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    Clinical Trial Results:
    MOSAIC - A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multicenter Study Evaluating the Efficacy and Safety of Selonsertib in Subjects with Moderate to Advanced Diabetic Kidney Disease

    Summary
    EudraCT number
    		 2018-003951-39
    Trial protocol
    		 GB   ES   IT  
    Global end of trial date
    03 Sep 2021

    Results information
    Results version number
    		 v3(current)
    This version publication date
    15 Dec 2022
    First version publication date
    16 Sep 2022
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Update to Ethnicity data in the baseline characteristics section.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-223-1017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04026165
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Japan Pharmaceutical Information Center: JapicCTI-194911
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@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
    03 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Sep 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate whether selonsertib (SEL) can slow the decline in kidney function in participants with moderate to advanced diabetic kidney disease (DKD).
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jul 2019
    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
    Australia: 6
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    Japan: 79
    Country: Number of subjects enrolled
    New Zealand: 16
    Country: Number of subjects enrolled
    United States: 251
    Worldwide total number of subjects
    384
    EEA total number of subjects
    0
    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)
    155
    From 65 to 84 years
    229
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in the United States, Japan, Canada, New Zealand, and Australia.

    Pre-assignment
    Screening details
    		 961 participants were screened.

    Period 1
    Period 1 title
    Run-in Placebo Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Run-in Placebo
    Arm description
    		 Participants received placebo to match selonsertib (SEL) tablet orally once daily for at least one week.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match SEL administered once daily for at least one week

    Number of subjects in period 1
    		Run-in Placebo
    Started
    384
    Completed
    362
    Not completed
    22
         Withdrew Consent
    2
         Enrollment Error
    13
         Significant Non-compliance with Study Drug
    1
         Protocol Violation
    2
         Run-in Failure
    4
    Period 2
    Period 2 title
    Run-in SEL Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Run-in SEL 18 mg
    Arm description
    		 Participants received SEL 18 mg tablet orally once daily for at least 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SEL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    18 mg administered once daily

    Number of subjects in period 2 [1]
    		Run-in SEL 18 mg
    Started
    357
    Completed
    311
    Not completed
    46
         Withdrew Consent
    10
         Enrollment Error
    4
         Death
    1
         Investigator's Discretion
    2
         Protocol Violation
    3
         Run-in Failure
    26
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Five participants discontinued the study after completing the Run-in Placebo (Period 1) and didn't enter the Run-in SEL period (Period 2).
    Period 3
    Period 3 title
    Randomised Period
    Is this the baseline period?
    		 Yes [2]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Randomised SEL 18 mg
    Arm description
    		 Participants received SEL 18 mg tablet orally once daily for at least 4 weeks in the Run-in period, were then randomised, and received SEL 18 mg tablet orally once daily for at least 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SEL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    18 mg administered once daily

    Arm title
    		 Randomised Placebo
    Arm description
    		 Participants received SEL 18 mg tablet orally once daily for at least 4 weeks in the Run-in period, were then randomised, and received placebo-to-match SEL tablet orally once daily for at least 48 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match SEL was administered once daily

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The baseline characteristics were measured in Period 1. However, baseline characteristics are presented for the Safety analysis set (n=667) by Randomisation status and Randomised treatment group. Therefore, period 3 was selected as the Baseline period due to system constraints so the treatment groups are correctly populated in the system.
    Number of subjects in period 3 [3] [4]
    		Randomised SEL 18 mg Randomised Placebo
    Started
    154
    156
    Completed
    140
    137
    Not completed
    14
    19
         Withdrew Consent
    5
    8
         Death
    5
    7
         Lost to Follow-up
    2
    2
         Investigator's Discretion
    2
    2
    Notes
    [3] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics were reported for the Safety Analysis Set only, which included participants who received at least one dose of Run-in SEL.
    [4] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Following the Run-in period, eligible participants were randomised to receive either SEL (18 mg) or placebo.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Randomised SEL 18 mg
    Reporting group description
    		 Participants received SEL 18 mg tablet orally once daily for at least 4 weeks in the Run-in period, were then randomised, and received SEL 18 mg tablet orally once daily for at least 48 weeks.

    Reporting group title
    Randomised Placebo
    Reporting group description
    		 Participants received SEL 18 mg tablet orally once daily for at least 4 weeks in the Run-in period, were then randomised, and received placebo-to-match SEL tablet orally once daily for at least 48 weeks.

    Reporting group values
    		 Randomised SEL 18 mg Randomised Placebo Total
    Number of subjects
    		 154 156 310
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65 ( 9.3 ) 66 ( 8.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 48 51 99
        Male
    		 106 105 211
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 2 0 2
        Asian
    		 41 44 85
        Black or African American
    		 26 22 48
        Native Hawaiian or Pacific Islander
    		 5 4 9
        White
    		 78 84 162
        Other
    		 2 2 4
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 132 136 268
        Hispanic or Latino
    		 21 19 40
        Unknown or Not Reported
    		 1 1 2
    Subject analysis sets

    Subject analysis set title
    Run-in SEL 18 mg, Not Randomised
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The analysis set included all participants who took at least 1 dose of Run-in SEL and were not randomised.

    Subject analysis sets values
    		 Run-in SEL 18 mg, Not Randomised
    Number of subjects
    47
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65 ( 9.7 )
    Gender categorical
    Units: Subjects
        Female
    12
        Male
    35
    Race
    Units: Subjects
        American Indian or Alaska Native
    0
        Asian
    4
        Black or African American
    4
        Native Hawaiian or Pacific Islander
    1
        White
    36
        Other
    2
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    39
        Hispanic or Latino
    8
        Unknown or Not Reported

    End points

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    End points reporting groups
    Reporting group title
    Run-in Placebo
    Reporting group description
    		 Participants received placebo to match selonsertib (SEL) tablet orally once daily for at least one week.
    Reporting group title
    Run-in SEL 18 mg
    Reporting group description
    		 Participants received SEL 18 mg tablet orally once daily for at least 4 weeks.
    Reporting group title
    Randomised SEL 18 mg
    Reporting group description
    		 Participants received SEL 18 mg tablet orally once daily for at least 4 weeks in the Run-in period, were then randomised, and received SEL 18 mg tablet orally once daily for at least 48 weeks.

    Reporting group title
    Randomised Placebo
    Reporting group description
    		 Participants received SEL 18 mg tablet orally once daily for at least 4 weeks in the Run-in period, were then randomised, and received placebo-to-match SEL tablet orally once daily for at least 48 weeks.

    Subject analysis set title
    Run-in SEL 18 mg, Not Randomised
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The analysis set included all participants who took at least 1 dose of Run-in SEL and were not randomised.

    Primary: Treatment-specific Baseline Estimated Glomerular Filtration Rate Based on Creatinine (eGFRcr)

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    End point title
    		 Treatment-specific Baseline Estimated Glomerular Filtration Rate Based on Creatinine (eGFRcr) [1]
    End point description
    The values of eGFRcr were calculated using the Chronic Kidney Disease Epidemiology (CKD-EPI) Creatinine Equation (2009). eGFRcr = 141*min(Standardized Serum Creatinine (Scr)/kappa, 1) ^alpha*max(Scr/ kappa, 1)^(-1.209)*0.993^Age*1.018[if female]*1.159[if Black], where kappa=0.7(females) or 0.9(males), alpha=-0.329(females) or -0.411(males). min indicates the minimum of Scr/kappa or 1, max indicates the maximum of Scr/kappa or 1, and age is in years. Treatment-specific Baselines = the average of Visits A and B values for Placebo, and the average of Visit C and Day 1 values for SEL. Visit A= enrollment, Visit B= 7-14 days after Visit A, Visit C= 21-28 days after Visit B, and Visit 1= 7-14 days after Visit C. The Full Analysis Set included all participants who were randomised in the study, and received at least one dose of study drug in the Randomisation Phase.
    End point type
    Primary
    End point timeframe
    Treatment-specific Baselines (From enrollment (Visit A) up to 14 days after Visit A for placebo and from Visit C up to 14 days after Visit C for SEL)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses was planned for this endpoint.
    End point values
    		 Randomised SEL 18 mg Randomised Placebo
    Number of subjects analysed
    154
    156
    Units: mL/min/1.73m^2
        arithmetic mean (standard deviation)
    32.7 ( 10.59 )
    34.9 ( 10.81 )
    No statistical analyses for this end point

    Primary: eGFRcr Slope

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    End point title
    		 eGFRcr Slope
    End point description
    The values of eGFRcr were calculated using the CKD-EPI Creatinine Equation (2009). eGFRcr = 141*min(Scr/kappa, 1) ^alpha*max(Scr/kappa, 1)^(-1.209)*0.993^Age*1.018[if female]*1.159[if Black], where kappa=0.7(females) or 0.9(males), alpha=-0.329(females) or -0.411(males). min indicates the minimum of Scr/kappa or 1, max indicates the maximum of Scr/kappa or 1, and age is in years. Treatment specific baselines for eGFRcr: average of Visit A (enrollment) and Visit B (7-14 days after Visit A) values for Placebo, and average of Visit C (21-28 days after Visit B, and Visit 1 (7-14 days after Visit C) values for SEL. Participants in the Full Analysis Set with available data were analysed.
    End point type
    Primary
    End point timeframe
    Treatment-specific Baselines through Week 84
    End point values
    		 Randomised SEL 18 mg Randomised Placebo
    Number of subjects analysed
    153
    156
    Units: mL/min/1.73m^2/year
        least squares mean (standard error)
    -2.29 ( 0.58 )
    -3.49 ( 0.58 )
    Statistical analysis title
    		 Randomised SEL 18 mg, Randomised Placebo
    Statistical analysis description
    Estimates were from a random slope model with change in eGFRcr from treatment-specific Baselines at Weeks 4, 8, 12, 24, 36, 48, 60, 72, and 84 as outcome, including terms for treatment-specific Baseline eGFRcr, pre-run-in urine albumin to creatinine ratio (UACR) category (< 1500 mg/g vs. >= 1500 mg/g), concomitant use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors at Randomisation, treatment group, week, and treatment-by-week interaction, where week has a random effect.
    Comparison groups
    Randomised SEL 18 mg v Randomised Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1439
    Method
    		 Random Slope Model
    Parameter type
    		 Difference in Adjusted Mean
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 2.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.82

    Secondary: Percentage of Participants with Kidney Clinical Events at Week 48

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    End point title
    		 Percentage of Participants with Kidney Clinical Events at Week 48
    End point description
    Kidney clinical events were defined as any of the following events: confirmed ≥ 40% decline in eGFRcr from baseline, or kidney failure (dialysis performed for at least 4 weeks, kidney transplantation, or confirmed decrease in eGFRcr to < 15 mL/min/1.73 m^2 for participants without dialysis or kidney transplantation), or death due to kidney disease. Participants in the Full Analysis Set were analysed.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Randomised SEL 18 mg Randomised Placebo
    Number of subjects analysed
    154
    156
    Units: percentage of participants
        number (not applicable)
    9.1
    9.0
    Statistical analysis title
    		 Randomised SEL 18 mg, Randomised Placebo
    Statistical analysis description
    95% exact CI based on the Santner-Snell method was presented for the difference in proportions between SEL and placebo arms.
    Comparison groups
    Randomised SEL 18 mg v Randomised Placebo
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8353 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Percentage
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.9
         upper limit
    		 11.4
    Notes
    [2] - p-value was based on Cochran-Mantel-Haenszel test stratified by Randomisation stratification factors. Randomisation stratification factors= pre-run-in eGFRcr stratum, pre-run-in UACR category and concomitant use of SGLT-2 inhibitors at Randomisation.

    Secondary: Time From Randomization to First Occurrence of a Kidney Clinical Event: Event Rate Per 100 Participant-years for First Occurrence of Kidney Clinical Event

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    End point title
    		 Time From Randomization to First Occurrence of a Kidney Clinical Event: Event Rate Per 100 Participant-years for First Occurrence of Kidney Clinical Event
    End point description
    Kidney clinical events were defined as any of the following events: confirmed ≥ 40% decline in eGFRcr from baseline, or kidney failure (dialysis performed for at least 4 weeks, kidney transplantation, or confirmed decrease in eGFRcr to < 15 mL/min/1.73 m^2 for participants without dialysis or kidney transplantation), or death due to kidney disease. This outcome measure was analyzed using event rate per 100 participant-years for first occurrence of kidney clinical event. Participant year was calculated as total follow-up duration across all participants in a given group. Follow-up duration was defined as time from Randomization to the earliest of study completion, premature study discontinuation, death, or event of interest in each row. Participants in the Full Analysis Set were analysed.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Week 101
    End point values
    		 Randomised SEL 18 mg Randomised Placebo
    Number of subjects analysed
    154
    156
    Units: events per 100 participant-years
        number (not applicable)
    13.4
    9.8
    Statistical analysis title
    		 Randomised SEL 18 mg, Randomised Placebo
    Statistical analysis description
    Hazard ratio and 95% CI were estimated using a stratified Cox proportional hazard model, stratified by randomisation stratification factors and were reported only for outcomes with more than 10 events, and have at least 1 event in each treatment arm.
    Comparison groups
    Randomised SEL 18 mg v Randomised Placebo
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.201 [3]
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 2.72
    Notes
    [3] - P-value was calculated using a stratified log-rank test, stratified by randomisation stratification factors.

    Secondary: Pre-run-in Baseline Estimated Glomerular Filtration Rate Based on Cystatin C (eGFRcys)

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    End point title
    		 Pre-run-in Baseline Estimated Glomerular Filtration Rate Based on Cystatin C (eGFRcys)
    End point description
    eGFRcys = Estimated Glomerular Filtration Rate calculated by CKD-EPI Cystatin C Equation (2012). eGFR = 133*min(Standardized Serum Cystatin (Scys)/0.8, 1) ^(-0.499)*max(Scys/0.8, 1)^(-1.328)*0.996^Age*0.932[if female]. min indicates the minimum of Scys/0.8 or 1, max indicates the maximum of Scr/0.8 or 1, and age is in years. Participants in the Full Analysis Set were analysed.
    End point type
    Secondary
    End point timeframe
    Pre-run-in Baseline (Pre-run in Baseline = Average of visit A (Enrollment) and Visit B (7-14 days after Visit A) eGFRcys values)
    End point values
    		 Randomised SEL 18 mg Randomised Placebo
    Number of subjects analysed
    154
    156
    Units: mL/min/1.73m^2
        arithmetic mean (standard deviation)
    33.6 ( 11.81 )
    32.4 ( 10.94 )
    No statistical analyses for this end point

    Secondary: eGFRcys Slope

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    End point title
    		 eGFRcys Slope
    End point description
    eGFRcys = Estimated Glomerular Filtration Rate calculated by CKD-EPI Cystatin C Equation (2012). eGFR = 133*min(Scys/0.8, 1) ^(-0.499)*max(Scys/0.8, 1)^(-1.328)*0.996^Age*0.932[if female]. min indicates the minimum of Scys/0.8 or 1, max indicates the maximum of Scr/0.8 or 1, and age is in years. Pre-run in Baseline = Average of Visit A (Enrollment) and Visit B (7-14 days after Visit A) eGFRcys values. Participants in the Full Analysis Set with available data were analysed.
    End point type
    Secondary
    End point timeframe
    Pre-run-in Baseline through Week 84
    End point values
    		 Randomised SEL 18 mg Randomised Placebo
    Number of subjects analysed
    153
    156
    Units: mL/min/1.73m^2/year
        least squares mean (standard error)
    -3.79 ( 0.51 )
    -4.23 ( 0.51 )
    Statistical analysis title
    		 Randomised SEL 18 mg, Randomised Placebo
    Statistical analysis description
    Estimates were from a random slope model with change in eGFRcys from pre-run-in Baseline at Weeks 4, 8, 12, 24, 36, 48, 60, 72, and 84 as outcome, including terms for pre-run-in Baseline eGFRcys, pre-run-in UACR category (< 1500 mg/g vs. >= 1500 mg/g), concomitant use of SGLT-2 inhibitors at Randomisation, treatment group, week, and treatment-by-week interaction, where week has a random effect.
    Comparison groups
    Randomised SEL 18 mg v Randomised Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5399
    Method
    		 Random Slope Model
    Parameter type
    		 Difference in Adjusted Mean
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.97
         upper limit
    		 1.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.72

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-Cause Mortality: Enrollment up to maximum duration of 107.1 weeks; Adverse Events: First dose in Run-in SEL phase up to last dose (maximum: 101 weeks) plus 30 days
    Adverse event reporting additional description
    All-Cause Mortality: The All Enrolled Analysis Set included all participants who were enrolled in the study. There were no deaths in the Run-in Placebo period. Adverse Events: The Safety Analysis Set included all participants who took at least 1 dose of Run-in SEL.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Run-in SEL 18 mg
    Reporting group description
    		 Participants received SEL 18 mg tablet orally once daily for at least 4 weeks.

    Reporting group title
    Randomised Placebo
    Reporting group description
    		 Participants received placebo-to-match SEL tablet orally once daily for at least 48 weeks after randomisation.

    Reporting group title
    Randomised SEL 18 mg
    Reporting group description
    		 Participants received SEL 18 mg tablet orally once daily for at least 48 weeks after ramdomisation.

    Serious adverse events
    		 Run-in SEL 18 mg Randomised Placebo Randomised SEL 18 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 357 (4.48%)
    45 / 156 (28.85%)
    45 / 154 (29.22%)
         number of deaths (all causes)
    1
    7
    5
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cancer metastatic
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Lipoma
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 357 (0.00%)
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood pressure inadequately ~ controlled
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 357 (0.28%)
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary ~ disease
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device end of service
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Arteriogram coronary abnormal
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carbon dioxide abnormal
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio ~ increased
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Contusion
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Post procedural complication
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Arteriovenous malformation
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    3 / 357 (0.84%)
    5 / 156 (3.21%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 357 (0.00%)
    5 / 156 (3.21%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 357 (0.00%)
    2 / 156 (1.28%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 357 (0.28%)
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    0 / 357 (0.00%)
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 357 (0.00%)
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sinus node dysfunction
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrogenic anaemia
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinopathy hypertensive
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 357 (0.00%)
    5 / 156 (3.21%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic mass
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Jaundice cholestatic
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 357 (0.84%)
    7 / 156 (4.49%)
    10 / 154 (6.49%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 9
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 357 (0.00%)
    3 / 156 (1.92%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 357 (0.56%)
    0 / 156 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Diabetic nephropathy
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal mass
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcapsular renal haematoma
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 357 (0.00%)
    3 / 156 (1.92%)
    5 / 154 (3.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    0 / 357 (0.00%)
    2 / 156 (1.28%)
    5 / 154 (3.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Covid-19 pneumonia
         subjects affected / exposed
    0 / 357 (0.00%)
    3 / 156 (1.92%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 357 (0.28%)
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scrotal abscess
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypervolaemia
         subjects affected / exposed
    0 / 357 (0.00%)
    3 / 156 (1.92%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 357 (0.28%)
    1 / 156 (0.64%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 357 (0.28%)
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 357 (0.00%)
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 357 (0.28%)
    0 / 156 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency
         subjects affected / exposed
    0 / 357 (0.00%)
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Run-in SEL 18 mg Randomised Placebo Randomised SEL 18 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 357 (10.36%)
    49 / 156 (31.41%)
    55 / 154 (35.71%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 357 (2.80%)
    7 / 156 (4.49%)
    11 / 154 (7.14%)
         occurrences all number
    10
    7
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 357 (0.28%)
    8 / 156 (5.13%)
    5 / 154 (3.25%)
         occurrences all number
    1
    9
    5
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    5 / 357 (1.40%)
    8 / 156 (5.13%)
    11 / 154 (7.14%)
         occurrences all number
    5
    8
    11
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    7 / 357 (1.96%)
    3 / 156 (1.92%)
    11 / 154 (7.14%)
         occurrences all number
    7
    3
    11
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 357 (0.28%)
    4 / 156 (2.56%)
    10 / 154 (6.49%)
         occurrences all number
    1
    5
    10
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    6 / 357 (1.68%)
    9 / 156 (5.77%)
    5 / 154 (3.25%)
         occurrences all number
    6
    10
    5
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    8 / 357 (2.24%)
    11 / 156 (7.05%)
    12 / 154 (7.79%)
         occurrences all number
    8
    12
    15
    Hypoglycaemia
         subjects affected / exposed
    4 / 357 (1.12%)
    9 / 156 (5.77%)
    6 / 154 (3.90%)
         occurrences all number
    4
    13
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jun 2019
    • To address comments received from regulatory agencies. • To provide further clarifications on guidelines for participants who permanently discontinued study drug and remained on study. • To correct minor errors and inconsistencies throughout the protocol.
    13 Apr 2020
    The Phase 3 study was designed based on the hypothesis that the acute decline in eGFR is solely an artefact of SEL’s interaction with kidney transporters. Based upon the measured GFR results from the GS-US-223-0110 Phase 1b iohexol study with SEL, this hypothesis was challenged. Importantly, the new data did not alter our understanding of the safety of selonsertib, and the acute changes in kidney function were reversible as expected. Accordingly, Gilead decided to convert the Phase 3 study to a Phase 2b study in order to confirm the results of the prior post-hoc Phase 2 analysis using a Run-in design that prospectively accounted for the acute decline in eGFR associated with SEL. Additionally, efficacy was assessed in multiple ways to evaluate for consistency of effect on kidney outcomes.

    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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