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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled Study Evaluating the Safety and Efficacy of Semaglutide, and the Fixed-Dose Combination of Cilofexor and Firsocostat, Alone and in Combination, in Subjects with Compensated Cirrhosis (F4) due to Nonalcoholic Steatohepatitis (NASH)

    Summary
    EudraCT number
    		 2021-001445-12
    Trial protocol
    		 ES   FR  
    Global end of trial date
    09 Dec 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Nov 2025
    First version publication date
    28 Nov 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-454-6075
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04971785
    WHO universal trial number (UTN)
    		 -
    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
    09 Dec 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Nov 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The goal of this clinical study is to understand whether the study drugs, semaglutide (SEMA) with the fixed-dose combination (FDC) of cilofexor/firsocostat (CILO/FIR), cause fibrosis improvement and Nonalcoholic Steatohepatitis (NASH) resolution in participants with cirrhosis due to NASH.
    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
    09 Aug 2021
    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
    United States: 349
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Japan: 17
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Spain: 14
    Worldwide total number of subjects
    457
    EEA total number of subjects
    43
    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)
    257
    From 65 to 84 years
    200
    85 years and over
    0

    Subject disposition

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

    Pre-assignment
    Screening details
    		 1595 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
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SEMA + CILO/FIR FDC
    Arm description
    		 Participants received semaglutide (SEMA) 3.0 mg/mL subcutaneous (SC) injection once weekly and cilofexor and firsocostat (CILO/FIR) 30 mg/20 mg fixed-dose combination (FDC) tablet orally, once daily up to 72 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered as subcutaneous injection.

    Investigational medicinal product name
    Cilofexor/Firsocostat
    Investigational medicinal product code
    GS-9674/GS-0976
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally.

    Arm title
    		 SEMA + PTM CILO/FIR
    Arm description
    		 Participants received SEMA 3.0 mg/mL SC injection, once weekly and Placebo-To-Match (PTM) CILO/FIR FDC tablet orally, once daily up to 72 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered as subcutaneous injection.

    Investigational medicinal product name
    PTM CILO/FIR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally.

    Arm title
    		 PTM SEMA + CILO/FIR FDC
    Arm description
    		 Participants received PTM SEMA SC injection, once weekly and CILO/FIR 30 mg/20 mg FDC tablet orally, once daily up to 72 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PTM SEMA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered as subcutaneous injection.

    Investigational medicinal product name
    Cilofexor/Firsocostat
    Investigational medicinal product code
    GS-9674/GS-0976
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally.

    Arm title
    		 PTM SEMA + PTM CILO/FIR
    Arm description
    		 Participants received PTM SEMA SC injection, once weekly and PTM CILO/FIR FDC tablet orally, once daily up to 72 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PTM SEMA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered as subcutaneous injection.

    Investigational medicinal product name
    PTM CILO/FIR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally.

    Number of subjects in period 1 [1]
    		SEMA + CILO/FIR FDC SEMA + PTM CILO/FIR PTM SEMA + CILO/FIR FDC PTM SEMA + PTM CILO/FIR
    Started
    124
    122
    123
    84
    Completed
    103
    104
    91
    65
    Not completed
    21
    18
    32
    19
         Withdrew Consent
    5
    5
    17
    7
         Adverse Event
    7
    8
    6
    3
         Death
    -
    1
    1
    -
         Investigator's Discretion
    3
    1
    1
    -
         Protocol Violation
    3
    1
    1
    2
         Site Terminated by Sponsor
    1
    1
    -
    -
         Lost to follow-up
    2
    1
    6
    7
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 4 participants who were randomized but not treated were not included in the Safety Analysis Set for Period 1 table reported above.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SEMA + CILO/FIR FDC
    Reporting group description
    		 Participants received semaglutide (SEMA) 3.0 mg/mL subcutaneous (SC) injection once weekly and cilofexor and firsocostat (CILO/FIR) 30 mg/20 mg fixed-dose combination (FDC) tablet orally, once daily up to 72 weeks.

    Reporting group title
    SEMA + PTM CILO/FIR
    Reporting group description
    		 Participants received SEMA 3.0 mg/mL SC injection, once weekly and Placebo-To-Match (PTM) CILO/FIR FDC tablet orally, once daily up to 72 weeks.

    Reporting group title
    PTM SEMA + CILO/FIR FDC
    Reporting group description
    		 Participants received PTM SEMA SC injection, once weekly and CILO/FIR 30 mg/20 mg FDC tablet orally, once daily up to 72 weeks.

    Reporting group title
    PTM SEMA + PTM CILO/FIR
    Reporting group description
    		 Participants received PTM SEMA SC injection, once weekly and PTM CILO/FIR FDC tablet orally, once daily up to 72 weeks.

    Reporting group values
    		 SEMA + CILO/FIR FDC SEMA + PTM CILO/FIR PTM SEMA + CILO/FIR FDC PTM SEMA + PTM CILO/FIR Total
    Number of subjects
    		 124 122 123 84 453
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 72 73 67 44 256
        From 65-84 years
    		 52 49 56 40 197
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61 ( 10.4 ) 61 ( 9.2 ) 62 ( 9.5 ) 63 ( 9.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 83 85 74 50 292
        Male
    		 41 37 49 34 161
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 28 23 30 19 100
        Not Hispanic or Latino
    		 95 99 90 62 346
        Not Collected
    		 1 0 3 3 7
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 3 1 1 2 7
        Asian
    		 11 9 15 3 38
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 2 1 1 5 9
        White
    		 100 108 98 66 372
        More than one race
    		 5 2 3 4 14
        Not Collected
    		 3 1 5 4 13

    End points

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    End points reporting groups
    Reporting group title
    SEMA + CILO/FIR FDC
    Reporting group description
    		 Participants received semaglutide (SEMA) 3.0 mg/mL subcutaneous (SC) injection once weekly and cilofexor and firsocostat (CILO/FIR) 30 mg/20 mg fixed-dose combination (FDC) tablet orally, once daily up to 72 weeks.

    Reporting group title
    SEMA + PTM CILO/FIR
    Reporting group description
    		 Participants received SEMA 3.0 mg/mL SC injection, once weekly and Placebo-To-Match (PTM) CILO/FIR FDC tablet orally, once daily up to 72 weeks.

    Reporting group title
    PTM SEMA + CILO/FIR FDC
    Reporting group description
    		 Participants received PTM SEMA SC injection, once weekly and CILO/FIR 30 mg/20 mg FDC tablet orally, once daily up to 72 weeks.

    Reporting group title
    PTM SEMA + PTM CILO/FIR
    Reporting group description
    		 Participants received PTM SEMA SC injection, once weekly and PTM CILO/FIR FDC tablet orally, once daily up to 72 weeks.

    Primary: Percentage of Participants Who Achieved ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 72 in Semaglutide (SEMA) + Cilofexor/Firsocostat (CILO/FIR) Fixed Dose Combination (FDC) Versus Placebo Groups

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    End point title
    		 Percentage of Participants Who Achieved ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 72 in Semaglutide (SEMA) + Cilofexor/Firsocostat (CILO/FIR) Fixed Dose Combination (FDC) Versus Placebo Groups [1]
    End point description
    Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH clinical research network (CRN) classification. Worsening of NASH was defined as ≥ 1-point increase from baseline in hepatocellular ballooning or lobular inflammation. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off. Participants in the Full Analysis Set in SEMA + CILO/FIR FDC and PTM SEMA + PTM CILO/FIR were analyzed. The Full Analysis Set included all randomized participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 72
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned only for arms: SEMA + CILO/FIR vs PTM SEMA + PTM CILO/FIR.
    End point values
    		 SEMA + CILO/FIR FDC PTM SEMA + PTM CILO/FIR
    Number of subjects analysed
    124
    84
    Units: percentage of participants
        number (confidence interval 95%)
    13.7 (8.2 to 21.0)
    8.3 (3.4 to 16.4)
    Statistical analysis title
    		 SEMA + CILO/FIR FDC vs PTM SEMA + PTM CILO/FIR
    Comparison groups
    PTM SEMA + PTM CILO/FIR v SEMA + CILO/FIR FDC
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.2289
    Method
    		 Stratified Mantel-Haenszel test
    Parameter type
    		 Difference in percentages
    Point estimate
    5.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 14.9
    Notes
    [2] - Percentage difference and 95% confidence interval (CI) between each pair of treatment groups were from stratified Mantel-Haenszel test with baseline diabetes status and baseline enhanced liver fibrosis (ELF) category as stratification factors.

    Secondary: Percentage of Participants Who Achieved ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 72 in SEMA + CILO/FIR FDC Versus SEMA Alone

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    End point title
    		 Percentage of Participants Who Achieved ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 72 in SEMA + CILO/FIR FDC Versus SEMA Alone [3]
    End point description
    Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH clinical research network classification (CRN) classification. Worsening of NASH was defined as ≥ 1-point increase from baseline in hepatocellular ballooning or lobular inflammation. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off. Participants in the Full Analysis Set in SEMA + CILO/FIR and SEMA + PTM CILO/FIR were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 72
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned only for arms: SEMA + CILO/FIR vs SEMA + PTM CILO/FIR.
    End point values
    		 SEMA + CILO/FIR FDC SEMA + PTM CILO/FIR
    Number of subjects analysed
    124
    122
    Units: percentage of participants
        number (confidence interval 95%)
    13.7 (8.2 to 21.0)
    15.6 (9.6 to 23.2)
    Statistical analysis title
    		 SEMA + CILO/FIR FDC vs SEMA + PTM CILO/FIR
    Statistical analysis description
    Percentage difference and 95% CI between each pair of treatment groups presented were from stratified Mantel-Haenszel test with baseline diabetes status and baseline ELF category as stratification factors.
    Comparison groups
    SEMA + CILO/FIR FDC v SEMA + PTM CILO/FIR
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6959
    Method
    		 Stratified Mantel-Haenszel test
    Parameter type
    		 Difference in percentages
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.1
         upper limit
    		 7.4

    Secondary: Percentage of Participants With NASH Resolution Without Worsening in Fibrosis at Week 72 in SEMA + CILO/FIR FDC Versus Placebo Groups

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    End point title
    		 Percentage of Participants With NASH Resolution Without Worsening in Fibrosis at Week 72 in SEMA + CILO/FIR FDC Versus Placebo Groups [4]
    End point description
    NASH resolution was defined as lobular inflammation of 0 or 1 and hepatocellular ballooning of 0. Worsening of NASH was defined as ≥ 1-point increase from baseline in hepatocellular ballooning or lobular inflammation. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off. Participants in the Full Analysis Set in SEMA + CILO/FIR FDC and PTM SEMA + PTM CILO/FIR with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 72
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned only for arms: SEMA + CILO/FIR FDC vs PTM SEMA + PTM CILO/FIR.
    End point values
    		 SEMA + CILO/FIR FDC PTM SEMA + PTM CILO/FIR
    Number of subjects analysed
    82
    49
    Units: percentage of participants
        number (confidence interval 95%)
    57.3 (45.9 to 68.2)
    22.4 (11.8 to 36.6)
    Statistical analysis title
    		 SEMA + CILO/FIR FDC vs PTM SEMA + PTM CILO/FIR
    Statistical analysis description
    Percentage difference and 95% CI between each pair of treatment groups presented are from stratified Mantel-Haenszel test with baseline diabetes status and baseline ELF category as stratification factors.
    Comparison groups
    SEMA + CILO/FIR FDC v PTM SEMA + PTM CILO/FIR
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Stratified Mantel-Haenszel test
    Parameter type
    		 Difference in percentages
    Point estimate
    35.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.8
         upper limit
    		 52.6

    Secondary: Percentage of Participants With NASH Resolution Without Worsening in Fibrosis In Participants Treated With SEMA + CILO/FIR FDC Versus CILO/FIR Alone Groups

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    End point title
    		 Percentage of Participants With NASH Resolution Without Worsening in Fibrosis In Participants Treated With SEMA + CILO/FIR FDC Versus CILO/FIR Alone Groups [5]
    End point description
    NASH resolution was defined as lobular inflammation of 0 or 1 and hepatocellular ballooning of 0. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off. Participants in the Full Analysis Set in SEMA + CILO/FIR FDC and PTM SEMA + CILO/FIR FDC with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 72
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned only for arms: SEMA + CILO/FIR vs PTM SEMA + CILO/FIR
    End point values
    		 SEMA + CILO/FIR FDC PTM SEMA + CILO/FIR FDC
    Number of subjects analysed
    82
    88
    Units: percentage of participants
        number (confidence interval 95%)
    57.3 (45.9 to 68.2)
    31.8 (22.3 to 42.6)
    Statistical analysis title
    		 SEMA + CILO/FIR FDC vs PTM SEMA + CILO/FIR FDC
    Statistical analysis description
    Percentage difference and 95% CI between each pair of treatment groups presented were from stratified Mantel-Haenszel test with baseline diabetes status and baseline ELF category as stratification factors.
    Comparison groups
    SEMA + CILO/FIR FDC v PTM SEMA + CILO/FIR FDC
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 Stratified Mantel-Haenszel test
    Parameter type
    		 Difference in percentages
    Point estimate
    26.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.3
         upper limit
    		 40.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality and Adverse events: Up to 72 weeks plus 35 days
    Adverse event reporting additional description
    All-cause mortality: The All Randomized Analysis Set included all participants who were randomized in the study. Adverse events: The Safety Analysis Set included all participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    SEMA + CILO/FIR FDC
    Reporting group description
    		 Participants received PTM SEMA SC injection, once weekly and PTM CILO/FIR FDC tablet orally, once daily up to 72 weeks.

    Reporting group title
    SEMA + PTM CILO/FIR
    Reporting group description
    		 Participants received SEMA 3.0 mg/mL SC injection, once weekly and Placebo-To-Match (PTM) CILO/FIR FDC tablet orally, once daily up to 72 weeks.

    Reporting group title
    PTM SEMA + CILO/FIR FDC
    Reporting group description
    		 Participants received PTM SEMA SC injection, once weekly and CILO/FIR 30 mg/20 mg FDC tablet orally, once daily up to 72 weeks.

    Reporting group title
    PTM SEMA + PTM CILO/FIR
    Reporting group description
    		 Participants received PTM SEMA SC injection, once weekly and PTM CILO/FIR FDC tablet orally, once daily up to 72 weeks.

    Serious adverse events
    		 SEMA + CILO/FIR FDC SEMA + PTM CILO/FIR PTM SEMA + CILO/FIR FDC PTM SEMA + PTM CILO/FIR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 124 (13.71%)
    13 / 122 (10.66%)
    18 / 123 (14.63%)
    11 / 84 (13.10%)
         number of deaths (all causes)
    0
    1
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    2 / 124 (1.61%)
    0 / 122 (0.00%)
    3 / 123 (2.44%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer recurrent
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ductal adenocarcinoma of pancreas
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant glioma
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the vulva
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Shock
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prosthetic cardiac valve stenosis
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heat exhaustion
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shoulder fracture
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Sensory loss
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Steatohepatitis
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 124 (0.81%)
    2 / 122 (1.64%)
    0 / 123 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    3 / 124 (2.42%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvi-ureteric obstruction
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diffuse idiopathic skeletal hyperostosis
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    2 / 123 (1.63%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis intestinal perforated
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural cellulitis
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SEMA + CILO/FIR FDC SEMA + PTM CILO/FIR PTM SEMA + CILO/FIR FDC PTM SEMA + PTM CILO/FIR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    101 / 124 (81.45%)
    97 / 122 (79.51%)
    85 / 123 (69.11%)
    60 / 84 (71.43%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 124 (2.42%)
    1 / 122 (0.82%)
    3 / 123 (2.44%)
    6 / 84 (7.14%)
         occurrences all number
    3
    1
    3
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 124 (5.65%)
    10 / 122 (8.20%)
    9 / 123 (7.32%)
    8 / 84 (9.52%)
         occurrences all number
    8
    11
    10
    8
    Headache
         subjects affected / exposed
    7 / 124 (5.65%)
    11 / 122 (9.02%)
    12 / 123 (9.76%)
    3 / 84 (3.57%)
         occurrences all number
    7
    11
    22
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    17 / 124 (13.71%)
    17 / 122 (13.93%)
    9 / 123 (7.32%)
    11 / 84 (13.10%)
         occurrences all number
    19
    17
    9
    11
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    59 / 124 (47.58%)
    49 / 122 (40.16%)
    29 / 123 (23.58%)
    19 / 84 (22.62%)
         occurrences all number
    70
    58
    38
    22
    Diarrhoea
         subjects affected / exposed
    34 / 124 (27.42%)
    25 / 122 (20.49%)
    16 / 123 (13.01%)
    15 / 84 (17.86%)
         occurrences all number
    41
    33
    19
    18
    Constipation
         subjects affected / exposed
    30 / 124 (24.19%)
    26 / 122 (21.31%)
    11 / 123 (8.94%)
    7 / 84 (8.33%)
         occurrences all number
    34
    27
    13
    8
    Vomiting
         subjects affected / exposed
    27 / 124 (21.77%)
    21 / 122 (17.21%)
    7 / 123 (5.69%)
    6 / 84 (7.14%)
         occurrences all number
    41
    28
    10
    6
    Abdominal pain
         subjects affected / exposed
    11 / 124 (8.87%)
    10 / 122 (8.20%)
    6 / 123 (4.88%)
    11 / 84 (13.10%)
         occurrences all number
    11
    11
    6
    12
    Abdominal pain upper
         subjects affected / exposed
    7 / 124 (5.65%)
    11 / 122 (9.02%)
    6 / 123 (4.88%)
    8 / 84 (9.52%)
         occurrences all number
    8
    12
    7
    8
    Abdominal distension
         subjects affected / exposed
    9 / 124 (7.26%)
    10 / 122 (8.20%)
    4 / 123 (3.25%)
    6 / 84 (7.14%)
         occurrences all number
    9
    11
    6
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    7 / 124 (5.65%)
    13 / 122 (10.66%)
    3 / 123 (2.44%)
    2 / 84 (2.38%)
         occurrences all number
    8
    13
    3
    2
    Dyspepsia
         subjects affected / exposed
    12 / 124 (9.68%)
    2 / 122 (1.64%)
    4 / 123 (3.25%)
    3 / 84 (3.57%)
         occurrences all number
    15
    2
    4
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 124 (2.42%)
    3 / 122 (2.46%)
    7 / 123 (5.69%)
    7 / 84 (8.33%)
         occurrences all number
    3
    3
    7
    7
    Dyspnoea
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 122 (0.82%)
    2 / 123 (1.63%)
    5 / 84 (5.95%)
         occurrences all number
    0
    1
    2
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    8 / 124 (6.45%)
    13 / 122 (10.66%)
    12 / 123 (9.76%)
    6 / 84 (7.14%)
         occurrences all number
    9
    13
    12
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 124 (6.45%)
    6 / 122 (4.92%)
    12 / 123 (9.76%)
    11 / 84 (13.10%)
         occurrences all number
    8
    6
    12
    12
    Back pain
         subjects affected / exposed
    8 / 124 (6.45%)
    7 / 122 (5.74%)
    8 / 123 (6.50%)
    7 / 84 (8.33%)
         occurrences all number
    8
    7
    8
    7
    Pain in extremity
         subjects affected / exposed
    2 / 124 (1.61%)
    4 / 122 (3.28%)
    7 / 123 (5.69%)
    3 / 84 (3.57%)
         occurrences all number
    2
    4
    7
    4
    Infections and infestations
    COVID-19
         subjects affected / exposed
    21 / 124 (16.94%)
    15 / 122 (12.30%)
    15 / 123 (12.20%)
    14 / 84 (16.67%)
         occurrences all number
    23
    15
    15
    15
    Urinary tract infection
         subjects affected / exposed
    13 / 124 (10.48%)
    6 / 122 (4.92%)
    8 / 123 (6.50%)
    3 / 84 (3.57%)
         occurrences all number
    23
    13
    8
    5
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 124 (5.65%)
    4 / 122 (3.28%)
    12 / 123 (9.76%)
    4 / 84 (4.76%)
         occurrences all number
    7
    4
    13
    7
    Sinusitis
         subjects affected / exposed
    8 / 124 (6.45%)
    8 / 122 (6.56%)
    4 / 123 (3.25%)
    6 / 84 (7.14%)
         occurrences all number
    9
    10
    4
    9
    Nasopharyngitis
         subjects affected / exposed
    7 / 124 (5.65%)
    4 / 122 (3.28%)
    6 / 123 (4.88%)
    4 / 84 (4.76%)
         occurrences all number
    11
    6
    6
    4
    Bronchitis
         subjects affected / exposed
    2 / 124 (1.61%)
    3 / 122 (2.46%)
    5 / 123 (4.07%)
    5 / 84 (5.95%)
         occurrences all number
    2
    3
    6
    5
    Influenza
         subjects affected / exposed
    1 / 124 (0.81%)
    2 / 122 (1.64%)
    3 / 123 (2.44%)
    5 / 84 (5.95%)
         occurrences all number
    1
    2
    4
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    19 / 124 (15.32%)
    20 / 122 (16.39%)
    7 / 123 (5.69%)
    5 / 84 (5.95%)
         occurrences all number
    19
    20
    7
    6
    Hypoglycaemia
         subjects affected / exposed
    14 / 124 (11.29%)
    4 / 122 (3.28%)
    3 / 123 (2.44%)
    5 / 84 (5.95%)
         occurrences all number
    42
    33
    6
    15
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 124 (1.61%)
    0 / 122 (0.00%)
    7 / 123 (5.69%)
    2 / 84 (2.38%)
         occurrences all number
    2
    0
    7
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2021
    • Included collection of a single pharmacokinetics (PK) blood sample at the early termination (ET) visit (anytime) and at unscheduled visits (anytime) that were performed for the purpose of safety evaluation (eg, serious adverse event follow-up). • “Anthropometric measurements” changed to “measurement of hip and waist circumference” throughout. • Included assessment of any findings related to gallstones or other hepatobiliary disease in addition to hepatocellular carcinoma (HCC) during screening and on-study abdominal ultrasounds. • Data monitoring committee (DMC) to be notified if study drug was withheld. • The protocol synopsis and the study procedures table were updated to align with the updates to the body of the protocol. • Administrative, editorial, and formatting updates, changes, corrections, and clarifications were made, where appropriate, throughout the document.
    26 Oct 2023
    • Changed the primary objective to evaluate only whether the combination of SEMA with the fixed-dose combination (FDC) of CILO/FIR causes fibrosis improvement without worsening of NASH compared with placebo; NASH resolution was no longer evaluated as part of the primary objective. The rationale for this change was that increasingly fibrosis improvement was recognized as the biomarker most likely to predict clinical benefit in a cirrhotic NASH study population, and this change allow fibrosis improvement to be tested independently as the highest priority hypothesis. • Added a secondary objective to evaluate whether the combination of SEMA with the FDC of CILO/FIR causes NASH resolution in participants with compensated cirrhosis due to NASH, as compared with placebo. • Changed coprimary endpoints to a single primary endpoint of fibrosis improvement without worsening of NASH in order to test fibrosis improvement independently as the highest priority hypothesis, appropriate for a cirrhotic NASH study population. • Information for statistical testing of the primary and secondary endpoints was changed to order analysis objectives in keeping with the changes to the endpoints, and for consistency with changes made in other sections. • Estimand strategy was added and updated for primary/secondary endpoints based on the modifications made to the endpoints in the protocol. • Statistical considerations section was updated to add “power calculation.” • Dose escalation schedule for SEMA was updated. • A list of study interventions and their marketing authorization status was added. • New section regarding definition of serious adverse drug reaction was added. • Section for “Liver-Related Clinical Events” was added. • Pregnancy reporting process and time period was updated. • The text related to “repeating liver-related laboratory assessments (ALT, AST, ALP, GGT, total bilirubin, INR) within 72 hours of initial results (or as soon as possible)” removed from toxicities

    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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