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    Clinical Trial Results:
    A randomized, double-blind, parallel-group, multicenter study to assess efficacy, safety, and tolerability of oral tropifexor (LJN452) & licogliflozin (LIK066) combination therapy and each monotherapy, compared with placebo for treatment of adult patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis.(ELIVATE)

    Summary
    EudraCT number
    		 2019-002324-32
    Trial protocol
    		 BE   DE   GB   ES   DK   IT   SK  
    Global end of trial date
    27 Oct 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Nov 2023
    First version publication date
    11 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLJN452D12201C
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04065841
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.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
    27 Oct 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of tropifexor + licogliflozin in combination therapy and each monotherapy treatment, as assessed by histologic improvement after 48 weeks compared to placebo in participants with NASH and stage 2 or 3 fibrosis.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Dec 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
    Argentina: 3
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Chile: 5
    Country: Number of subjects enrolled
    Colombia: 4
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Estonia: 5
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    India: 4
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Japan: 15
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Mexico: 23
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 2
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Singapore: 11
    Country: Number of subjects enrolled
    South Africa: 5
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    United States: 86
    Worldwide total number of subjects
    233
    EEA total number of subjects
    45
    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)
    186
    From 65 to 84 years
    47
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 234 participants were randomized at 81 sites.

    Pre-assignment
    Screening details
    		 One of the randomized participants in the tropifexor group was not treated due to loss of interest in the study.

    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, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 tropifexor monotherapy
    Arm description
    		 Tropifexor monotherapy arm: tropifexor 140 mcg capsule (+ placebo matching licogliflozin tablet), once daily orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tropifexor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Tropifexor monotherapy arm: tropifexor 140 mcg capsule (+ placebo matching licogliflozin tablet), once daily orally

    Arm title
    		 licogliflozin monotherapy
    Arm description
    		 Licogliflozin monotherapy arm: licogliflozin 30 mg tablet (+ placebo matching tropifexor capsule), once daily orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Licogliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Licogliflozin monotherapy arm: licogliflozin 30 mg tablet (+ placebo matching tropifexor capsule), once daily orally

    Arm title
    		 combination therapy
    Arm description
    		 Combination therapy arm: tropifexor 140 mcg capsule + licogliflozin 30 mg tablet, once daily orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    tropifexor + licogliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Combination therapy arm: tropifexor 140 mcg capsule + licogliflozin 30 mg tablet, once daily orally

    Arm title
    		 Placebo
    Arm description
    		 Placebo arm: placebo matching tropifexor capsule + placebo matching licogliflozin tablet, once daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo arm: placebo matching tropifexor capsule + placebo matching licogliflozin tablet, once daily

    Number of subjects in period 1
    		tropifexor monotherapy licogliflozin monotherapy combination therapy Placebo
    Started
    53
    55
    84
    41
    Completed
    24
    33
    42
    21
    Not completed
    29
    22
    42
    20
         Physician decision
    1
    -
    -
    -
         Consent withdrawn by subject
    1
    1
    2
    -
         Study terminated by Sponsor
    22
    16
    28
    17
         Adverse event, non-fatal
    4
    2
    10
    1
         Lost to follow-up
    1
    2
    2
    2
         Protocol deviation
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    tropifexor monotherapy
    Reporting group description
    		 Tropifexor monotherapy arm: tropifexor 140 mcg capsule (+ placebo matching licogliflozin tablet), once daily orally

    Reporting group title
    licogliflozin monotherapy
    Reporting group description
    		 Licogliflozin monotherapy arm: licogliflozin 30 mg tablet (+ placebo matching tropifexor capsule), once daily orally

    Reporting group title
    combination therapy
    Reporting group description
    		 Combination therapy arm: tropifexor 140 mcg capsule + licogliflozin 30 mg tablet, once daily orally

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo arm: placebo matching tropifexor capsule + placebo matching licogliflozin tablet, once daily

    Reporting group values
    		 tropifexor monotherapy licogliflozin monotherapy combination therapy Placebo Total
    Number of subjects
    		 53 55 84 41 233
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0 0 0
        Between 18 and 65 years
    		 42 39 70 35 186
        >=65 years
    		 11 16 14 6 47
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 54.5 ( 11.09 ) 56.0 ( 12.13 ) 54.7 ( 10.82 ) 54.9 ( 10.22 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 26 34 43 26 129
        Male
    		 27 21 41 15 104
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 39 40 63 32 174
        Black or African American
    		 0 4 3 0 7
        Asian
    		 9 10 17 5 41
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 0 1
        American Indian or Alaska Native
    		 4 0 0 4 8
        Unknown
    		 0 1 1 0 2

    End points

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    End points reporting groups
    Reporting group title
    tropifexor monotherapy
    Reporting group description
    		 Tropifexor monotherapy arm: tropifexor 140 mcg capsule (+ placebo matching licogliflozin tablet), once daily orally

    Reporting group title
    licogliflozin monotherapy
    Reporting group description
    		 Licogliflozin monotherapy arm: licogliflozin 30 mg tablet (+ placebo matching tropifexor capsule), once daily orally

    Reporting group title
    combination therapy
    Reporting group description
    		 Combination therapy arm: tropifexor 140 mcg capsule + licogliflozin 30 mg tablet, once daily orally

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo arm: placebo matching tropifexor capsule + placebo matching licogliflozin tablet, once daily

    Primary: Histological improvement: Proportion of participants who responded at Week 48 compared with baseline

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    End point title
    		 Histological improvement: Proportion of participants who responded at Week 48 compared with baseline [1]
    End point description
    Response was defined as at least a one-stage improvement in fibrosis without worsening of nonalcoholic steatohepatitis (NASH) Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis.
    End point type
    Primary
    End point timeframe
    Baseline, Week 48
    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 analysis was planned for this primary outcome.
    End point values
    		 tropifexor monotherapy licogliflozin monotherapy combination therapy Placebo
    Number of subjects analysed
    23
    28
    34
    17
    Units: Participants
    6
    9
    10
    4
    No statistical analyses for this end point

    Primary: Proportion of participants with resolution of NASH and no worsening of fibrosis

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    End point title
    		 Proportion of participants with resolution of NASH and no worsening of fibrosis [2]
    End point description
    Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis.
    End point type
    Primary
    End point timeframe
    48 weeks
    Notes
    [2] - 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 analysis was planned for this primary outcome.
    End point values
    		 tropifexor monotherapy licogliflozin monotherapy combination therapy Placebo
    Number of subjects analysed
    23
    28
    34
    17
    Units: Participants
    5
    3
    10
    2
    No statistical analyses for this end point

    Secondary: Proportion of participants with at least one stage improvement in fibrosis

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    End point title
    		 Proportion of participants with at least one stage improvement in fibrosis
    End point description
    Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 tropifexor monotherapy licogliflozin monotherapy combination therapy Placebo
    Number of subjects analysed
    23
    28
    34
    17
    Units: Participants
    6
    10
    11
    4
    No statistical analyses for this end point

    Secondary: Proportion of participants who achieved resolution of NASH and no worsening of fibrosis OR improvement in fibrosis by at least one stage without worsening of NASH

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    End point title
    		 Proportion of participants who achieved resolution of NASH and no worsening of fibrosis OR improvement in fibrosis by at least one stage without worsening of NASH
    End point description
    Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 tropifexor monotherapy licogliflozin monotherapy combination therapy Placebo
    Number of subjects analysed
    23
    28
    34
    17
    Units: Participants
    8
    10
    14
    5
    No statistical analyses for this end point

    Secondary: Proportion of participants with at least two stage improvement in fibrosis without worsening of NASH

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    End point title
    		 Proportion of participants with at least two stage improvement in fibrosis without worsening of NASH
    End point description
    Fibrosis staging and Non-alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 tropifexor monotherapy licogliflozin monotherapy combination therapy Placebo
    Number of subjects analysed
    23
    28
    34
    17
    Units: Participants
    3
    4
    3
    3
    No statistical analyses for this end point

    Secondary: Proportion of participants achieving 5% or more reduction in body weight at Week 48 compared with baseline

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    End point title
    		 Proportion of participants achieving 5% or more reduction in body weight at Week 48 compared with baseline
    End point description
    Whether the participants had 5% or more reduction in body weight.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 tropifexor monotherapy licogliflozin monotherapy combination therapy Placebo
    Number of subjects analysed
    23
    32
    35
    24
    Units: Participants
    12
    9
    28
    3
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 48 in percent liver fat content based on magnetic resonance imaging - proton density fat fraction (MRI - PDFF)

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    End point title
    		 Change from Baseline to Week 48 in percent liver fat content based on magnetic resonance imaging - proton density fat fraction (MRI - PDFF)
    End point description
    Change in liver fat content based on MRI-PDFF.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 tropifexor monotherapy licogliflozin monotherapy combination therapy Placebo
    Number of subjects analysed
    15
    19
    21
    20
    Units: Percent liver fat
        arithmetic mean (standard deviation)
    -6.57 ( 5.913 )
    -2.64 ( 5.866 )
    -7.69 ( 6.702 )
    -2.58 ( 3.599 )
    No statistical analyses for this end point

    Secondary: Change in GGT over time

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    End point title
    		 Change in GGT over time
    End point description
    To evaluate the relationship of investigational treatment and gamma-glutamyl transferase (GGT), a marker of cholestasis and oxidative stress. Due to early termination and a small sample size, the analysis could not be performed.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 tropifexor monotherapy licogliflozin monotherapy combination therapy Placebo
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    Units: Participants
    Notes
    [3] - Due to early termination and a small sample size, the analysis could not be performed.
    [4] - Due to early termination and a small sample size, the analysis could not be performed.
    [5] - Due to early termination and a small sample size, the analysis could not be performed.
    [6] - Due to early termination and a small sample size, the analysis could not be performed.
    No statistical analyses for this end point

    Secondary: Change in ALT and AST over time

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    End point title
    		 Change in ALT and AST over time
    End point description
    To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH (ALT and AST). Due to early termination and a small sample size, the analysis could not be performed. ALT=alanine transaminase AST=aspartate aminotransferase
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 tropifexor monotherapy licogliflozin monotherapy combination therapy Placebo
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    0 [10]
    Units: Participants
    Notes
    [7] - Due to early termination and a small sample size, the analysis could not be performed.
    [8] - Due to early termination and a small sample size, the analysis could not be performed.
    [9] - Due to early termination and a small sample size, the analysis could not be performed.
    [10] - Due to early termination and a small sample size, the analysis could not be performed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 52 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    LJN452
    Reporting group description
    		 LJN452

    Reporting group title
    LIK066
    Reporting group description
    		 LIK066

    Reporting group title
    All Patients
    Reporting group description
    		 All Patients

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Combination
    Reporting group description
    		 Combination

    Serious adverse events
    		 LJN452 LIK066 All Patients Placebo Combination
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 55 (5.45%)
    14 / 233 (6.01%)
    3 / 41 (7.32%)
    4 / 84 (4.76%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian cancer
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural fever
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    1 / 41 (2.44%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    1 / 41 (2.44%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoperitoneum
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemobilia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    1 / 41 (2.44%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    1 / 41 (2.44%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    1 / 233 (0.43%)
    0 / 41 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LJN452 LIK066 All Patients Placebo Combination
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 53 (66.04%)
    39 / 55 (70.91%)
    151 / 233 (64.81%)
    23 / 41 (56.10%)
    54 / 84 (64.29%)
    Investigations
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 55 (3.64%)
    8 / 233 (3.43%)
    3 / 41 (7.32%)
    2 / 84 (2.38%)
         occurrences all number
    1
    2
    8
    3
    2
    Glucose urine present
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 55 (5.45%)
    7 / 233 (3.00%)
    0 / 41 (0.00%)
    2 / 84 (2.38%)
         occurrences all number
    2
    3
    7
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 55 (3.64%)
    7 / 233 (3.00%)
    0 / 41 (0.00%)
    2 / 84 (2.38%)
         occurrences all number
    4
    2
    8
    0
    2
    Headache
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 55 (1.82%)
    12 / 233 (5.15%)
    6 / 41 (14.63%)
    3 / 84 (3.57%)
         occurrences all number
    3
    1
    13
    6
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 53 (0.00%)
    5 / 55 (9.09%)
    6 / 233 (2.58%)
    1 / 41 (2.44%)
    0 / 84 (0.00%)
         occurrences all number
    0
    6
    7
    1
    0
    Fatigue
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 55 (0.00%)
    5 / 233 (2.15%)
    1 / 41 (2.44%)
    1 / 84 (1.19%)
         occurrences all number
    3
    0
    5
    1
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 55 (5.45%)
    12 / 233 (5.15%)
    2 / 41 (4.88%)
    5 / 84 (5.95%)
         occurrences all number
    2
    3
    12
    2
    5
    Dyspepsia
         subjects affected / exposed
    2 / 53 (3.77%)
    4 / 55 (7.27%)
    9 / 233 (3.86%)
    1 / 41 (2.44%)
    2 / 84 (2.38%)
         occurrences all number
    2
    4
    9
    1
    2
    Diarrhoea
         subjects affected / exposed
    7 / 53 (13.21%)
    21 / 55 (38.18%)
    55 / 233 (23.61%)
    6 / 41 (14.63%)
    21 / 84 (25.00%)
         occurrences all number
    10
    48
    105
    8
    39
    Abdominal pain upper
         subjects affected / exposed
    4 / 53 (7.55%)
    2 / 55 (3.64%)
    8 / 233 (3.43%)
    1 / 41 (2.44%)
    1 / 84 (1.19%)
         occurrences all number
    5
    2
    9
    1
    1
    Flatulence
         subjects affected / exposed
    4 / 53 (7.55%)
    4 / 55 (7.27%)
    11 / 233 (4.72%)
    0 / 41 (0.00%)
    3 / 84 (3.57%)
         occurrences all number
    4
    4
    13
    0
    5
    Nausea
         subjects affected / exposed
    6 / 53 (11.32%)
    4 / 55 (7.27%)
    19 / 233 (8.15%)
    2 / 41 (4.88%)
    7 / 84 (8.33%)
         occurrences all number
    11
    4
    24
    2
    7
    Vomiting
         subjects affected / exposed
    7 / 53 (13.21%)
    2 / 55 (3.64%)
    14 / 233 (6.01%)
    2 / 41 (4.88%)
    3 / 84 (3.57%)
         occurrences all number
    9
    2
    16
    2
    3
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 53 (0.00%)
    4 / 55 (7.27%)
    5 / 233 (2.15%)
    0 / 41 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    4
    5
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    20 / 53 (37.74%)
    9 / 55 (16.36%)
    55 / 233 (23.61%)
    4 / 41 (9.76%)
    22 / 84 (26.19%)
         occurrences all number
    26
    11
    68
    5
    26
    Rash
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 55 (5.45%)
    7 / 233 (3.00%)
    2 / 41 (4.88%)
    0 / 84 (0.00%)
         occurrences all number
    3
    6
    11
    2
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 55 (5.45%)
    3 / 233 (1.29%)
    0 / 41 (0.00%)
    0 / 84 (0.00%)
         occurrences all number
    0
    3
    3
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 53 (7.55%)
    0 / 55 (0.00%)
    5 / 233 (2.15%)
    0 / 41 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    4
    0
    6
    0
    2
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 55 (5.45%)
    6 / 233 (2.58%)
    1 / 41 (2.44%)
    2 / 84 (2.38%)
         occurrences all number
    0
    3
    6
    1
    2
    Back pain
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 55 (3.64%)
    6 / 233 (2.58%)
    3 / 41 (7.32%)
    0 / 84 (0.00%)
         occurrences all number
    1
    2
    6
    3
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 53 (1.89%)
    10 / 55 (18.18%)
    29 / 233 (12.45%)
    9 / 41 (21.95%)
    9 / 84 (10.71%)
         occurrences all number
    1
    10
    29
    9
    9
    Urinary tract infection
         subjects affected / exposed
    3 / 53 (5.66%)
    6 / 55 (10.91%)
    15 / 233 (6.44%)
    2 / 41 (4.88%)
    4 / 84 (4.76%)
         occurrences all number
    6
    10
    27
    4
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2020
    Included a placebo arm to minimize sources of bias and to ensure reliable inference with respect to the safety and effectiveness of the treatments; increased sample size to accommodate addition of placebo arm, change of hypothesis tests, update in response rate assumptions and to increase statistical power; provided guidance for study conduct in the context of the COVID-19 or other pandemic.
    30 Apr 2021
    Introduced the tropifexor single 140 µg hard gelatin capsule as a replacement for 3 lower dose hard gelatin capsules that made up this dose (one each of 10 µg, 30 µg and 100 µg); corrected the definition of “no worsening of NASH” to align with definitions in the FDA and EMA guidance documents; included additional emerging guidance for study conduct in the context of the COVID-19 or other public health emergency as declared by Local or Regional authorities, i.e., pandemic, epidemic or natural disaster.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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