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    Clinical Trial Results:
    A randomized, double-blind, multicenter study to assess the safety, tolerability, and efficacy of a combination treatment of tropifexor (LJN452) and cenicriviroc (CVC) in adult patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis (TANDEM)

    Summary
    EudraCT number
    		 2017-004208-24
    Trial protocol
    		 GB   CZ   DE   BE   FR   PT   ES   LV   IT  
    Global end of trial date
    15 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Oct 2021
    First version publication date
    30 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLJC242A2201J
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03517540
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novaris Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Study Director, 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
    15 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2020
    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 the safety and tolerability of tropifexor + CVC in patients with NASH and fibrosis (stage 2 or 3 as per NASH CRN histological score, F2/F3) by monitoring adverse events, vital signs and laboratory values during 48 weeks of treatment as compared to monotherapy with each of tropifexor and CVC. The endpoint for the primary objective was to evaluate the occurrence of AEs, SAEs, AEs resulting in discontinuation of study treatment, AESIs, and changes in vital signs and laboratory values over 48 weeks of treatment.
    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
    		 Cenicriviroc (CVC) is a C-C chemokine receptors type 2 and 5 dual antagonist under evaluation for treating liver fibrosis in adults with nonalcoholic steatohepatitis (NASH)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Sep 2018
    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: 8
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Czechia: 2
    Country: Number of subjects enrolled
    Egypt: 1
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    India: 7
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    United States: 101
    Worldwide total number of subjects
    193
    EEA total number of subjects
    37
    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)
    149
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 193 participants enrolled at 65 sites in 17 countries

    Pre-assignment
    Screening details
    		 450 of 643 subjects discontinued during screening phase

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind [1]
    Roles blinded
    		 Subject, Monitor, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LJN452 140 mcg
    Arm description
    		 tropifexor 140 mcg, once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Arm A: tropifexor 140 mcg, once daily
    Investigational medicinal product code
    LJN452
    Other name
    tropifexor
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants in this arm received tropifexor 140 mcg capsule once daily

    Arm title
    		 CVC 150 mg
    Arm description
    		 Cenicriviroc (CVC) 150 mg, once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Arm B: CVC 150 mg, once daily
    Investigational medicinal product code
    CVC
    Other name
    cenicriviroc
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants in this arm received CVC 150 mg capsule once daily

    Arm title
    		 LJN452 140 mcg + CVC 150 mg
    Arm description
    		 tropifexor 140 mcg + CVC 150 mg, once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Arm C: tropifexor 140 mcg + CVC 150 mg, once daily
    Investigational medicinal product code
    LJN452 + CVC
    Other name
    tropifexor and cenicriviroc
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participannts in this group received tropifexor 140 mcg capsule + CVC 150 mg capsule once daily

    Arm title
    		 LJN452 90 mcg + CVC 150 mg
    Arm description
    		 tropifexor 90 mcg + CVC 150 mg, once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Arm D: tropifexor 90 mcg + CVC 150 mg, once daily.
    Investigational medicinal product code
    LJN452 + CVC
    Other name
    tropifexor and cenicriviroc
    Pharmaceutical forms
    Capsule
    Routes of administration
    Intratumoral use, Oral use
    Dosage and administration details
    Participannts in this group received tropifexor 90 mcg capsule + CVC 150 mg capsule once daily

    Notes
    [1] - The roles blinded appear to be inconsistent with a double blind trial.
    Justification: This was a double-blind study: patients, Investigator staff, persons performing the assessments, and Novartis clinical trial team (or delegates) remained blinded to the identity of study treatments from the time of randomization (until final database lock).
    Number of subjects in period 1
    		LJN452 140 mcg CVC 150 mg LJN452 140 mcg + CVC 150 mg LJN452 90 mcg + CVC 150 mg
    Started
    50
    48
    47
    48
    Completed
    36
    41
    38
    43
    Not completed
    14
    7
    9
    5
         Consent withdrawn by subject
    3
    4
    1
    3
         Adverse event, non-fatal
    9
    3
    8
    1
         Protocol deviation
    2
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LJN452 140 mcg
    Reporting group description
    		 tropifexor 140 mcg, once daily

    Reporting group title
    CVC 150 mg
    Reporting group description
    		 Cenicriviroc (CVC) 150 mg, once daily

    Reporting group title
    LJN452 140 mcg + CVC 150 mg
    Reporting group description
    		 tropifexor 140 mcg + CVC 150 mg, once daily

    Reporting group title
    LJN452 90 mcg + CVC 150 mg
    Reporting group description
    		 tropifexor 90 mcg + CVC 150 mg, once daily

    Reporting group values
    		 LJN452 140 mcg CVC 150 mg LJN452 140 mcg + CVC 150 mg LJN452 90 mcg + CVC 150 mg Total
    Number of subjects
    		 50 48 47 48 193
    Age Categorical
    Units: participants
        <65
    		 35 39 37 38 149
        >=65
    		 15 9 10 10 44
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.8 ( 13.35 ) 53.7 ( 11.79 ) 54.7 ( 12.65 ) 54.9 ( 12.29 ) -
    Sex/Gender, Customized
    Units: participants
        Male
    		 20 17 18 25 80
        Female
    		 30 31 29 23 113
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 41 44 40 43 168
        Asian
    		 7 4 5 5 21
        Black
    		 1 0 2 0 3
        Unknown
    		 1 0 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    LJN452 140 mcg
    Reporting group description
    		 tropifexor 140 mcg, once daily

    Reporting group title
    CVC 150 mg
    Reporting group description
    		 Cenicriviroc (CVC) 150 mg, once daily

    Reporting group title
    LJN452 140 mcg + CVC 150 mg
    Reporting group description
    		 tropifexor 140 mcg + CVC 150 mg, once daily

    Reporting group title
    LJN452 90 mcg + CVC 150 mg
    Reporting group description
    		 tropifexor 90 mcg + CVC 150 mg, once daily

    Primary: Number of participants with Adverse Events

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    End point title
    		 Number of participants with Adverse Events [1]
    End point description
    Occurrence of adverse events and serious adverse events Adverse Events (AEs) are any untoward sign or symptom that occurs during the study treatment and then up to 66 weeks
    End point type
    Primary
    End point timeframe
    AEs and SAEs were collected from first dose of study treatment until end of study treatment at week 48 and then up to maximum duration of 66 weeks
    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 outcome
    End point values
    		 LJN452 140 mcg CVC 150 mg LJN452 140 mcg + CVC 150 mg LJN452 90 mcg + CVC 150 mg
    Number of subjects analysed
    50
    48
    47
    48
    Units: participants
        Number of participants with at least one AE
    42
    41
    40
    42
        Number of participants with at least one SAE
    5
    3
    4
    10
        Deaths
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Proportion of participants who have at least a one point improvement in fibrosis

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    End point title
    		 Proportion of participants who have at least a one point improvement in fibrosis
    End point description
    Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy
    End point type
    Secondary
    End point timeframe
    baseline to 48 Weeks
    End point values
    		 LJN452 140 mcg CVC 150 mg LJN452 140 mcg + CVC 150 mg LJN452 90 mcg + CVC 150 mg
    Number of subjects analysed
    31
    38
    37
    40
    Units: participants
    10
    12
    11
    13
    Statistical analysis title
    		 At least 1 point improvement in fibrosis
    Statistical analysis description
    Proportion of participants with at least one improvement point in fibrosis
    Comparison groups
    LJN452 140 mcg + CVC 150 mg v LJN452 140 mcg
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.688
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 2.63
    Statistical analysis title
    		 At least 1 point improvement in fibrosis
    Statistical analysis description
    Proportion of participants with at least one improvement point in fibrosis
    Comparison groups
    LJN452 140 mcg v LJN452 90 mcg + CVC 150 mg
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.985
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.99
    Statistical analysis title
    		 At least 1 point improvement in fibrosis
    Statistical analysis description
    Proportion of participants with at least one improvement point in fibrosis
    Comparison groups
    LJN452 140 mcg + CVC 150 mg v LJN452 90 mcg + CVC 150 mg
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.87
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 2.84
    Statistical analysis title
    		 At least 1 point improvement in fibrosis
    Statistical analysis description
    Proportion of participants with at least one improvement point in fibrosis
    Comparison groups
    CVC 150 mg v LJN452 90 mcg + CVC 150 mg
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.71
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 3.61

    Secondary: Proportion of participants with resolution of steatohepatitis

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    End point title
    		 Proportion of participants with resolution of steatohepatitis
    End point description
    Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy
    End point type
    Secondary
    End point timeframe
    baseline to 48 weeks
    End point values
    		 LJN452 140 mcg CVC 150 mg LJN452 140 mcg + CVC 150 mg LJN452 90 mcg + CVC 150 mg
    Number of subjects analysed
    31
    38
    37
    40
    Units: participants
    8
    8
    5
    9
    Statistical analysis title
    		 Participants with resolution of Steatohepatitis
    Statistical analysis description
    Proportion of participants with resolution of Steatohepatitis
    Comparison groups
    LJN452 140 mcg v LJN452 140 mcg + CVC 150 mg
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.136
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.08
         upper limit
    		 1.61
    Statistical analysis title
    		 Participants with resolution of Steatohepatitis
    Statistical analysis description
    Proportion of participants with resolution of Steatohepatitis
    Comparison groups
    LJN452 140 mcg v LJN452 90 mcg + CVC 150 mg
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.747
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 2.9
    Statistical analysis title
    		 Participants with resolution of Steatohepatitis
    Statistical analysis description
    Proportion of participants with resolution of Steatohepatitis
    Comparison groups
    CVC 150 mg v LJN452 140 mcg + CVC 150 mg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.784
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 3.63
    Statistical analysis title
    		 Participants with resolution of Steatohepatitis
    Statistical analysis description
    Proportion of participants with resolution of Steatohepatitis
    Comparison groups
    CVC 150 mg v LJN452 90 mcg + CVC 150 mg
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.521
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 5.69

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Tropifexor 140mcg
    Reporting group description
    		 Tropifexor 140mcg

    Reporting group title
    CVC 150mg
    Reporting group description
    		 CVC 150mg

    Reporting group title
    Tropifexor 140mg + CVC 150mg
    Reporting group description
    		 Tropifexor 140mg + CVC 150mg

    Reporting group title
    Tropifexor 90mg + CVC 150mg
    Reporting group description
    		 Tropifexor 90mg + CVC 150mg

    Serious adverse events
    		 Tropifexor 140mcg CVC 150mg Tropifexor 140mg + CVC 150mg Tropifexor 90mg + CVC 150mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 50 (10.00%)
    3 / 48 (6.25%)
    4 / 47 (8.51%)
    10 / 48 (20.83%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 47 (2.13%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 47 (2.13%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression suicidal
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 47 (2.13%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anaesthetic complication
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 47 (2.13%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary dyskinesia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder polyp
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spondylitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Euglycaemic diabetic ketoacidosis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         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
    		 Tropifexor 140mcg CVC 150mg Tropifexor 140mg + CVC 150mg Tropifexor 90mg + CVC 150mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 50 (78.00%)
    30 / 48 (62.50%)
    33 / 47 (70.21%)
    32 / 48 (66.67%)
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 48 (0.00%)
    1 / 47 (2.13%)
    0 / 48 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    3
    0
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 48 (6.25%)
    2 / 47 (4.26%)
    1 / 48 (2.08%)
         occurrences all number
    2
    3
    2
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 48 (4.17%)
    5 / 47 (10.64%)
    3 / 48 (6.25%)
         occurrences all number
    4
    2
    5
    4
    Fatigue
         subjects affected / exposed
    7 / 50 (14.00%)
    4 / 48 (8.33%)
    5 / 47 (10.64%)
    4 / 48 (8.33%)
         occurrences all number
    7
    4
    5
    4
    Oedema peripheral
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    0
    0
    4
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 48 (6.25%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 48 (6.25%)
    1 / 47 (2.13%)
    4 / 48 (8.33%)
         occurrences all number
    2
    3
    1
    4
    Abdominal pain
         subjects affected / exposed
    5 / 50 (10.00%)
    3 / 48 (6.25%)
    5 / 47 (10.64%)
    2 / 48 (4.17%)
         occurrences all number
    5
    5
    5
    2
    Abdominal pain upper
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 48 (4.17%)
    5 / 47 (10.64%)
    2 / 48 (4.17%)
         occurrences all number
    4
    2
    6
    2
    Constipation
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 48 (4.17%)
    6 / 47 (12.77%)
    3 / 48 (6.25%)
         occurrences all number
    5
    3
    6
    3
    Diarrhoea
         subjects affected / exposed
    2 / 50 (4.00%)
    7 / 48 (14.58%)
    4 / 47 (8.51%)
    0 / 48 (0.00%)
         occurrences all number
    2
    9
    4
    0
    Dyspepsia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    3 / 47 (6.38%)
    2 / 48 (4.17%)
         occurrences all number
    1
    0
    3
    4
    Flatulence
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 48 (2.08%)
    3 / 47 (6.38%)
    2 / 48 (4.17%)
         occurrences all number
    1
    1
    3
    2
    Nausea
         subjects affected / exposed
    2 / 50 (4.00%)
    6 / 48 (12.50%)
    7 / 47 (14.89%)
    6 / 48 (12.50%)
         occurrences all number
    2
    6
    9
    6
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    20 / 50 (40.00%)
    10 / 48 (20.83%)
    15 / 47 (31.91%)
    10 / 48 (20.83%)
         occurrences all number
    23
    10
    21
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 48 (2.08%)
    3 / 47 (6.38%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    3
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 50 (12.00%)
    3 / 48 (6.25%)
    6 / 47 (12.77%)
    1 / 48 (2.08%)
         occurrences all number
    6
    3
    7
    1
    Back pain
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 48 (6.25%)
    5 / 47 (10.64%)
    4 / 48 (8.33%)
         occurrences all number
    1
    3
    5
    6
    Muscle spasms
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 48 (4.17%)
    3 / 47 (6.38%)
    1 / 48 (2.08%)
         occurrences all number
    1
    2
    3
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    3 / 47 (6.38%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Pain in extremity
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 48 (6.25%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    3
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    3 / 47 (6.38%)
    1 / 48 (2.08%)
         occurrences all number
    2
    0
    4
    1
    Ear infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    3 / 47 (6.38%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 48 (2.08%)
    3 / 47 (6.38%)
    3 / 48 (6.25%)
         occurrences all number
    1
    1
    3
    3
    Nasopharyngitis
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 48 (6.25%)
    2 / 47 (4.26%)
    2 / 48 (4.17%)
         occurrences all number
    3
    3
    2
    2
    Sinusitis
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 48 (2.08%)
    4 / 47 (8.51%)
    3 / 48 (6.25%)
         occurrences all number
    2
    1
    4
    3
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 48 (4.17%)
    5 / 47 (10.64%)
    5 / 48 (10.42%)
         occurrences all number
    3
    3
    6
    5
    Urinary tract infection
         subjects affected / exposed
    7 / 50 (14.00%)
    3 / 48 (6.25%)
    2 / 47 (4.26%)
    4 / 48 (8.33%)
         occurrences all number
    7
    5
    2
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jun 2018
    • Revision to information fortropifexor, cenicriviroc and the combination, including non-clinical data, clinical pharmacology data, toxicology data, combination safety considerations, drug-drug interaction data for the combination and the rationale for use of the combination in this study • Exclusion criteria 14: Revised cut-off values for total bilirubin and alkaline phosphatase. The units were consistently stated in mg/dL. Exclusion criteria 25: Revised platelets limit. • Section 5.5.8.1: Revised dose limit for rosuvastatin and simvastatin to 10 mg daily, since CVC co-administration may increase their exposure and added the caution to monitor closely. • Section 9.5.4: Added additional details on population PK analysis • Other clarifications and corrections
    11 Dec 2018
    • Included occurrence of sleep disturbances in the exploratory objectives for Patient Reported Outcomes (PROs) • Section 6, Table 6-1: The footnotes were revised to clarify the instructions for liver biopsy and FibroScan® • Section 6.5.6 and Table 6-1: Monthly pregnancy test was required during the study and updated to specify the instructions for urine pregnancy test. • Other clarifications and corrections
    07 May 2020
    At the time of amendment (V03) release, enrollment was completed with 193 patients randomized. This amendment provides the option to extend the study treatment for patients who are unable to come to site for the week 48 visit as scheduled due to COVID-19 pandemic restrictions. • Section 3.6: Updated to clarify the possible benefits and risks of longer study treatment • Section 5.5.2: updated to include the stepwise approach to extend study treatment for patients who were unable to come to the study site for their Week-48, End of treatment (EOT) visit as scheduled per study protocol due to COVID-19 pandemic related restrictions • Section 6 and table 6.1: updated to include remote consultation for patients who were unable to come to the study site for their study visits (except Week-48, End-of-treatment visit) as scheduled per study protocol due to COVID-19 pandemic-related restrictions. The footnotes were revised to clarify the instructions for urine pregnancy test and study treatment extension. • Section 9.5.1: updated to clarify analysis plan for the delayed Week 48, End-of-Treatment (EOT) visits due to COVID-19 pandemic related restrictions

    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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