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    Clinical Trial Results:
    A Randomized, Double-Blind, Parallel-Group Clinical Trial to Assess the Efficacy of Essentiale on Hepatic Steatosis Added to Standard of Care Versus Placebo Added to Standard of Care, in Non-Alcoholic Fatty Liver Disease (NAFLD) Associated with Type 2 Diabetes Mellitus (T2DM) and/or Hyperlipidemia and/or Obesity

    Summary
    EudraCT number
    		 2021-006069-39
    Trial protocol
    		 DE   PL  
    Global end of trial date
    06 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 May 2025
    First version publication date
    14 May 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    LPS16141
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1244-1278
    Sponsors
    Sponsor organisation name
    Sanofi-Aventis Recherche & Developpement
    Sponsor organisation address
    157 Avenue Charles de Gaulle , Neuilly-sur-Seine Cedex, France, 92200
    Public contact
    Trial Transparency Team, Sanofi-Aventis Recherche & Developpement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi-Aventis Recherche & Developpement, Contact-US@sanofi.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
    06 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of Essentiale added to SoC (lifestyle modification [diet and physical activity/exercise]) compared with placebo added to SoC (lifestyle modification [diet and physical activity/exercise]) in patients with NAFLD associated with T2DM and/or hyperlipidemia and/or obesity.
    Protection of trial subjects
    The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki, ICH GCP, and all applicable regulations.
    Background therapy
    		 Standard of care (lifestyle modification [diet and physical activity/exercise])
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    01 Nov 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 84
    Country: Number of subjects enrolled
    Germany: 109
    Worldwide total number of subjects
    193
    EEA total number of subjects
    193
    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)
    164
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 237 subjects were assessed for eligibility, of whom 44 subjects (18.6%) were screen failures. A total of 193 subjects were randomized (ITT set) to receive either Essentiale + SoC (n=97) or placebo + SoC (n=96).

    Pre-assignment
    Screening details
    		 A total of 237 subjects were assessed for eligibility, 193 of whom were randomized [Essentiale + SoC (n=97) or placebo + SoC (n=96)]. Of the 193 participants enrolled, no participants discontinued the study before receiving treatment in both arms.

    Pre-assignment period milestones
    Number of subjects started
    		 193
    Number of subjects completed
    		 193

    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
    Blinding implementation details
    The IRT system was programmed with blind-breaking instructions. Blinding was maintained throughout the study until the final assessment for the final subject was entered into the database, and the database lock was performed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Essentiale arm
    Arm description
    		 Essentiale 1800 mg/day orally + SoC (lifestyle modification, ie, diet and physical activity/exercise)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Essentiale
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Essentiale 1800 mg/day (2 capsules [300 mg each] thrice daily) for 6 months

    Arm title
    		 Placebo arm
    Arm description
    		 Placebo + SoC (lifestyle modification, ie, diet and physical activity/exercise)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo (2 capsules thrice daily) for 6 months

    Number of subjects in period 1
    		Essentiale arm Placebo arm
    Started
    97
    96
    Completed
    88
    84
    Not completed
    9
    12
         Consent withdrawn by subject
    5
    7
         Physician decision
    1
    -
         Adverse event, non-fatal
    1
    1
         Not specified
    -
    2
         Noncompliance with study drug
    1
    1
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Essentiale arm
    Reporting group description
    		 Essentiale 1800 mg/day orally + SoC (lifestyle modification, ie, diet and physical activity/exercise)

    Reporting group title
    Placebo arm
    Reporting group description
    		 Placebo + SoC (lifestyle modification, ie, diet and physical activity/exercise)

    Reporting group values
    		 Essentiale arm Placebo arm Total
    Number of subjects
    		 97 96 193
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 79 85 164
        From 65-84 years
    		 18 11 29
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.6 ( 12.95 ) 52.8 ( 11.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 45 43 88
        Male
    		 52 53 105
    Controlled attenuation parameter
    The controlled attenuation parameter (CAP) was measured to assess the severity of liver steatosis at all visits during the study. The CAP technique is a proprietary algorithm based on the ultrasonic attenuation coefficient of the shear wave of transient elastography, an estimate of the total ultrasonic attenuation at 3.5 MHz. It is expressed in dB/meter. At baseline, the majority of subjects in both treatment arms were in a CAP score category S3 (≥280 dB/m)
    Units: Subjects
        S0: CAP score is <248 dB/m
    		 0 0 0
        S1: CAP score is ≥248 dB/m and <268 dB/m
    		 6 8 14
        S2: CAP score is ≥268 dB/m and <280 dB/m
    		 9 11 20
        S3: CAP score is ≥280 dB/m
    		 82 77 159
        Not done
    		 0 0 0
    Liver Stiffness Measurement
    FibroScan simultaneously assessed liver stiffness by measuring the propagation of an elastic shear wave through the liver parenchyma, and it is expressed in kPa, with higher values indicating greater stiffness. Liver stiffness measurements were performed at all visits during the study. Inclusion criteria allowed recruitment of patients F1 - F3 fibrosis stage as defined by LSM 5-13 kPa. Statistical analysis was done to include F4, based on another specific threshold.
    Units: Subjects
        F1: Mild fibrosis (<=7 kPa)
    		 59 58 117
        F2: Moderate fibrosis (7.1–8.8 kPa)
    		 22 20 42
        F3: Severe fibrosis (8.9–11.6 kPa)
    		 8 14 22
        F4: Cirrhosis or advanced fibrosis (>11.6 kPa)
    		 8 4 12
        Not done
    		 0 0 0
    BMI Category
    Units: Subjects
        Underweight (<18.5kg/m2)
    		 0 0 0
        Normal (18.5kg/m2 to <25kg/m2)
    		 3 3 6
        Overweight (25kg/m2 to <30kg/m2)
    		 16 11 27
        Obese (>=30kg/m2)
    		 78 82 160
        Missing
    		 0 0 0
    NAFLD Classification (T2D)
    The NAFLD classifications are made up of T2DM defined as a baseline HbA1c of 8.0% or above.
    Units: Subjects
        Yes
    		 17 10 27
        No
    		 80 86 166
    NAFLD Classification (Hyperlipidemia)
    The NAFLD classifications are made up of hyperlipidemia defined as baseline triglycerides above 1.6935 mmol/L.
    Units: Subjects
        Yes
    		 58 57 115
        No
    		 39 39 78
    NAFLD Classification (Obesity)
    The NAFLD classifications are made up of obesity defined as a baseline BMI of 30 kg/m2 or above.
    Units: Subjects
        Yes
    		 78 82 160
        No
    		 19 14 33
    Subject analysis sets

    Subject analysis set title
    mITT set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT set included 165 subjects (85.5%) of the enrolled population (82 subjects [84.5%] in the Essentiale + SoC arm and 83 subjects [86.5%] in the placebo + SoC arm). All subjects from the randomization set with evaluable CAP scores at baseline, at least 1 postbaseline CAP measurement, and who received the randomized treatment (at least 80% of the study drug planned to be given within 6 months). All analyses using the mITT were done according to the randomized treatment.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received at least 1 dose of the randomized treatment. All analyses using the safety set were done according to the treatment actually received.

    Subject analysis sets values
    		 mITT set Safety set
    Number of subjects
    165
    193
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    140
    164
        From 65-84 years
    25
    29
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52.9 ( 11.48 )
    52.7 ( 11.99 )
    Gender categorical
    Units: Subjects
        Female
    75
    88
        Male
    90
    105
    Controlled attenuation parameter
    The controlled attenuation parameter (CAP) was measured to assess the severity of liver steatosis at all visits during the study. The CAP technique is a proprietary algorithm based on the ultrasonic attenuation coefficient of the shear wave of transient elastography, an estimate of the total ultrasonic attenuation at 3.5 MHz. It is expressed in dB/meter. At baseline, the majority of subjects in both treatment arms were in a CAP score category S3 (≥280 dB/m)
    Units: Subjects
        S0: CAP score is <248 dB/m
    0
    0
        S1: CAP score is ≥248 dB/m and <268 dB/m
    12
    14
        S2: CAP score is ≥268 dB/m and <280 dB/m
    17
    20
        S3: CAP score is ≥280 dB/m
    136
    159
        Not done
    0
    0
    Liver Stiffness Measurement
    FibroScan simultaneously assessed liver stiffness by measuring the propagation of an elastic shear wave through the liver parenchyma, and it is expressed in kPa, with higher values indicating greater stiffness. Liver stiffness measurements were performed at all visits during the study. Inclusion criteria allowed recruitment of patients F1 - F3 fibrosis stage as defined by LSM 5-13 kPa. Statistical analysis was done to include F4, based on another specific threshold.
    Units: Subjects
        F1: Mild fibrosis (<=7 kPa)
    102
    117
        F2: Moderate fibrosis (7.1–8.8 kPa)
    37
    42
        F3: Severe fibrosis (8.9–11.6 kPa)
    18
    22
        F4: Cirrhosis or advanced fibrosis (>11.6 kPa)
    8
    12
        Not done
    0
    0
    BMI Category
    Units: Subjects
        Underweight (<18.5kg/m2)
    0
    0
        Normal (18.5kg/m2 to <25kg/m2)
    5
    6
        Overweight (25kg/m2 to <30kg/m2)
    25
    27
        Obese (>=30kg/m2)
    135
    160
        Missing
    0
    0
    NAFLD Classification (T2D)
    The NAFLD classifications are made up of T2DM defined as a baseline HbA1c of 8.0% or above.
    Units: Subjects
        Yes
    22
    27
        No
    143
    166
    NAFLD Classification (Hyperlipidemia)
    The NAFLD classifications are made up of hyperlipidemia defined as baseline triglycerides above 1.6935 mmol/L.
    Units: Subjects
        Yes
    100
    115
        No
    65
    78
    NAFLD Classification (Obesity)
    The NAFLD classifications are made up of obesity defined as a baseline BMI of 30 kg/m2 or above.
    Units: Subjects
        Yes
    135
    160
        No
    30
    33

    End points

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    End points reporting groups
    Reporting group title
    Essentiale arm
    Reporting group description
    		 Essentiale 1800 mg/day orally + SoC (lifestyle modification, ie, diet and physical activity/exercise)

    Reporting group title
    Placebo arm
    Reporting group description
    		 Placebo + SoC (lifestyle modification, ie, diet and physical activity/exercise)

    Subject analysis set title
    mITT set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT set included 165 subjects (85.5%) of the enrolled population (82 subjects [84.5%] in the Essentiale + SoC arm and 83 subjects [86.5%] in the placebo + SoC arm). All subjects from the randomization set with evaluable CAP scores at baseline, at least 1 postbaseline CAP measurement, and who received the randomized treatment (at least 80% of the study drug planned to be given within 6 months). All analyses using the mITT were done according to the randomized treatment.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received at least 1 dose of the randomized treatment. All analyses using the safety set were done according to the treatment actually received.

    Primary: Change in steatosis, as measured by transient elastography (CAP score)

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    End point title
    		 Change in steatosis, as measured by transient elastography (CAP score)
    End point description
    Change from baseline to 6 month in steatosis measured by transient elastography (CAP score) defined as the CAP score at 6 month minus the CAP score at baseline. Analysis was performed on modified intent-to-treat (mITT) analysis set.
    End point type
    Primary
    End point timeframe
    From baseline to 6months
    End point values
    		 Essentiale arm Placebo arm
    Number of subjects analysed
    82
    83
    Units: dB/m
    least squares mean (standard error)
        Change from Baseline
    -24.6 ( 4.68 )
    -9.79 ( 4.68 )
    Statistical analysis title
    		 CAP score
    Statistical analysis description
    For the analysis of the primary efficacy endpoint (change in steatosis, as measured by transient elastography [CAP score] from baseline to 6 months), a mixed-effect model with repeated measures (MMRM) was used to test the hypothesis.
    Comparison groups
    Essentiale arm v Placebo arm
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0269 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -14.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.89
         upper limit
    		 -1.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.63
    Notes
    [1] - The level of statistical significance was defined as a P value less than 0.05.

    Secondary: Change in QoL total score, as measured by the CLDQ-NAFLD/NASH

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    End point title
    		 Change in QoL total score, as measured by the CLDQ-NAFLD/NASH
    End point description
    Change from baseline to 6 month in Change in QoL total score, as measured by the CLDQ-NAFLD/NASH, from baseline to 6 months. Analysis was performed on modified ittent-to-treat (mITT) analysis set.
    End point type
    Secondary
    End point timeframe
    From baseline to 6 months
    End point values
    		 Essentiale arm Placebo arm
    Number of subjects analysed
    82
    83
    Units: Score
    least squares mean (standard error)
        Change from Baseline
    0.44 ( 0.06 )
    0.28 ( 0.06 )
    Statistical analysis title
    		 QoL total score of the CLDQ-NAFLD/NASH
    Statistical analysis description
    For the analysis of the secondary efficacy endpoint a mixed-effect model with repeated measures (MMRM) was used to test the hypothesis.
    Comparison groups
    Essentiale arm v Placebo arm
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.2445 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08
    Notes
    [2] - The linear mixed model with repeated measures (MMRM) analysis
    [3] - The level of statistical significance was defined as a P value less than 0.05.

    Secondary: Change in symptom evaluation (global overall symptoms (GOS)) for Asthenia

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    End point title
    		 Change in symptom evaluation (global overall symptoms (GOS)) for Asthenia
    End point description
    Change from baseline to 6 month in in symptom evaluation (using the GOS scale) from baseline to 6 months for Asthenia. Analysis was performed on modified ittent-to-treat (mITT) analysis set.
    End point type
    Secondary
    End point timeframe
    From the baseline to 6 months
    End point values
    		 Essentiale arm Placebo arm
    Number of subjects analysed
    82
    83
    Units: Score
    least squares mean (standard error)
        Change from Baseline
    -0.69 ( 0.12 )
    -0.46 ( 0.11 )
    Statistical analysis title
    		 Asthenia (Loss of Energy)
    Statistical analysis description
    For the analysis of the secondary efficacy endpoint a mixed-effect model with repeated measures (MMRM) was used to test the hypothesis.
    Comparison groups
    Placebo arm v Essentiale arm
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.5808 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Notes
    [4] - The linear mixed model with repeated measures (MMRM) analysis
    [5] - The level of statistical significance was defined as a P value less than 0.05.

    Secondary: Change in symptom evaluation (global overall symptoms (GOS)) for Feeling depressed

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    End point title
    		 Change in symptom evaluation (global overall symptoms (GOS)) for Feeling depressed
    End point description
    Change from baseline to 6 month in in symptom evaluation (using the GOS scale) from baseline to 6 months for Feeling depressed. Analysis was performed on modified intent-to-treat (mITT) analysis set.
    End point type
    Secondary
    End point timeframe
    From baseline to 6 months
    End point values
    		 Essentiale arm Placebo arm
    Number of subjects analysed
    82
    83
    Units: Score
    least squares mean (standard error)
        Change from Baseline
    -0.46 ( 0.12 )
    -0.46 ( 0.12 )
    Statistical analysis title
    		 Feeling Depressed
    Statistical analysis description
    For the analysis of the secondary efficacy endpoint a mixed-effect model with repeated measures (MMRM) was used to test the hypothesis.
    Comparison groups
    Essentiale arm v Placebo arm
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Notes
    [6] - The level of statistical significance was defined as a P value less than 0.05.

    Secondary: Change in symptom evaluation (global overall symptoms (GOS)) for Fatigue

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    End point title
    		 Change in symptom evaluation (global overall symptoms (GOS)) for Fatigue
    End point description
    Change from baseline to 6 month in in symptom evaluation (using the GOS scale) from baseline to 6 months for Fatigue. Analysis was performed on modified intent-to-treat (mITT) analysis set.
    End point type
    Secondary
    End point timeframe
    From baseline to 6 months
    End point values
    		 Essentiale arm Placebo arm
    Number of subjects analysed
    82
    83
    Units: Score
    least squares mean (standard error)
        Change from Baseline
    -0.71 ( 0.12 )
    -0.46 ( 0.12 )
    Statistical analysis title
    		 Fatigue
    Statistical analysis description
    For the analysis of the secondary efficacy endpoint a mixed-effect model with repeated measures (MMRM) was used to test the hypothesis.
    Comparison groups
    Essentiale arm v Placebo arm
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5808 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Notes
    [7] - The level of statistical significance was defined as a P value less than 0.05.

    Secondary: Change in symptom evaluation (global overall symptoms (GOS)) for Abdominal pain/discomfort

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    End point title
    		 Change in symptom evaluation (global overall symptoms (GOS)) for Abdominal pain/discomfort
    End point description
    Change from baseline to 6 month in in symptom evaluation (using the GOS scale) from baseline to 6 months for abdominal pain/discomfort. Analysis was performed on modified intent-to-treat (mITT) analysis set.
    End point type
    Secondary
    End point timeframe
    From baseline to 6 months
    End point values
    		 Essentiale arm Placebo arm
    Number of subjects analysed
    82
    83
    Units: Score
    least squares mean (standard error)
        Change from Baseline
    -0.53 ( 0.11 )
    -0.61 ( 0.11 )
    Statistical analysis title
    		 Abdominal Pain/Discomfort
    Statistical analysis description
    For the analysis of the secondary efficacy endpoint a mixed-effect model with repeated measures (MMRM) was used to test the hypothesis.
    Comparison groups
    Essentiale arm v Placebo arm
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Notes
    [8] - The level of statistical significance was defined as a P value less than 0.05.

    Secondary: Adverse events (AEs), serious adverse events (SAEs), including adverse events of special interest (AESIs).

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    End point title
    		 Adverse events (AEs), serious adverse events (SAEs), including adverse events of special interest (AESIs).
    End point description
    An AE was defined as any untoward medical occurrence in a subject who received study drug and did not necessarily have to have a causal relationship with the treatment. SAEs were defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (from the first administration to the last administration + 5 days).
    End point type
    Secondary
    End point timeframe
    From baseline up to the last administration + 5 days.
    End point values
    		 Essentiale arm Placebo arm
    Number of subjects analysed
    97
    96
    Units: Subjects
        Total Patients Exposed At Risk
    97
    96
        Total Patients Affected by Serious TEAE
    5
    3
        Total Patients Affected by Non Serious TEAE
    23
    18
        Total Deaths (all causes)
    0
    0
        Total Deaths Resulting From AE
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline up to the last administration + 5 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Essentiale + SOC
    Reporting group description
    		 -

    Reporting group title
    Placebo + SoC
    Reporting group description
    		 -

    Serious adverse events
    		 Essentiale + SOC Placebo + SoC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 97 (5.15%)
    3 / 96 (3.13%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal neoplasm
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Tibia fracture
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocarditis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Essentiale + SOC Placebo + SoC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 97 (23.71%)
    18 / 96 (18.75%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 97 (10.31%)
    8 / 96 (8.33%)
         occurrences all number
    18
    12
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 97 (9.28%)
    8 / 96 (8.33%)
         occurrences all number
    11
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 97 (6.19%)
    6 / 96 (6.25%)
         occurrences all number
    6
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 May 2022
    The protocol was updated with the required statements, measures, and provided benefit-risk discussions with regards to the SARS-COV-2 pandemic in response to the regulatory query.
    15 Jul 2022
    Any reference to Russia and China were removed, as these countries were dropped off from the study. Any reference to the investigator’s brochure was replaced with summary of product characteristics. The important identified risks for Essentiale were updated to include data on drug-related AEs. Approximate number of sites involved in the study were updated and the information was clarified to be recorded in the eDiary.

    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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