vesatolimod 1 mg tablet once a week for 12 weeks

    Reporting group title
    Vesatolimod 2 mg 12 Weeks (Cohort C)
    Reporting group description
    		 Vesatolimod 2 mg tablet once a week for 12 weeks

    Reporting group title
    Vesatolimod 4 mg 12 Weeks (Cohort C)
    Reporting group description
    		 Vesatolimod 4 mg tablet once a week for 12 weeks

    Reporting group title
    Placebo 12 Weeks (Cohort C)
    Reporting group description
    		 Placebo tablet once a week for 12 weeks

    Primary: Mean Change in Serum Hepatitis B Surface Antigen (HBsAg) (log10 IU/ml) at Week 24

    		 Close Top of page
    End point title
    		 Mean Change in Serum Hepatitis B Surface Antigen (HBsAg) (log10 IU/ml) at Week 24
    End point description
    Participants in the Full Analysis Set (participants who were randomized and received at least 1 dose of study drug) with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Vesatolimod 1 mg 4 Weeks (Cohort A) Vesatolimod 2 mg 4 Weeks (Cohort A) Vesatolimod 4 mg 4 Weeks (Cohort A) Placebo 4 Weeks (Cohort A) Vesatolimod 1 mg 8 Weeks (Cohort B) Vesatolimod 2 mg 8 Weeks (Cohort B) Vesatolimod 4 mg 8 Weeks (Cohort B) Placebo 8 Weeks (Cohort B) Vesatolimod 1 mg 12 Weeks (Cohort C) Vesatolimod 2 mg 12 Weeks (Cohort C) Vesatolimod 4 mg 12 Weeks (Cohort C) Placebo 12 Weeks (Cohort C)
    Number of subjects analysed
    16
    14
    15
    5
    17
    17
    16
    5
    16
    17
    12
    6
    Units: log10 IU/mL
        least squares mean (confidence interval 95%)
    -0.011 (-0.054 to 0.031)
    0.033 (-0.012 to 0.079)
    -0.018 (-0.062 to 0.026)
    -0.035 (-0.109 to 0.040)
    -0.081 (-0.145 to -0.016)
    -0.081 (-0.147 to -0.014)
    -0.082 (-0.148 to -0.015)
    -0.163 (-0.281 to -0.045)
    -0.015 (-0.057 to 0.027)
    0.000 (-0.041 to 0.042)
    0.000 (-0.046 to 0.047)
    0.001 (-0.057 to 0.058)
    Statistical analysis title
    		 Treatment Diff (vesatolimod 1 mg 4 wk vs placebo)
    Statistical analysis description
    A mixed effect model for repeated measures (MMRM) was used to analyze HBsAg change from baseline, which included treatment, baseline HBsAg level (> 5000 IU/mL or ≤ 5000 IU/mL), HBeAg baseline status (positive or negative), visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement.
    Comparison groups
    Vesatolimod 1 mg 4 Weeks (Cohort A) v Placebo 4 Weeks (Cohort A)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.59 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Mean
    Point estimate
    0.023
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.061
         upper limit
    		 0.108
    Notes
    [1] - Statistical comparison
    [2] - P-values between treatment groups with placebo were not adjusted for multiplicity due to exploratory nature of the study.
    Statistical analysis title
    		 Treatment Diff (vesatolimod 2 mg 4 wk vs placebo)
    Statistical analysis description
    A MMRM was used to analyze HBsAg change from baseline, which included treatment, baseline HBsAg level (> 5000 IU/mL or ≤ 5000 IU/mL), HBeAg baseline status (positive or negative), visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement.
    Comparison groups
    Vesatolimod 2 mg 4 Weeks (Cohort A) v Placebo 4 Weeks (Cohort A)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.12 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Mean
    Point estimate
    0.068
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.018
         upper limit
    		 0.154
    Notes
    [3] - Statistical comparison
    [4] - P-values between treatment groups with placebo were not adjusted for multiplicity due to exploratory nature of the study.
    Statistical analysis title
    		 Treatment Diff (vesatolimod 4 mg 4 wk vs placebo)
    Statistical analysis description
    A MMRM was used to analyze HBsAg change from baseline, which included treatment, baseline HBsAg level (> 5000 IU/mL or ≤ 5000 IU/mL), HBeAg baseline status (positive or negative), visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement.
    Comparison groups
    Vesatolimod 4 mg 4 Weeks (Cohort A) v Placebo 4 Weeks (Cohort A)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.701 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Mean
    Point estimate
    0.017
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.069
         upper limit
    		 0.102
    Notes
    [5] - Statistical comparison
    [6] - P-values between treatment groups with placebo were not adjusted for multiplicity due to exploratory nature of the study.
    Statistical analysis title
    		 Treatment Diff (vesatolimod 1 mg 8 wk vs placebo)
    Statistical analysis description
    A MMRM was used to analyze HBsAg change from baseline, which included treatment, baseline HBsAg level (> 5000 IU/mL or ≤ 5000 IU/mL), HBeAg baseline status (positive or negative), visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement.
    Comparison groups
    Vesatolimod 1 mg 8 Weeks (Cohort B) v Placebo 8 Weeks (Cohort B)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.21 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Mean
    Point estimate
    0.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.046
         upper limit
    		 0.21
    Notes
    [7] - Statistical comparison
    [8] - P-values between treatment groups with placebo were not adjusted for multiplicity due to exploratory nature of the study.
    Statistical analysis title
    		 Treatment Diff (vesatolimod 2 mg 8 wk vs placebo)
    Statistical analysis description
    A MMRM was used to analyze HBsAg change from baseline, which included treatment, baseline HBsAg level (> 5000 IU/mL or ≤ 5000 IU/mL), HBeAg baseline status (positive or negative), visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement.
    Comparison groups
    Vesatolimod 2 mg 8 Weeks (Cohort B) v Placebo 8 Weeks (Cohort B)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.207 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Mean
    Point estimate
    0.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.046
         upper limit
    		 0.21
    Notes
    [9] - Statistical comparison
    [10] - P-values between treatment groups with placebo were not adjusted for multiplicity due to exploratory nature of the study.
    Statistical analysis title
    		 Treatment Diff (vesatolimod 4 mg 8 wk vs placebo)
    Statistical analysis description
    A MMRM was used to analyze HBsAg change from baseline, which included treatment, baseline HBsAg level (> 5000 IU/mL or ≤ 5000 IU/mL), HBeAg baseline status (positive or negative), visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement.
    Comparison groups
    Vesatolimod 4 mg 8 Weeks (Cohort B) v Placebo 8 Weeks (Cohort B)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.216 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Mean
    Point estimate
    0.081
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.048
         upper limit
    		 0.21
    Notes
    [11] - Statistical comparison
    [12] - P-values between treatment groups with placebo were not adjusted for multiplicity due to exploratory nature of the study.
    Statistical analysis title
    		 Treatment Diff (vesatolimod 1 mg 12 wk vs placebo)
    Statistical analysis description
    A MMRM was used to analyze HBsAg change from baseline, which included treatment, baseline HBsAg level (> 5000 IU/mL or ≤ 5000 IU/mL), HBeAg baseline status (positive or negative), visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement.
    Comparison groups
    Vesatolimod 1 mg 12 Weeks (Cohort C) v Placebo 12 Weeks (Cohort C)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.652 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Mean
    Point estimate
    -0.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.081
         upper limit
    		 0.051
    Notes
    [13] - Statistical comparison
    [14] - P-values between treatment groups with placebo were not adjusted for multiplicity due to exploratory nature of the study.
    Statistical analysis title
    		 Treatment Diff (vesatolimod 2 mg 12 wk vs placebo)
    Statistical analysis description
    A MMRM was used to analyze HBsAg change from baseline, which included treatment, baseline HBsAg level (> 5000 IU/mL or ≤ 5000 IU/mL), HBeAg baseline status (positive or negative), visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement.
    Comparison groups
    Vesatolimod 2 mg 12 Weeks (Cohort C) v Placebo 12 Weeks (Cohort C)
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.994 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Mean
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.066
         upper limit
    		 0.065
    Notes
    [15] - Statistical comparison
    [16] - P-values between treatment groups with placebo were not adjusted for multiplicity due to exploratory nature of the study.
    Statistical analysis title
    		 Treatment Diff (vesatolimod 4 mg 12 wk vs placebo)
    Statistical analysis description
    A MMRM was used to analyze HBsAg change from baseline, which included treatment, baseline HBsAg level (> 5000 IU/mL or ≤ 5000 IU/mL), HBeAg baseline status (positive or negative), visit and treatment-by-visit interaction as fixed effect and visit as repeated measurement.
    Comparison groups
    Vesatolimod 4 mg 12 Weeks (Cohort C) v Placebo 12 Weeks (Cohort C)
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.996 [18]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Mean
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.069
         upper limit
    		 0.069
    Notes
    [17] - Statistical comparison
    [18] - P-values between treatment groups with placebo were not adjusted for multiplicity due to exploratory nature of the study.

    Secondary: Proportion of Participants With HBeAg Loss and Seroconversion

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    End point title
    		 Proportion of Participants With HBeAg Loss and Seroconversion
    End point description
    HBeAg loss is defined as qualitative HBeAg result changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBeAg seroconversion is defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit within the targeted time window. Participants who have missing information were assumed to have no HBeAg loss and no HBeAg seroconversion. Only participants who were HBeAg+ at baseline were included. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Weeks 24 and 48
    End point values
    		 Vesatolimod 1 mg 4 Weeks (Cohort A) Vesatolimod 2 mg 4 Weeks (Cohort A) Vesatolimod 4 mg 4 Weeks (Cohort A) Placebo 4 Weeks (Cohort A) Vesatolimod 1 mg 8 Weeks (Cohort B) Vesatolimod 2 mg 8 Weeks (Cohort B) Vesatolimod 4 mg 8 Weeks (Cohort B) Placebo 8 Weeks (Cohort B) Vesatolimod 1 mg 12 Weeks (Cohort C) Vesatolimod 2 mg 12 Weeks (Cohort C) Vesatolimod 4 mg 12 Weeks (Cohort C) Placebo 12 Weeks (Cohort C)
    Number of subjects analysed
    4
    4
    4
    1
    5
    3
    3
    0 [19]
    3
    3
    2
    2
    Units: percentage of participants
    number (not applicable)
        Week 24
    0
    0
    0
    0
    20.0
    0
    0
    0
    0
    0
    0
        Week 48
    0
    0
    0
    0
    20.0
    0
    0
    33.3
    0
    0
    0
    Notes
    [19] - No participants in this group had HBeAg+ at baseline.
    No statistical analyses for this end point

    Secondary: Proportion of Participants With HBsAg Loss and Seroconversion

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    End point title
    		 Proportion of Participants With HBsAg Loss and Seroconversion
    End point description
    HBsAg loss was defined as qualitative HBsAg result changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBsAg seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit within the targeted time window. Participants who have missing information were assumed to have no HBsAg loss and no HBsAg seroconversion. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Weeks 24 and 48
    End point values
    		 Vesatolimod 1 mg 4 Weeks (Cohort A) Vesatolimod 2 mg 4 Weeks (Cohort A) Vesatolimod 4 mg 4 Weeks (Cohort A) Placebo 4 Weeks (Cohort A) Vesatolimod 1 mg 8 Weeks (Cohort B) Vesatolimod 2 mg 8 Weeks (Cohort B) Vesatolimod 4 mg 8 Weeks (Cohort B) Placebo 8 Weeks (Cohort B) Vesatolimod 1 mg 12 Weeks (Cohort C) Vesatolimod 2 mg 12 Weeks (Cohort C) Vesatolimod 4 mg 12 Weeks (Cohort C) Placebo 12 Weeks (Cohort C)
    Number of subjects analysed
    16
    15
    16
    5
    18
    17
    17
    5
    16
    17
    14
    6
    Units: percentage of participants
    number (not applicable)
        Week 24
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Week 48
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Mean Change in log10 IU/ml Serum HBsAg at Week 4

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    End point title
    		 Mean Change in log10 IU/ml Serum HBsAg at Week 4
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 4
    End point values
    		 Vesatolimod 1 mg 4 Weeks (Cohort A) Vesatolimod 2 mg 4 Weeks (Cohort A) Vesatolimod 4 mg 4 Weeks (Cohort A) Placebo 4 Weeks (Cohort A) Vesatolimod 1 mg 8 Weeks (Cohort B) Vesatolimod 2 mg 8 Weeks (Cohort B) Vesatolimod 4 mg 8 Weeks (Cohort B) Placebo 8 Weeks (Cohort B) Vesatolimod 1 mg 12 Weeks (Cohort C) Vesatolimod 2 mg 12 Weeks (Cohort C) Vesatolimod 4 mg 12 Weeks (Cohort C) Placebo 12 Weeks (Cohort C)
    Number of subjects analysed
    15
    14
    14
    5
    18
    17
    17
    5
    16
    17
    13
    6
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    -0.009 ( 0.0505 )
    0.025 ( 0.0514 )
    -0.008 ( 0.0516 )
    -0.017 ( 0.0600 )
    -0.003 ( 0.0574 )
    0.014 ( 0.0794 )
    -0.001 ( 0.0436 )
    0.046 ( 0.0648 )
    -0.034 ( 0.0375 )
    -0.023 ( 0.0529 )
    -0.001 ( 0.0627 )
    -0.041 ( 0.0955 )
    No statistical analyses for this end point

    Secondary: Mean Change in log10 IU/ml Serum HBsAg at Week 8

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    End point title
    		 Mean Change in log10 IU/ml Serum HBsAg at Week 8
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 8
    End point values
    		 Vesatolimod 1 mg 4 Weeks (Cohort A) Vesatolimod 2 mg 4 Weeks (Cohort A) Vesatolimod 4 mg 4 Weeks (Cohort A) Placebo 4 Weeks (Cohort A) Vesatolimod 1 mg 8 Weeks (Cohort B) Vesatolimod 2 mg 8 Weeks (Cohort B) Vesatolimod 4 mg 8 Weeks (Cohort B) Placebo 8 Weeks (Cohort B) Vesatolimod 1 mg 12 Weeks (Cohort C) Vesatolimod 2 mg 12 Weeks (Cohort C) Vesatolimod 4 mg 12 Weeks (Cohort C) Placebo 12 Weeks (Cohort C)
    Number of subjects analysed
    16
    13
    15
    4
    17
    17
    17
    4
    16
    17
    12
    6
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    -0.029 ( 0.0666 )
    0.002 ( 0.0544 )
    -0.035 ( 0.0649 )
    -0.013 ( 0.0440 )
    0.000 ( 0.0442 )
    0.006 ( 0.0772 )
    0.020 ( 0.0596 )
    0.006 ( 0.0600 )
    -0.021 ( 0.0376 )
    -0.033 ( 0.0487 )
    -0.013 ( 0.0426 )
    -0.019 ( 0.0483 )
    No statistical analyses for this end point

    Secondary: Mean Change in log10 IU/ml Serum HBsAg at Week 12

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    End point title
    		 Mean Change in log10 IU/ml Serum HBsAg at Week 12
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Vesatolimod 1 mg 4 Weeks (Cohort A) Vesatolimod 2 mg 4 Weeks (Cohort A) Vesatolimod 4 mg 4 Weeks (Cohort A) Placebo 4 Weeks (Cohort A) Vesatolimod 1 mg 8 Weeks (Cohort B) Vesatolimod 2 mg 8 Weeks (Cohort B) Vesatolimod 4 mg 8 Weeks (Cohort B) Placebo 8 Weeks (Cohort B) Vesatolimod 1 mg 12 Weeks (Cohort C) Vesatolimod 2 mg 12 Weeks (Cohort C) Vesatolimod 4 mg 12 Weeks (Cohort C) Placebo 12 Weeks (Cohort C)
    Number of subjects analysed
    14
    14
    15
    5
    17
    17
    16
    5
    16
    16
    12
    6
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    -0.050 ( 0.0755 )
    0.017 ( 0.0646 )
    -0.004 ( 0.0546 )
    -0.023 ( 0.0623 )
    -0.031 ( 0.0817 )
    -0.005 ( 0.0843 )
    -0.021 ( 0.0716 )
    -0.020 ( 0.0666 )
    -0.023 ( 0.0545 )
    -0.034 ( 0.0549 )
    -0.010 ( 0.0621 )
    -0.024 ( 0.0661 )
    No statistical analyses for this end point

    Secondary: Mean Change in log10 IU/ml Serum HBsAg at Week 48

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    End point title
    		 Mean Change in log10 IU/ml Serum HBsAg at Week 48
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 Vesatolimod 1 mg 4 Weeks (Cohort A) Vesatolimod 2 mg 4 Weeks (Cohort A) Vesatolimod 4 mg 4 Weeks (Cohort A) Placebo 4 Weeks (Cohort A) Vesatolimod 1 mg 8 Weeks (Cohort B) Vesatolimod 2 mg 8 Weeks (Cohort B) Vesatolimod 4 mg 8 Weeks (Cohort B) Placebo 8 Weeks (Cohort B) Vesatolimod 1 mg 12 Weeks (Cohort C) Vesatolimod 2 mg 12 Weeks (Cohort C) Vesatolimod 4 mg 12 Weeks (Cohort C) Placebo 12 Weeks (Cohort C)
    Number of subjects analysed
    16
    13
    14
    4
    17
    16
    15
    5
    16
    17
    12
    6
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    -0.048 ( 0.1054 )
    -0.055 ( 0.1400 )
    -0.071 ( 0.0857 )
    -0.067 ( 0.0831 )
    -0.035 ( 0.0923 )
    -0.024 ( 0.0679 )
    -0.114 ( 0.2169 )
    -0.324 ( 0.6811 )
    -0.083 ( 0.0858 )
    -0.071 ( 0.1076 )
    -0.054 ( 0.0715 )
    -0.063 ( 0.1011 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 12 weeks plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set: participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Vesatolimod 1 mg 4 Weeks (Cohort A)
    Reporting group description
    		 Vesatolimod 1 mg tablet once a week for 4 weeks

    Reporting group title
    Vesatolimod 2 mg 4 Weeks (Cohort A)
    Reporting group description
    		 Vesatolimod 2 mg tablet once a week for 4 weeks

    Reporting group title
    Vesatolimod 4 mg 4 Weeks (Cohort A)
    Reporting group description
    		 Vesatolimod 4 mg tablet once a week for 4 weeks

    Reporting group title
    Placebo 4 Weeks (Cohort A)
    Reporting group description
    		 Placebo tablet once a week for 4 weeks

    Reporting group title
    Vesatolimod 1 mg 8 Weeks (Cohort B)
    Reporting group description
    		 Vesatolimod 1 mg tablet once a week for 8 weeks

    Reporting group title
    Vesatolimod 2 mg 8 Weeks (Cohort B)
    Reporting group description
    		 Vesatolimod 2 mg tablet once a week for 8 weeks

    Reporting group title
    Vesatolimod 4 mg 8 Weeks (Cohort B)
    Reporting group description
    		 Vesatolimod 4 mg tablet once a week for 8 weeks

    Reporting group title
    Placebo 8 Weeks (Cohort B)
    Reporting group description
    		 Placebo tablet once a week for 8 weeks

    Reporting group title
    Vesatolimod 1 mg 12 Weeks (Cohort C)
    Reporting group description
    		 Vesatolimod 1 mg tablet once a week for 12 weeks

    Reporting group title
    Vesatolimod 2 mg 12 Weeks (Cohort C)
    Reporting group description
    		 Vesatolimod 2 mg tablet once a week for 12 weeks

    Reporting group title
    Vesatolimod 4 mg 12 Weeks (Cohort C)
    Reporting group description
    		 Vesatolimod 4 mg tablet once a week for 12 weeks

    Reporting group title
    Placebo 12 Weeks (Cohort C)
    Reporting group description
    		 Placebo tablet once a week for 12 weeks

    Serious adverse events
    		 Vesatolimod 1 mg 4 Weeks (Cohort A) Vesatolimod 2 mg 4 Weeks (Cohort A) Vesatolimod 4 mg 4 Weeks (Cohort A) Placebo 4 Weeks (Cohort A) Vesatolimod 1 mg 8 Weeks (Cohort B) Vesatolimod 2 mg 8 Weeks (Cohort B) Vesatolimod 4 mg 8 Weeks (Cohort B) Placebo 8 Weeks (Cohort B) Vesatolimod 1 mg 12 Weeks (Cohort C) Vesatolimod 2 mg 12 Weeks (Cohort C) Vesatolimod 4 mg 12 Weeks (Cohort C) Placebo 12 Weeks (Cohort C)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vesatolimod 1 mg 4 Weeks (Cohort A) Vesatolimod 2 mg 4 Weeks (Cohort A) Vesatolimod 4 mg 4 Weeks (Cohort A) Placebo 4 Weeks (Cohort A) Vesatolimod 1 mg 8 Weeks (Cohort B) Vesatolimod 2 mg 8 Weeks (Cohort B) Vesatolimod 4 mg 8 Weeks (Cohort B) Placebo 8 Weeks (Cohort B) Vesatolimod 1 mg 12 Weeks (Cohort C) Vesatolimod 2 mg 12 Weeks (Cohort C) Vesatolimod 4 mg 12 Weeks (Cohort C) Placebo 12 Weeks (Cohort C)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 16 (62.50%)
    12 / 15 (80.00%)
    13 / 16 (81.25%)
    4 / 5 (80.00%)
    12 / 18 (66.67%)
    7 / 17 (41.18%)
    10 / 17 (58.82%)
    4 / 5 (80.00%)
    12 / 16 (75.00%)
    12 / 17 (70.59%)
    9 / 14 (64.29%)
    3 / 6 (50.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma of liver
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    2 / 16 (12.50%)
    1 / 17 (5.88%)
    5 / 14 (35.71%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    1
    2
    3
    17
    0
    Chills
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    3
    2
    1
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    4 / 16 (25.00%)
    3 / 15 (20.00%)
    3 / 16 (18.75%)
    1 / 5 (20.00%)
    2 / 18 (11.11%)
    0 / 17 (0.00%)
    2 / 17 (11.76%)
    1 / 5 (20.00%)
    4 / 16 (25.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    4
    3
    3
    1
    2
    0
    2
    1
    4
    2
    1
    1
    Feeling cold
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Feeling hot
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    4 / 16 (25.00%)
    0 / 17 (0.00%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    3
    0
    4
    0
    8
    0
    Malaise
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Mucosal dryness
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    3 / 16 (18.75%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    2 / 16 (12.50%)
    1 / 17 (5.88%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
         occurrences all number
    3
    0
    4
    0
    0
    2
    2
    1
    4
    1
    6
    1
    Thirst
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Vessel puncture site bruise
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Pollakiuria
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Erectile dysfunction
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Nasal obstruction
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    3
    0
    0
    1
    0
    1
    0
    0
    Pharyngeal oedema
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    0
    0
    0
    0
    0
    Sneezing
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Throat irritation
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    1
    0
    0
    Initial insomnia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 5 (20.00%)
    2 / 18 (11.11%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    1
    0
    0
    0
    0
    1
    Irritability
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Middle insomnia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Panic attack
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Blood pressure abnormal
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    2
    Weight decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
    2 / 17 (11.76%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    0
    2
    2
    1
    0
    0
    1
    0
    0
    Dizziness postural
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 15 (20.00%)
    2 / 16 (12.50%)
    2 / 5 (40.00%)
    6 / 18 (33.33%)
    2 / 17 (11.76%)
    4 / 17 (23.53%)
    2 / 5 (40.00%)
    4 / 16 (25.00%)
    3 / 17 (17.65%)
    3 / 14 (21.43%)
    3 / 6 (50.00%)
         occurrences all number
    3
    4
    2
    2
    7
    3
    4
    2
    5
    3
    8
    4
    Hypoaesthesia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Mental impairment
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Parosmia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Ear and labyrinth disorders
    Ear swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Vertigo positional
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Eye disorders
    Asthenopia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Diplopia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Glaucoma
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Photophobia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Photopsia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Vitreous floaters
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    3 / 17 (17.65%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    1
    0
    Dental caries
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 15 (6.67%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    1
    0
    1
    0
    1
    0
    0
    0
    0
    1
    Epigastric discomfort
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Mouth cyst
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    3 / 18 (16.67%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    4
    0
    0
    0
    1
    0
    2
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Alopecia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Nail growth abnormal
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Psoriasis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Micturition frequency decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Nocturia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Muscle fatigue
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    1
    4
    0
    3
    0
    3
    0
    Neck pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Spinal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Diverticulitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Gingivitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    1
    1
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    1
    0
    0
    Oral pustule
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Root canal infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    1
    1
    1
    0
    0
    1
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    0
    1
    0
    Iron deficiency
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Bursitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2014
    ● Subject visits were restructured to align with data analysis objectives. ● The background section was updated. ● The exploratory objectives were clarified. ● Expectations for pharmacogenomics and pharmacokinetic substudies were clarified. ● The screening window was increased from 28 days to 45 days and rescreening requirements were clarified. ● One inclusion criterion was updated based upon new laboratory standards. ● One exclusion criterion was updated based upon Food and Drug Administration (FDA) feedback regarding liver cirrhosis and bridging fibrosis. ● The study drug description, handling, dosage, and administration sections were clarified due to multiple supplies of study drug. ● The description of dose-limiting toxicities and discontinuation events were revised.
    19 Feb 2015
    ● Addition of quality of life (QOL) surveys (Short Form 36 [SF-36], Chronic Liver Disease Questionnaire [CLDQ], and Work Productivity and Activity Impairment Questionnaire [WPAI]) to be conducted at baseline/Day 1; Weeks 12, 24, and 48; and the early discontinuation visit (if applicable) for subjects in Cohort C only.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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