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    Clinical Trial Results:
    Multicenter, double-blind, parallel-group, randomised, 48 weeks, dose-ranging, placebo-controlled phase II trial to evaluate efficacy, safety and tolerability of multiple subcutaneous (s.c.) doses of BI456906 in patients with non-alcoholic steatohepatitis (NASH) and fibrosis

    Summary
    EudraCT number
    		 2020-002723-11
    Trial protocol
    		 FR   BE   NL   PT   CZ   DE   HU   AT   GR   PL   IT  
    Global end of trial date
    21 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jan 2025
    First version publication date
    02 Jan 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1404-0043
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04771273
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.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
    02 Feb 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Nov 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary trial objectives were to demonstrate a non-flat dose response curve, to evaluate the size of the treatment effect (using the absolute difference in proportions of patients with NASH and fibrosis that show histological improvement between Survodutide [BI 456906] and placebo treatment at Week 48), and to characterize the dose-response relationship.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all subjects as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jul 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 58
    Country: Number of subjects enrolled
    Hong Kong: 14
    Country: Number of subjects enrolled
    Japan: 77
    Country: Number of subjects enrolled
    Korea, Republic of: 10
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 43
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Poland: 78
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    United States: 632
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Malaysia: 16
    Country: Number of subjects enrolled
    New Zealand: 13
    Country: Number of subjects enrolled
    Singapore: 13
    Worldwide total number of subjects
    1153
    EEA total number of subjects
    235
    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)
    937
    From 65 to 84 years
    216
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a trial in patients with non-alcoholic steatohepatitis (NASH). Main parameters for inclusion of patients and for evaluation of treatment response were based on the histological evaluation from the liver biopsy and non-invasive imaging modalities.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility prior to participation in the trial. Patients who met the eligibility criteria at an initial screening visit had a second screening visit for biopsy to confirm their eligibility, if no sufficient material from a historical biopsy within the 6 months prior to randomisation was available.

    Period 1
    Period 1 title
    Randomisation period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor
    Blinding implementation details
    This trial has a double-blind design across dose groups. Patients, investigators, central reviewers, and everyone involved in trial conduct or analysis or with any other interest in this double-blind trial (except for an interim analysis which was performed for internal planning purposes by an independent team within the sponsor) remained blinded with regard to the randomised treatment assignments until after the main database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Survodutide 2.4 mg - planned maintenance treatment
    Arm description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3). were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 2.4 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Survodutide 4.8 mg - planned maintenance treatment
    Arm description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3). were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 4.8 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Survodutide 6.0 mg - planned maintenance treatment
    Arm description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3). were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 6.0 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo - planned maintenance treatment
    Arm description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3). were administered once weekly, subcutaneously a solution for injection of placebo matching survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Survodutide 2.4 mg - planned maintenance treatment Survodutide 4.8 mg - planned maintenance treatment Survodutide 6.0 mg - planned maintenance treatment Placebo - planned maintenance treatment
    Started
    73
    73
    75
    74
    Completed
    73
    72
    74
    74
    Not completed
    0
    1
    1
    0
         Not treated
    -
    1
    1
    -
    Period 2
    Period 2 title
    Dose Escalation + Maintenance Periods
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor
    Blinding implementation details
    This trial has a double-blind design across dose groups. Patients, investigators, central reviewers, and everyone involved in trial conduct or analysis or with any other interest in this double-blind trial (except for an interim analysis which was performed for internal planning purposes by an independent team within the sponsor) remained blinded with regard to the randomised treatment assignments until after the main database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Survodutide 2.4 mg - planned maintenance treatment
    Arm description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 2.4 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Survodutide
    Investigational medicinal product code
    Other name
    BI 456906
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 2.4 mg of survodutide.

    Arm title
    		 Survodutide 4.8 mg - planned maintenance treatment
    Arm description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 4.8 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Survodutide
    Investigational medicinal product code
    Other name
    BI 456906
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3). were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 4.8 mg of survodutide.

    Arm title
    		 Survodutide 6.0 mg - planned maintenance treatment
    Arm description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 6.0 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Survodutide
    Investigational medicinal product code
    Other name
    BI 456906
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3). were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 6.0 mg of survodutide.

    Arm title
    		 Placebo - planned maintenance treatment
    Arm description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were administered once weekly, subcutaneously a solution for injection of placebo matching survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match BI 456906
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3). were administered once weekly, subcutaneously a solution for injection of placebo matching survodutide.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: In this period the subjects who were randomized in this trial are reported. The baseline characteristics are not reported for the randomized subjects but for the treated subjects.
    Number of subjects in period 2 [2]
    		Survodutide 2.4 mg - planned maintenance treatment Survodutide 4.8 mg - planned maintenance treatment Survodutide 6.0 mg - planned maintenance treatment Placebo - planned maintenance treatment
    Started
    73
    72
    74
    74
    Completed
    53
    55
    49
    64
    Not completed
    20
    17
    25
    10
         Other reasons than listed
    6
    2
    2
    4
         Adverse event, non-fatal
    12
    14
    17
    2
         Perceived lack of efficacy
    -
    -
    -
    2
         Burden of study procedures
    2
    -
    -
    -
         Change of residence
    -
    1
    3
    1
         Protocol deviation
    -
    -
    3
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Out of 1153 subjects screened only 293 subjects were treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Survodutide 2.4 mg - planned maintenance treatment
    Reporting group description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 2.4 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.

    Reporting group title
    Survodutide 4.8 mg - planned maintenance treatment
    Reporting group description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 4.8 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.

    Reporting group title
    Survodutide 6.0 mg - planned maintenance treatment
    Reporting group description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 6.0 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.

    Reporting group title
    Placebo - planned maintenance treatment
    Reporting group description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were administered once weekly, subcutaneously a solution for injection of placebo matching survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period).

    Reporting group values
    		 Survodutide 2.4 mg - planned maintenance treatment Survodutide 4.8 mg - planned maintenance treatment Survodutide 6.0 mg - planned maintenance treatment Placebo - planned maintenance treatment Total
    Number of subjects
    		 73 72 74 74 293
    Age categorical
    Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. Patients are analyzed according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 60 62 62 64 248
        From 65-84 years
    		 13 10 12 10 45
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. Patients are analyzed according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: years
        arithmetic mean (standard deviation)
    		 49.6 ( 13.7 ) 50.2 ( 12.9 ) 50.4 ( 13.1 ) 53.0 ( 11.5 ) -
    Sex: Female, Male
    Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. Patients are analyzed according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Participants
        Female
    		 36 34 41 44 155
        Male
    		 37 38 33 30 138
    Ethnicity (NIH/OMB)
    Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. Patients are analyzed according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        Hispanic or Latino
    		 14 19 26 22 81
        Not Hispanic or Latino
    		 59 53 48 52 212
        Unknown or Not Reported
    		 0 0 0 0 0
    Race (NIH/OMB)
    Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. Patients are analyzed according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 1 0 1
        Asian
    		 24 22 17 17 80
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 1 1
        Black or African American
    		 2 3 0 0 5
        White
    		 46 47 56 56 205
        More than one race
    		 1 0 0 0 1
        Unknown or Not Reported
    		 0 0 0 0 0
    Number of participants at each category of liver fibrosis stage at baseline
    Number of participants at each category of liver fibrosis stage at baseline is reported. The total score for the fibrosis stage ranges from 0 to 4 with higher score indication worsening of the disease and the stages of fibrosis based on their location are the following: - 1A Zone 3, perisinusoidal, delicate; - 1B Zone 3, perisinuosoidal, dense; - 1C Portal, periportal only; - 2 Zone 3, perisinusoidal + portal, periportal only; - 3 Bridging fibrosis; - 4 Cirrhosis.
    Units: Subjects
        Stage 1A
    		 0 3 3 2 8
        Stage 1B
    		 17 7 14 9 47
        Stage 1C
    		 3 3 6 3 15
        Stage 2
    		 30 36 24 30 120
        Stage 3
    		 23 23 27 30 103
    Number of participants in each category of diabetes at baseline
    Number of participants at each category of diabetes at baseline is reported. The reported categories of diabetes stratification are the following: Yes, No. Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. Patients are analyzed according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        Diabetes = No
    		 44 43 44 45 176
        Diabetes = Yes
    		 29 29 30 29 117
    Number of patients in each category of NAS score
    The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) is the sum of subscores for steatosis (scored 0-3), lobular inflammation (scored 0-3) and ballooning (scored 0-2), and the total score ranges from 0 to 8 with higher scores representing worsening of the disease. The reported categories of NAS score range are: 0; 1; 2; 3; 4; 5; 6; 7; 8. Patients are analyzed according to the planned maintenance dose strength they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        NAS total score = 0
    		 0 0 0 0 0
        NAS total score = 1
    		 0 0 0 0 0
        NAS total score = 2
    		 0 0 0 0 0
        NAS total score = 3
    		 0 0 0 0 0
        NAS total score = 4
    		 21 20 26 22 89
        NAS total score = 5
    		 27 21 17 28 93
        NAS total score = 6
    		 17 22 26 8 73
        NAS total score = 7
    		 8 8 5 16 37
        NAS total score = 8
    		 0 1 0 0 1
    Number of patients in each category of the NAS sub-score steatosis
    The NAS represents the sum of subscores for steatosis (scored 0-3), lobular inflammation (scored 0-3) and ballooning (scored 0-2), and the total score ranges from 0 to 8 with higher scores representing worsening of the disease. Number of patients in each category of the score range for steatosis is reported. Treated set - planned maintenance treatment. Patients are analyzed according to the planned maintenance dose strength they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        Steatosis total score = 0
    		 0 0 0 0 0
        Steatosis total score = 1
    		 6 0 1 3 10
        Steatosis total score = 2
    		 38 38 49 43 168
        Steatosis total score = 3
    		 29 34 24 28 115
    Number of patients in each category of the NAS sub-scores (ballooning)
    The NAS represents the sum of subscores for steatosis (scored 0-3), lobular inflammation (scored 0-3) and ballooning (scored 0-2), and the total score ranges from 0 to 8 with higher scores representing worsening of the disease. Number of patients in each category of the score range for ballooning is reported. Treated set - planned maintenance treatment. Patients are analyzed according to the planned maintenance dose strength they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        Ballooning total score = 0
    		 0 0 0 0 0
        Ballooning total score = 1
    		 55 55 53 49 212
        Ballooning total score = 2
    		 18 17 21 25 81
    Number of patients in each category of the NAS sub-score lobular inflammation
    The NAS represents the sum of subscores for steatosis (scored 0-3), lobular inflammation (scored 0-3) and ballooning (scored 0-2), and the total score ranges from 0 to 8 with higher scores representing worsening of the disease. Number of patients in each category of the score range for lobular inflammation is reported. Treated set - planned maintenance treatment. Patients are analyzed according to the planned maintenance dose strength they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        Lobular inflammation score = 0
    		 0 0 0 0 0
        Lobular inflammation score = 1
    		 32 31 36 37 136
        Lobular inflammation score = 2
    		 38 40 36 32 146
        Lobular inflammation score = 3
    		 3 1 2 5 11
    The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) at baseline
    The NAS represents the sum of subscores for steatosis (scored 0-3), lobular inflammation (scored 0-3) and ballooning (scored 0-2), and the total score ranges from 0 to 8 with higher scores representing worsening of the disease. Treated set - planned maintenance treatment. Patients are analyzed according to the planned maintenance dose strength they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 5.2 ( 1.0 ) 5.3 ( 1.1 ) 5.1 ( 1.0 ) 5.2 ( 1.1 ) -
    Subject analysis sets

    Subject analysis set title
    Survodutide 2.4 mg - actual maintenance treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This arm includes patients who were treated with 2.4 mg of survodutide administered weekly at the start of the maintenance period, for patients who reached the maintenance period, regardless of whether this was the randomised (planned) dose or not, and regardless of whether the patient stayed on that dose throughout the maintenance period. This arm includes also those patients for whom the next maintenance dose up from the dose at treatment discontinuation was 2.4 mg of survodutide administered weekly, for patients who discontinued treatment prior to the maintenance period, regardless of the reason for the treatment discontinuation.

    Subject analysis set title
    Survodutide 4.8 mg - actual maintenance treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This arm includes patients who were treated with 4.8 mg of survodutide administered weekly at the start of the maintenance period, for patients who reached the maintenance period, regardless of whether this was the randomised (planned) dose or not, and regardless of whether the patient stayed on that dose throughout the maintenance period. This arm includes also those patients for whom the next maintenance dose up from the dose at treatment discontinuation was 4.8 mg of survodutide administered weekly, for patients who discontinued treatment prior to the maintenance period, regardless of the reason for the treatment discontinuation.

    Subject analysis set title
    Survodutide 6.0 mg - actual maintenance treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This arm includes patients who were treated with 6.0 mg of survodutide administered weekly at the start of the maintenance period, for patients who reached the maintenance period, regardless of whether this was the randomised (planned) dose or not, and regardless of whether the patient stayed on that dose throughout the maintenance period. This arm includes also those patients for whom the next maintenance dose up from the dose at treatment discontinuation was 6.0 mg of survodutide administered weekly, for patients who discontinued treatment prior to the maintenance period, regardless of the reason for the treatment discontinuation.

    Subject analysis set title
    Placebo - actual maintenance treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This arm includes patients who were treated with placebo matching survodutide administered weekly at the start of the maintenance period, for patients who reached the maintenance period, regardless of whether this was the randomised (planned) dose or not, and regardless of whether the patient stayed on that dose throughout the maintenance period. This arm includes also those patients who were receiving placebo matching survodutide administered weekly and who discontinued treatment prior to the maintenance period, regardless of the reason for the treatment discontinuation.

    Subject analysis sets values
    		 Survodutide 2.4 mg - actual maintenance treatment Survodutide 4.8 mg - actual maintenance treatment Survodutide 6.0 mg - actual maintenance treatment Placebo - actual maintenance treatment
    Number of subjects
    93
    69
    52
    79
    Age categorical
    Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. Patients are analyzed according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    76
    60
    45
    67
        From 65-84 years
    17
    9
    7
    12
        85 years and over
    0
    0
    0
    0
    Age Continuous
    Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. Patients are analyzed according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: years
        arithmetic mean (standard deviation)
    50.6 ( 13.5 )
    49.5 ( 12.9 )
    49.9 ( 12.8 )
    52.8 ( 11.9 )
    Sex: Female, Male
    Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. Patients are analyzed according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Participants
        Female
    49
    31
    29
    46
        Male
    44
    38
    23
    33
    Ethnicity (NIH/OMB)
    Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. Patients are analyzed according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        Hispanic or Latino
    20
    17
    21
    23
        Not Hispanic or Latino
    73
    52
    31
    56
        Unknown or Not Reported
    0
    0
    0
    0
    Race (NIH/OMB)
    Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. Patients are analyzed according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        American Indian or Alaska Native
    0
    0
    1
    19
        Asian
    27
    22
    12
    0
        Native Hawaiian or Other Pacific Islander
    0
    0
    0
    1
        Black or African American
    2
    3
    0
    0
        White
    63
    44
    39
    59
        More than one race
    1
    0
    0
    0
        Unknown or Not Reported
    0
    0
    0
    0
    Number of participants at each category of liver fibrosis stage at baseline
    Number of participants at each category of liver fibrosis stage at baseline is reported. The total score for the fibrosis stage ranges from 0 to 4 with higher score indication worsening of the disease and the stages of fibrosis based on their location are the following: - 1A Zone 3, perisinusoidal, delicate; - 1B Zone 3, perisinuosoidal, dense; - 1C Portal, periportal only; - 2 Zone 3, perisinusoidal + portal, periportal only; - 3 Bridging fibrosis; - 4 Cirrhosis.
    Units: Subjects
        Stage 1A
    0
    3
    3
    2
        Stage 1B
    16
    9
    11
    11
        Stage 1C
    5
    3
    4
    3
        Stage 2
    42
    30
    16
    32
        Stage 3
    30
    24
    18
    31
    Number of participants in each category of diabetes at baseline
    Number of participants at each category of diabetes at baseline is reported. The reported categories of diabetes stratification are the following: Yes, No. Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. Patients are analyzed according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        Diabetes = No
    54
    40
    34
    48
        Diabetes = Yes
    39
    29
    18
    31
    Number of patients in each category of NAS score
    The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) is the sum of subscores for steatosis (scored 0-3), lobular inflammation (scored 0-3) and ballooning (scored 0-2), and the total score ranges from 0 to 8 with higher scores representing worsening of the disease. The reported categories of NAS score range are: 0; 1; 2; 3; 4; 5; 6; 7; 8. Patients are analyzed according to the planned maintenance dose strength they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        NAS total score = 0
    0
    0
    0
    0
        NAS total score = 1
    0
    0
    0
    0
        NAS total score = 2
    0
    0
    0
    0
        NAS total score = 3
    0
    0
    0
    0
        NAS total score = 4
    27
    19
    19
    24
        NAS total score = 5
    34
    19
    12
    28
        NAS total score = 6
    23
    22
    17
    11
        NAS total score = 7
    9
    8
    4
    16
        NAS total score = 8
    0
    1
    0
    0
    Number of patients in each category of the NAS sub-score steatosis
    The NAS represents the sum of subscores for steatosis (scored 0-3), lobular inflammation (scored 0-3) and ballooning (scored 0-2), and the total score ranges from 0 to 8 with higher scores representing worsening of the disease. Number of patients in each category of the score range for steatosis is reported. Treated set - planned maintenance treatment. Patients are analyzed according to the planned maintenance dose strength they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        Steatosis total score = 0
    0
    0
    0
    0
        Steatosis total score = 1
    6
    0
    1
    3
        Steatosis total score = 2
    49
    39
    33
    47
        Steatosis total score = 3
    38
    30
    18
    29
    Number of patients in each category of the NAS sub-scores (ballooning)
    The NAS represents the sum of subscores for steatosis (scored 0-3), lobular inflammation (scored 0-3) and ballooning (scored 0-2), and the total score ranges from 0 to 8 with higher scores representing worsening of the disease. Number of patients in each category of the score range for ballooning is reported. Treated set - planned maintenance treatment. Patients are analyzed according to the planned maintenance dose strength they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        Ballooning total score = 0
    0
    0
    0
    0
        Ballooning total score = 1
    70
    50
    39
    53
        Ballooning total score = 2
    23
    19
    13
    26
    Number of patients in each category of the NAS sub-score lobular inflammation
    The NAS represents the sum of subscores for steatosis (scored 0-3), lobular inflammation (scored 0-3) and ballooning (scored 0-2), and the total score ranges from 0 to 8 with higher scores representing worsening of the disease. Number of patients in each category of the score range for lobular inflammation is reported. Treated set - planned maintenance treatment. Patients are analyzed according to the planned maintenance dose strength they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: Subjects
        Lobular inflammation score = 0
    0
    0
    0
    0
        Lobular inflammation score = 1
    43
    28
    26
    39
        Lobular inflammation score = 2
    48
    40
    24
    34
        Lobular inflammation score = 3
    2
    1
    2
    6
    The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) at baseline
    The NAS represents the sum of subscores for steatosis (scored 0-3), lobular inflammation (scored 0-3) and ballooning (scored 0-2), and the total score ranges from 0 to 8 with higher scores representing worsening of the disease. Treated set - planned maintenance treatment. Patients are analyzed according to the planned maintenance dose strength they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    Units: score on a scale
        arithmetic mean (standard deviation)
    5.2 ( 1.0 )
    5.3 ( 1.1 )
    5.1 ( 1.0 )
    5.2 ( 1.1 )

    End points

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    End points reporting groups
    Reporting group title
    Survodutide 2.4 mg - planned maintenance treatment
    Reporting group description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3). were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 2.4 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.

    Reporting group title
    Survodutide 4.8 mg - planned maintenance treatment
    Reporting group description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3). were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 4.8 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.

    Reporting group title
    Survodutide 6.0 mg - planned maintenance treatment
    Reporting group description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3). were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 6.0 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.

    Reporting group title
    Placebo - planned maintenance treatment
    Reporting group description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3). were administered once weekly, subcutaneously a solution for injection of placebo matching survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period).
    Reporting group title
    Survodutide 2.4 mg - planned maintenance treatment
    Reporting group description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 2.4 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.

    Reporting group title
    Survodutide 4.8 mg - planned maintenance treatment
    Reporting group description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 4.8 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.

    Reporting group title
    Survodutide 6.0 mg - planned maintenance treatment
    Reporting group description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were to be administered once weekly, subcutaneously a solution for injection of survodutide at a starting dose of 0.3 milligrams (mg) followed by a dose escalation up to the maintenance dose of 6.0 mg of survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period). Patients not tolerating the assigned dose due to gastrointestinal adverse events had the option of a dose adjustment which could lead to a maintenance dose lower than the dose the patient was randomized to.

    Reporting group title
    Placebo - planned maintenance treatment
    Reporting group description
    		 Patients with non-alcoholic steatohepatitis (NASH) with non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥4 and fibrosis stage 1-3 (F1-F3) were administered once weekly, subcutaneously a solution for injection of placebo matching survodutide. The total treatment duration was 48 weeks (consisting of up to 24 weeks dose escalation period and at least 24 weeks maintenance period).

    Subject analysis set title
    Survodutide 2.4 mg - actual maintenance treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This arm includes patients who were treated with 2.4 mg of survodutide administered weekly at the start of the maintenance period, for patients who reached the maintenance period, regardless of whether this was the randomised (planned) dose or not, and regardless of whether the patient stayed on that dose throughout the maintenance period. This arm includes also those patients for whom the next maintenance dose up from the dose at treatment discontinuation was 2.4 mg of survodutide administered weekly, for patients who discontinued treatment prior to the maintenance period, regardless of the reason for the treatment discontinuation.

    Subject analysis set title
    Survodutide 4.8 mg - actual maintenance treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This arm includes patients who were treated with 4.8 mg of survodutide administered weekly at the start of the maintenance period, for patients who reached the maintenance period, regardless of whether this was the randomised (planned) dose or not, and regardless of whether the patient stayed on that dose throughout the maintenance period. This arm includes also those patients for whom the next maintenance dose up from the dose at treatment discontinuation was 4.8 mg of survodutide administered weekly, for patients who discontinued treatment prior to the maintenance period, regardless of the reason for the treatment discontinuation.

    Subject analysis set title
    Survodutide 6.0 mg - actual maintenance treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This arm includes patients who were treated with 6.0 mg of survodutide administered weekly at the start of the maintenance period, for patients who reached the maintenance period, regardless of whether this was the randomised (planned) dose or not, and regardless of whether the patient stayed on that dose throughout the maintenance period. This arm includes also those patients for whom the next maintenance dose up from the dose at treatment discontinuation was 6.0 mg of survodutide administered weekly, for patients who discontinued treatment prior to the maintenance period, regardless of the reason for the treatment discontinuation.

    Subject analysis set title
    Placebo - actual maintenance treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This arm includes patients who were treated with placebo matching survodutide administered weekly at the start of the maintenance period, for patients who reached the maintenance period, regardless of whether this was the randomised (planned) dose or not, and regardless of whether the patient stayed on that dose throughout the maintenance period. This arm includes also those patients who were receiving placebo matching survodutide administered weekly and who discontinued treatment prior to the maintenance period, regardless of the reason for the treatment discontinuation.

    Primary: Improvement (yes/ no) from baseline in liver histological findings based on liver biopsy after 48 weeks of treatment in patients with NASH (NAS ≥ 4, fibrosis F1-F3) - actual maintenance treatment

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    End point title
    		 Improvement (yes/ no) from baseline in liver histological findings based on liver biopsy after 48 weeks of treatment in patients with NASH (NAS ≥ 4, fibrosis F1-F3) - actual maintenance treatment
    End point description
    Percentage of patients who had an improvement from baseline in liver histological findings based on liver biopsy after 48 weeks of treatment is reported. Percentages were rounded to one decimal place. Improvement in histological findings was defined as a composite of improvement in NASH and no worsening of fibrosis. Improvement in non-alcoholic steatohepatitis (NASH) was defined as decrease of at least 2 points in non-alcoholic fatty liver disease (NAFLD) activity score (NAS) with at least 1 point decrease in NAS subscore of either lobular inflammation or ballooning. Patients without post-baseline data were considered non-responders. Patients are analyzed according to the actual treatment they received at the start of the dose maintenance period (for patients who reached the maintenance period) or the next maintenance dose up from the dose at treatment discontinuation (for patients who discontinued treatment prior to the maintenance period).
    End point type
    Primary
    End point timeframe
    At baseline and at 48 weeks.
    End point values
    		 Survodutide 2.4 mg - actual maintenance treatment Survodutide 4.8 mg - actual maintenance treatment Survodutide 6.0 mg - actual maintenance treatment Placebo - actual maintenance treatment
    Number of subjects analysed
    93
    69
    52
    79
    Units: Percentage of participants
        number (not applicable)
    38.7
    63.8
    55.8
    15.2
    Statistical analysis title
    		 Logistic regression-2.4 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included actual treatment, presence of diabetes of any type and Baseline Fibrosis Score. Firth’s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.001 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.66
         upper limit
    		 7.25
    Notes
    [1] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 2.4 mg" vs. "Placebo".
    [2] - The p−value reported is considered nominal.
    Statistical analysis title
    		 Logistic regression-4.8 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included actual treatment, presence of diabetes of any type and Baseline Fibrosis Score. Firth’s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 4.8 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    9.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.35
         upper limit
    		 20.85
    Notes
    [3] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 4.8 mg" vs. "Placebo".
    [4] - The p−value reported is considered nominal.
    Statistical analysis title
    		 Logistic regression-6.0 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included actual treatment, presence of diabetes of any type and Baseline Fibrosis Score. Firth’s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    7.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.1
         upper limit
    		 16.16
    Notes
    [5] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 6.0 mg" vs. "Placebo".
    [6] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MCP-Mod linear model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050).
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Survodutide 4.8 mg - actual maintenance treatment v Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod linear model fit
    Confidence interval
    Notes
    [7] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept, and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors. P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed. Linear model fit assumption.
    Statistical analysis title
    		 MCP-Mod exponential-1 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050).
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Survodutide 4.8 mg - actual maintenance treatment v Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod exponential-1 model fit
    Confidence interval
    Notes
    [8] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept, and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors. P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed. MCP-Mod exponential-1 model assumption: 25% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod exponential-2 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050).
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Survodutide 4.8 mg - actual maintenance treatment v Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.0008
    Method
    		 MCP-Mod exponential -2 model fit
    Confidence interval
    Notes
    [9] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors. P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed. MCP-Mod exponential-2 model assumption: 5% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod Emax1 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050).
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Survodutide 4.8 mg - actual maintenance treatment v Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod Emax1 model fit
    Confidence interval
    Notes
    [10] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors. P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed. MCP-Mod Emax1 model assumption: 50% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod Emax2 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050).
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Survodutide 4.8 mg - actual maintenance treatment v Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod Emax2 model fit
    Confidence interval
    Notes
    [11] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors. P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed. MCP-Mod Emax2 model assumption: 80% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod quadratic model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050).
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Survodutide 4.8 mg - actual maintenance treatment v Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod quadratic model fit
    Confidence interval
    Notes
    [12] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors. P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed. MCP-Mod quadratic model assumption: Maximum effect is achieved at dose 4.8 mg.

    Primary: Improvement (yes/ no) from baseline in liver histological findings based on liver biopsy after 48 weeks of treatment in patients with NASH (NAS ≥ 4, fibrosis F1-F3) - planned maintenance treatment

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    End point title
    		 Improvement (yes/ no) from baseline in liver histological findings based on liver biopsy after 48 weeks of treatment in patients with NASH (NAS ≥ 4, fibrosis F1-F3) - planned maintenance treatment
    End point description
    Percentage of patients who had an improvement from baseline in liver histological findings based on liver biopsy after 48 weeks of treatment is reported. Percentages were rounded to one decimal place. Improvement in histological findings was defined as a composite of improvement in non-alcoholic steatohepatitis (NASH) and no worsening of fibrosis. Improvement in NASH was defined as decrease of at least 2 points in non-alcoholic fatty liver disease (NAFLD) activity score (NAS) with at least 1 point decrease in NAS subscore of either lobular inflammation or ballooning. Patients without post-baseline data were considered non-responders. Patients are analyzed for this endpoint according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    End point type
    Primary
    End point timeframe
    At baseline and after 48 weeks of treatment.
    End point values
    		 Survodutide 2.4 mg - planned maintenance treatment Survodutide 4.8 mg - planned maintenance treatment Survodutide 6.0 mg - planned maintenance treatment Placebo - planned maintenance treatment
    Number of subjects analysed
    73
    72
    74
    74
    Units: percentage of participants
        number (not applicable)
    46.6
    62.5
    43.2
    13.5
    Statistical analysis title
    		 Logistic regression-2.4 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model includes planned treatment, presence of diabetes of any type and Baseline Fibrosis Score. Firth’s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.0001 [14]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.46
         upper limit
    		 12.28
    Notes
    [13] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 2.4 mg" vs. "Placebo".
    [14] - The p−value reported is considered nominal.
    Statistical analysis title
    		 Logistic regression-6.0 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model includes planned treatment, presence of diabetes of any type and Baseline Fibrosis Score. Firth’s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.0001 [16]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.18
         upper limit
    		 10.91
    Notes
    [15] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 6.0 mg" vs. "Placebo".
    [16] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MCP-Mod linear model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050).
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Survodutide 4.8 mg - planned maintenance treatment v Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.0001
    Method
    		 MCP-Mod linear model fit
    Confidence interval
    Notes
    [17] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors. P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed. Linear model fit assumption.
    Statistical analysis title
    		 Logistic regression-4.8 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model includes planned treatment, presence of diabetes of any type and Baseline Fibrosis Score. Firth’s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 4.8 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 < 0.0001 [19]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    10.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.49
         upper limit
    		 22.87
    Notes
    [18] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 4.8 mg" vs. "Placebo".
    [19] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MCP-Mod exponential-1 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050).
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Survodutide 4.8 mg - planned maintenance treatment v Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.0115
    Method
    		 MCP-Mod exponential-1 model fit
    Confidence interval
    Notes
    [20] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept, and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors. P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed. Model assumption: 25% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod exponential-2 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050).
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Survodutide 4.8 mg - planned maintenance treatment v Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.2204
    Method
    		 MCP-Mod exponential-2 model fit
    Confidence interval
    Notes
    [21] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept, and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors. P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed. Model assumption: 5% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod Emax1 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050).
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Survodutide 4.8 mg - planned maintenance treatment v Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod Emax1 model fit
    Confidence interval
    Notes
    [22] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept, and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors. P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed. Model assumption: 50% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod Emax2 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050).
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Survodutide 4.8 mg - planned maintenance treatment v Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod Emax2 model fit
    Confidence interval
    Notes
    [23] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors. P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed. Model assumption: 80% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod quadratic model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050).
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Survodutide 4.8 mg - planned maintenance treatment v Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod quadratic model fit
    Confidence interval
    Notes
    [24] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept, and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors. P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed. Model assumption: Maximum effect is achieved at dose 4.8 mg.

    Secondary: Improvement of liver fat content (yes/ no) defined as at least 30% relative reduction in liver fat content after 48 weeks of treatment compared to baseline assessed by MRI-PDFF - actual maintenance treatment

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    End point title
    		 Improvement of liver fat content (yes/ no) defined as at least 30% relative reduction in liver fat content after 48 weeks of treatment compared to baseline assessed by MRI-PDFF - actual maintenance treatment
    End point description
    Percentage of participants with improvement in liver fat content is reported. Improvement in liver fat content was defined as percentage reduction from baseline of ≥30% in liver fat content after 48 weeks of treatment compared to baseline. Percentages were rounded to one decimal place. Liver fat content was assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF). Patients without post-baseline values were imputed as non-responders. Treated set - actual maintenance treatment. Patients are analyzed according to the actual treatment they received at the start of the dose maintenance period (for patients who reached the maintenance period) or the next maintenance dose up from the dose at treatment discontinuation (for patients who discontinued treatment prior to the maintenance period). Number of patients analyzed reflects the number of patients included in the analysis model.
    End point type
    Secondary
    End point timeframe
    At baseline and after 48 weeks.
    End point values
    		 Survodutide 2.4 mg - actual maintenance treatment Survodutide 4.8 mg - actual maintenance treatment Survodutide 6.0 mg - actual maintenance treatment Placebo - actual maintenance treatment
    Number of subjects analysed
    93
    69
    52
    79
    Units: Percentage of participants
        number (not applicable)
    50.5
    66.7
    76.9
    16.5
    Statistical analysis title
    		 Logistic regression-2.4 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included actual treatment, presence of diabetes of any type, baseline liver fat content and baseline fibrosis score. Firth’s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 < 0.0001 [26]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.47
         upper limit
    		 10.4
    Notes
    [25] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 2.4 mg" vs. "Placebo".
    [26] - The p−value reported is considered nominal.
    Statistical analysis title
    		 Logistic regression-6.0 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included actual treatment, presence of diabetes of any type, baseline liver fat content and baseline fibrosis score. Firth’s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 < 0.0001 [28]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    16.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.69
         upper limit
    		 38.73
    Notes
    [27] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 6.0 mg" vs. "Placebo".
    [28] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MCP-Mod linear model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050). P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed.
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Survodutide 4.8 mg - actual maintenance treatment v Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod linear model fit
    Confidence interval
    Notes
    [29] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors, and baseline liver fat content (assessed by MRI-PDFF) as a continuous linear covariate. Linear model fit assumption.
    Statistical analysis title
    		 MCP-Mod quadratic model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050). P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed.
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Survodutide 4.8 mg - actual maintenance treatment v Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod quadratic model fit
    Confidence interval
    Notes
    [30] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors, and baseline liver fat content (assessed by MRI-PDFF) as a continuous linear covariate. MCP-Mod quadratic model assumption: Maximum effect is achieved at dose 4.8 mg.
    Statistical analysis title
    		 MCP-Mod exponential-2 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050). P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed.
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Survodutide 4.8 mg - actual maintenance treatment v Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod exponential-2 model fit
    Confidence interval
    Notes
    [31] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept, and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors, and baseline liver fat content (assessed by MRI-PDFF) as a continuous linear covariate. MCP-Mod exponential-2 model assumption: 5% of maximum effect achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod Emax1 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050). P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed.
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Survodutide 4.8 mg - actual maintenance treatment v Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod Emax1 model fit
    Confidence interval
    Notes
    [32] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors, and baseline liver fat content (assessed by MRI-PDFF) as a continuous linear covariate. MCP-Mod Emax1 model assumption: 50% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod Emax2 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050). P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed.
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Survodutide 4.8 mg - actual maintenance treatment v Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod Emax2 model fit
    Confidence interval
    Notes
    [33] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept, and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors, and baseline liver fat content (assessed by MRI-PDFF) as a continuous linear covariate. MCP-Mod Emax2 model assumption: 80% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 Logistic regression-4.8 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included actual treatment, presence of diabetes of any type, baseline liver fat content and baseline fibrosis score. Firth’s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 4.8 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 < 0.0001 [35]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    9.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.36
         upper limit
    		 20.51
    Notes
    [34] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 4.8 mg" vs. "Placebo".
    [35] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MCP-Mod exponential-1 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050). P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed.
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Survodutide 4.8 mg - actual maintenance treatment v Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [36]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod exponential-1 model fit
    Confidence interval
    Notes
    [36] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept, and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors, and baseline liver fat content (assessed by MRI-PDFF) as a continuous linear covariate. MCP-Mod exponential-1 model assumption: 25% of maximum effect is achieved at dose 3.0 mg.

    Secondary: Improvement of liver fat content (yes/ no) defined as at least 30% relative reduction in liver fat content after 48 weeks of treatment compared to baseline assessed by MRI-PDFF - planned maintenance treatment

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    End point title
    		 Improvement of liver fat content (yes/ no) defined as at least 30% relative reduction in liver fat content after 48 weeks of treatment compared to baseline assessed by MRI-PDFF - planned maintenance treatment
    End point description
    Percentage of participants with improvement in liver fat content is reported. Improvement in liver fat content was defined as percentage reduction from baseline of ≥30% in liver fat content after 48 weeks of treatment compared to baseline. Liver fat content was assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF). Patients without post-baseline values were imputed as non-responders. Patients are analyzed for this endpoint according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    End point type
    Secondary
    End point timeframe
    At baseline and at 48 weeks.
    End point values
    		 Survodutide 2.4 mg - planned maintenance treatment Survodutide 4.8 mg - planned maintenance treatment Survodutide 6.0 mg - planned maintenance treatment Placebo - planned maintenance treatment
    Number of subjects analysed
    73
    72
    74
    74
    Units: Percentage of participants
        number (not applicable)
    63.0
    66.7
    56.8
    13.5
    Statistical analysis title
    		 MCP-Mod linear model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050). P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed.
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Survodutide 4.8 mg - planned maintenance treatment v Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod linear model fit
    Confidence interval
    Notes
    [37] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept, and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors, and baseline liver fat content (assessed by MRI-PDFF) as a continuous linear covariate. Linear model fit assumption.
    Statistical analysis title
    		 Logistic regression-6.0 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included planned treatment, presence of diabetes of any type, baseline liver fat content and baseline fibrosis score. Firth’s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 other [38]
    P-value
    		 < 0.0001 [39]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    8.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.66
         upper limit
    		 18.5
    Notes
    [38] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 6.0 mg" vs. "Placebo".
    [39] - The p−value reported is considered nominal.
    Statistical analysis title
    		 Logistic regression-4.8 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included planned treatment, presence of diabetes of any type, baseline liver fat content and baseline fibrosis score. Firth’s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 4.8 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other [40]
    P-value
    		 < 0.0001 [41]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    12.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.3
         upper limit
    		 27.45
    Notes
    [40] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 4.8 mg" vs. "Placebo".
    [41] - The p−value reported is considered nominal.
    Statistical analysis title
    		 Logistic regression-2.4 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included planned treatment, presence of diabetes of any type, baseline liver fat content and baseline fibrosis score. Firth’s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [42]
    P-value
    		 < 0.0001 [43]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    10.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.6
         upper limit
    		 23.45
    Notes
    [42] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 2.4 mg" vs. "Placebo".
    [43] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MCP-Mod Emax2 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050). P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed.
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Survodutide 4.8 mg - planned maintenance treatment v Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [44]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod Emax2 model fit
    Confidence interval
    Notes
    [44] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors, and baseline liver fat content (assessed by MRI-PDFF) as a continuous linear covariate. MCP-Mod Emax2 model assumption: 80% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod Emax1 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050). P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed.
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Survodutide 4.8 mg - planned maintenance treatment v Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [45]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod Emax1 model fit
    Confidence interval
    Notes
    [45] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors, and baseline liver fat content (assessed by MRI-PDFF) as a continuous linear covariate. MCP-Mod Emax1 model assumption: 50% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod exponential-2 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050). P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed.
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Survodutide 4.8 mg - planned maintenance treatment v Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [46]
    P-value
    		 = 0.0925
    Method
    		 MCP-Mod exponential-2 model fit
    Confidence interval
    Notes
    [46] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors, and baseline liver fat content (assessed by MRI-PDFF) as a continuous linear covariate. MCP-Mod exponential-2 model assumption: 5% of maximum effect is achieved at dose 3.0 mg.
    Statistical analysis title
    		 MCP-Mod quadratic model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050). P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed.
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Survodutide 4.8 mg - planned maintenance treatment v Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [47]
    P-value
    		 < 0.0001
    Method
    		 MCP-Mod quadratic model fit
    Confidence interval
    Notes
    [47] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept, and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors, and baseline liver fat content (assessed by MRI-PDFF) as a continuous linear covariate. MCP-Mod quadratic model assumption: Maximum effect is achieved at dose 4.8 mg.
    Statistical analysis title
    		 MCP-Mod exponential-1 model fit
    Statistical analysis description
    A flat vs. non-flat dose-response relationship across the 3 doses of survodutide and placebo was tested using the MCP-Mod approach which evaluated simultaneously 6 different plausible dose-response patterns (linear, exponential1, exponential2, Emax1, Emax2, quadratic) while keeping full control of the type I error (one-sided alpha of 0.050). P-values from the contrast tests corresponding to each dose response pattern evaluated were adjusted for the multiple comparisons performed.
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Survodutide 4.8 mg - planned maintenance treatment v Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [48]
    P-value
    		 = 0.0031
    Method
    		 MCP-Mod exponential-1 model fit
    Confidence interval
    Notes
    [48] - Logistic regression estimates were used as input for the MCP-Mod. The logistic regression model was fitted without an intercept and included presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and the dose group as factors, and baseline liver fat content (assessed by MRI-PDFF) as a continuous linear covariate. MCP-Mod exponential-1 model assumption: 25% of maximum effect is achieved at dose 3.0 mg.

    Secondary: Absolute change of liver fat content from baseline after 48 weeks of treatment assessed by MRI-PDFF - actual maintenance treatment

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    End point title
    		 Absolute change of liver fat content from baseline after 48 weeks of treatment assessed by MRI-PDFF - actual maintenance treatment
    End point description
    Absolute change of liver fat content (percentage [%]) from baseline after 48 weeks of treatment is reported. Liver fat content was assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF). Least Squares Mean (Standard error) were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors. Patients are analyzed according to the actual treatment they received at the start of the dose maintenance period (for patients who reached the maintenance period) or the next maintenance dose up from the dose at treatment discontinuation (for patients who discontinued treatment prior to the maintenance period). Number of patients analyzed reflects the number of patients included in the analysis model.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements from baseline and at Week 28 and at Week 48 after first drug administration. MMRM estimates of absolute change from baseline to Week 48 is reported.
    End point values
    		 Survodutide 2.4 mg - actual maintenance treatment Survodutide 4.8 mg - actual maintenance treatment Survodutide 6.0 mg - actual maintenance treatment Placebo - actual maintenance treatment
    Number of subjects analysed
    68
    60
    51
    73
    Units: percentage of liver fat content
        least squares mean (confidence interval 95%)
    -10.48 (-11.92 to -9.04)
    -12.80 (-14.32 to -11.28)
    -12.96 (-14.62 to -11.30)
    -1.89 (-3.26 to -0.51)
    Statistical analysis title
    		 MMRM - 2.4 mg Survodutide vs. Placebo
    Statistical analysis description
    Least Squares Mean differences and 95% confidence interval were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors.
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 other [49]
    P-value
    		 < 0.0001 [50]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -8.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.59
         upper limit
    		 -6.6
    Notes
    [49] - No confirmatory hypothesis testing was performed. The number of subjects in this analysis included all the subjects for an MMRM analysis, in which all subjects contribute to variability and covariance matrix estimates, even if not part of the pairwise comparison being presented, i.e.,252 subjects. Mean Difference (Net) was calculated as: Least Squares Mean of "Survodutide 2.4 mg"- Least Squares Mean of "Placebo".
    [50] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MMRM - 6.0 mg Survodutide vs. Placebo
    Statistical analysis description
    Least Squares Mean differences and 95% confidence interval were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors.
    Comparison groups
    Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other [51]
    P-value
    		 < 0.0001 [52]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -11.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.23
         upper limit
    		 -8.92
    Notes
    [51] - No confirmatory hypothesis testing was performed. The number of subjects in this analysis included all the subjects for an MMRM analysis, in which all subjects contribute to variability and covariance matrix estimates, even if not part of the pairwise comparison being presented, i.e.,252 subjects. Mean Difference (Net) was calculated as: Least Squares Mean of "Survodutide 6.0 mg"- Least Squares Mean of "Placebo".
    [52] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MMRM - 4.8 mg Survodutide vs. Placebo
    Statistical analysis description
    Least Squares Mean differences and 95% confidence interval were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors.
    Comparison groups
    Survodutide 4.8 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 other [53]
    P-value
    		 < 0.0001 [54]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -10.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.96
         upper limit
    		 -8.86
    Notes
    [53] - No confirmatory hypothesis testing was performed. The number of subjects in this analysis included all the subjects for an MMRM analysis, in which all subjects contribute to variability and covariance matrix estimates, even if not part of the pairwise comparison being presented, i.e.,252 subjects. Mean Difference (Net) was calculated as: Least Squares Mean of "Survodutide 4.8 mg"- Least Squares Mean of "Placebo".
    [54] - The p−value reported is considered nominal.

    Secondary: Absolute change of liver fat content from baseline after 48 weeks of treatment assessed by MRI-PDFF - planned maintenance treatment

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    End point title
    		 Absolute change of liver fat content from baseline after 48 weeks of treatment assessed by MRI-PDFF - planned maintenance treatment
    End point description
    Absolute change of liver fat content from baseline after 48 weeks of treatment is reported. Liver fat content was assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF). Least Squares Mean (Standard error) were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors. Patients are analyzed for this endpoint according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose. Number of patients analyzed reflects the number of patients included in the analysis model.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements from baseline and at Week 28 and at Week 48 after first drug administration. MMRM estimates of absolute change from baseline to Week 48 is reported.
    End point values
    		 Survodutide 2.4 mg - planned maintenance treatment Survodutide 4.8 mg - planned maintenance treatment Survodutide 6.0 mg - planned maintenance treatment Placebo - planned maintenance treatment
    Number of subjects analysed
    61
    64
    58
    69
    Units: percentage of liver fat content
        least squares mean (confidence interval 95%)
    -10.73 (-12.25 to -9.22)
    -12.40 (-13.90 to -10.91)
    -12.48 (-14.06 to -10.89)
    -1.61 (-3.04 to -0.19)
    Statistical analysis title
    		 MMRM - 2.4 mg Survodutide vs. Placebo
    Statistical analysis description
    Least Squares Mean differences and 95% confidence interval were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors.
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other [55]
    P-value
    		 < 0.0001 [56]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -9.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.21
         upper limit
    		 -7.03
    Notes
    [55] - No confirmatory hypothesis testing was performed. The number of subjects "in this analysis" included all the subjects for an MMRM analysis, in which all subjects contribute to variability and covariance matrix estimates, even if not part of the pairwise comparison being presented, i.e.,252 subjects. Mean Difference (Net) was calculated as: Least Squares Mean of "Survodutide 2.4 mg"- Least Squares Mean of "Placebo".
    [56] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MMRM - 6.0 mg Survodutide vs. Placebo
    Statistical analysis description
    Least Squares Mean differences and 95% confidence interval were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors.
    Comparison groups
    Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 other [57]
    P-value
    		 < 0.0001 [58]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -10.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13
         upper limit
    		 -8.73
    Notes
    [57] - No confirmatory hypothesis testing was performed. The number of subjects "in this analysis" included all the subjects for an MMRM analysis, in which all subjects contribute to variability and covariance matrix estimates, even if not part of the pairwise comparison being presented, i.e.,252 subjects. Mean Difference (Net) was calculated as: Least Squares Mean of "Survodutide 6.0 mg"- Least Squares Mean of "Placebo".
    [58] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MMRM - 4.8 mg Survodutide vs. Placebo
    Statistical analysis description
    Least Squares Mean differences and 95% confidence interval were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors.
    Comparison groups
    Survodutide 4.8 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 other [59]
    P-value
    		 < 0.0001 [60]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -10.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.85
         upper limit
    		 -8.73
    Notes
    [59] - No confirmatory hypothesis testing was performed. The number of subjects "in this analysis" included all the subjects for an MMRM analysis, in which all subjects contribute to variability and covariance matrix estimates, even if not part of the pairwise comparison being presented, i.e.,252 subjects. Mean Difference (Net) was calculated as: Least Squares Mean of "Survodutide 4.8 mg"- Least Squares Mean of "Placebo".
    [60] - The p−value reported is considered nominal.

    Secondary: Percent change of liver fat content from baseline after 48 weeks of treatment assessed by MRI-PDFF - actual maintenance treatment

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    End point title
    		 Percent change of liver fat content from baseline after 48 weeks of treatment assessed by MRI-PDFF - actual maintenance treatment
    End point description
    Percent change of liver fat content (percentage [%]) from baseline after 48 weeks of treatment is reported. Liver fat content was assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF). Least Squares Mean (Standard error) were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors. Patients are analyzed according to the actual treatment they received at the start of the dose maintenance period (for patients who reached the maintenance period) or the next maintenance dose up from the dose at treatment discontinuation (for patients who discontinued treatment prior to the maintenance period). Number of patients analyzed reflects the number of patients included in the analysis model.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements from baseline and at Week 28 and at Week 48 after first drug administration. MMRM estimates of percent change from baseline to Week 48 is reported.
    End point values
    		 Survodutide 2.4 mg - actual maintenance treatment Survodutide 4.8 mg - actual maintenance treatment Survodutide 6.0 mg - actual maintenance treatment Placebo - actual maintenance treatment
    Number of subjects analysed
    68
    60
    51
    73
    Units: percent change of liver fat content
        least squares mean (confidence interval 95%)
    -50.92 (-58.05 to -43.80)
    -62.79 (-70.26 to -55.32)
    -64.30 (-72.48 to -56.12)
    -7.28 (-14.06 to -0.50)
    Statistical analysis title
    		 MMRM - 2.4 mg Survodutide vs. Placebo
    Statistical analysis description
    Least Squares Mean differences and 95% confidence interval were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors.
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 other [61]
    P-value
    		 < 0.0001 [62]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -43.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.49
         upper limit
    		 -33.79
    Notes
    [61] - No confirmatory hypothesis testing was performed. The number of subjects in this analysis included all the subjects for an MMRM analysis, in which all subjects contribute to variability and covariance matrix estimates, even if not part of the pairwise comparison being presented, i.e.,252 subjects. Mean Difference (Net) was calculated as: Least Squares Mean of "Survodutide 2.4 mg"- Least Squares Mean of "Placebo".
    [62] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MMRM - 4.8 mg Survodutide vs. Placebo
    Statistical analysis description
    Least Squares Mean differences and 95% confidence interval were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors.
    Comparison groups
    Survodutide 4.8 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 other [63]
    P-value
    		 < 0.0001 [64]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -55.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -65.61
         upper limit
    		 -45.42
    Notes
    [63] - No confirmatory hypothesis testing was performed. The number of subjects in this analysis included all the subjects for an MMRM analysis, in which all subjects contribute to variability and covariance matrix estimates, even if not part of the pairwise comparison being presented, i.e.,252 subjects. Mean Difference (Net) was calculated as: Least Squares Mean of "Survodutide 4.8 mg"- Least Squares Mean of "Placebo".
    [64] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MMRM - 6.0 mg Survodutide vs. Placebo
    Statistical analysis description
    Least Squares Mean differences and 95% confidence interval were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors.
    Comparison groups
    Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other [65]
    P-value
    		 < 0.0001 [66]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -57.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -67.66
         upper limit
    		 -46.39
    Notes
    [65] - No confirmatory hypothesis testing was performed. The number of subjects in this analysis included all the subjects for an MMRM analysis, in which all subjects contribute to variability and covariance matrix estimates, even if not part of the pairwise comparison being presented, i.e.,252 subjects. Mean Difference (Net) was calculated as: Least Squares Mean of "Survodutide 6.0 mg"- Least Squares Mean of "Placebo".
    [66] - The p−value reported is considered nominal.

    Secondary: Percent change of liver fat content from baseline after 48 weeks of treatment assessed by MRI-PDFF - planned maintenance treatment

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    End point title
    		 Percent change of liver fat content from baseline after 48 weeks of treatment assessed by MRI-PDFF - planned maintenance treatment
    End point description
    Percent change of liver fat content (percentage [%]) from baseline after 48 weeks of treatment is reported. Liver fat content was assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF). Least Squares Mean (Standard error) were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors. Patients are analyzed for this endpoint according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose. Only patients which were included in the analysis model of this endpoint are reported.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements from baseline and at Week 28 and at Week 48 after first drug administration. MMRM estimates of percent change from baseline to Week 48 is reported.
    End point values
    		 Survodutide 2.4 mg - planned maintenance treatment Survodutide 4.8 mg - planned maintenance treatment Survodutide 6.0 mg - planned maintenance treatment Placebo - planned maintenance treatment
    Number of subjects analysed
    61
    64
    58
    69
    Units: percent change of liver fat content
        least squares mean (confidence interval 95%)
    -52.20 (-59.66 to -44.75)
    -60.82 (-68.16 to -53.48)
    -61.97 (-69.78 to -54.16)
    -5.71 (-12.70 to 1.28)
    Statistical analysis title
    		 MMRM - 2.4 mg Survodutide vs. Placebo
    Statistical analysis description
    Least Squares Mean differences and 95% confidence interval were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors.
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other [67]
    P-value
    		 < 0.0001 [68]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -46.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -56.74
         upper limit
    		 -36.25
    Notes
    [67] - No confirmatory hypothesis testing was performed. The number of subjects in this analysis included all the subjects for an MMRM analysis, in which all subjects contribute to variability and covariance matrix estimates, even if not part of the pairwise comparison being presented, i.e.,252 subjects. Mean Difference (Net) was calculated as: Least Squares Mean of "Survodutide 2.4 mg"- Least Squares Mean of "Placebo".
    [68] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MMRM - 4.8 mg Survodutide vs. Placebo
    Statistical analysis description
    Least Squares Mean differences and 95% confidence interval were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors.
    Comparison groups
    Survodutide 4.8 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 other [69]
    P-value
    		 < 0.0001 [70]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -55.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -65.25
         upper limit
    		 -44.98
    Notes
    [69] - No confirmatory hypothesis testing was performed. The number of subjects in this analysis included all the subjects for an MMRM analysis, in which all subjects contribute to variability and covariance matrix estimates, even if not part of the pairwise comparison being presented, i.e.,252 subjects. Mean Difference (Net) was calculated as: Least Squares Mean of "Survodutide 4.8 mg"- Least Squares Mean of "Placebo".
    [70] - The p−value reported is considered nominal.
    Statistical analysis title
    		 MMRM - 6.0 mg Survodutide vs. Placebo
    Statistical analysis description
    Least Squares Mean differences and 95% confidence interval were calculated from mixed-effect model for repeated measures (MMRM) including fixed effects for baseline liver fat content (%) as a continuous linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3], visit, treatment by visit interaction and baseline by visit interaction as factors.
    Comparison groups
    Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 other [71]
    P-value
    		 < 0.0001 [72]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -56.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -66.76
         upper limit
    		 -45.77
    Notes
    [71] - No confirmatory hypothesis testing was performed. The number of subjects in this analysis included all the subjects for an MMRM analysis, in which all subjects contribute to variability and covariance matrix estimates, even if not part of the pairwise comparison being presented, i.e.,252 subjects. Mean Difference (Net) was calculated as: Least Squares Mean of "Survodutide 6.0 mg"- Least Squares Mean of "Placebo".
    [72] - The p−value reported is considered nominal.

    Secondary: Improvement of fibrosis (yes/ no) defined as at least one stage decrease in fibrosis stage after 48 weeks of treatment assessed by liver biopsy - actual maintenance treatment

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    End point title
    		 Improvement of fibrosis (yes/ no) defined as at least one stage decrease in fibrosis stage after 48 weeks of treatment assessed by liver biopsy - actual maintenance treatment
    End point description
    Percentage of participants with improvement of liver fibrosis is reported. Improvement of fibrosis was defined as at least one stage decrease in fibrosis stage after 48 weeks of treatment assessed by liver biopsy. The total score for the fibrosis stage ranges from 0 to 4 with higher score indication worsening of the disease and the stages of fibrosis based on their location are the following: - 1A Zone 3, perisinusoidal, delicate; - 1B Zone 3, perisinuosoidal, dense; - 1C Portal, periportal only; - 2 Zone 3, perisinusoidal + portal, periportal only; - 3 Bridging fibrosis; - 4 Cirrhosis. For analysis purposes no distinction was made between stages 1A, 1B and 1C. Patients are analyzed according to the actual treatment they received at the start of the dose maintenance period (for patients who reached the maintenance period) or the next maintenance dose up from the dose at treatment discontinuation (for patients who discontinued treatment prior to the maintenance period).
    End point type
    Secondary
    End point timeframe
    At baseline and after 48 weeks of treatment.
    End point values
    		 Survodutide 2.4 mg - actual maintenance treatment Survodutide 4.8 mg - actual maintenance treatment Survodutide 6.0 mg - actual maintenance treatment Placebo - actual maintenance treatment
    Number of subjects analysed
    93
    69
    52
    79
    Units: Percentage of participants
        number (not applicable)
    30.1
    34.8
    44.2
    21.5
    Statistical analysis title
    		 Logistic regression-2.4 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included actual treatment, presence of diabetes of any type and baseline fibrosis score. Firth‘s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 2.4 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 other [73]
    P-value
    		 = 0.1894 [74]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 3.26
    Notes
    [73] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 2.4 mg" vs. "Placebo".
    [74] - The p−value reported is considered nominal.
    Statistical analysis title
    		 Logistic regression-6.0 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included actual treatment, presence of diabetes of any type and baseline fibrosis score. Firth‘s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 6.0 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 other [75]
    P-value
    		 = 0.0028 [76]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.52
         upper limit
    		 7.45
    Notes
    [75] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 6.0 mg" vs. "Placebo".
    [76] - The p−value reported is considered nominal.
    Statistical analysis title
    		 Logistic regression-4.8 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included actual treatment, presence of diabetes of any type and baseline fibrosis score. Firth‘s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 4.8 mg - actual maintenance treatment v Placebo - actual maintenance treatment
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 other [77]
    P-value
    		 = 0.0685 [78]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 4.2
    Notes
    [77] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 4.8 mg" vs. "Placebo".
    [78] - The p−value reported is considered nominal.

    Secondary: Improvement of fibrosis (yes/ no) defined as at least one stage decrease in fibrosis stage after 48 weeks of treatment assessed by liver biopsy - planned maintenance treatment

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    End point title
    		 Improvement of fibrosis (yes/ no) defined as at least one stage decrease in fibrosis stage after 48 weeks of treatment assessed by liver biopsy - planned maintenance treatment
    End point description
    Percentage of participants with improvement of liver fibrosis is reported. Improvement of fibrosis was defined as at least one stage decrease in fibrosis stage after 48 weeks of treatment assessed by liver biopsy. The total score for the fibrosis stage ranges from 0 to 4 with higher score indication worsening of the disease and the stages of fibrosis based on their location are the following: - 1A Zone 3, perisinusoidal, delicate; - 1B Zone 3, perisinuosoidal, dense; - 1C Portal, periportal only; - 2 Zone 3, perisinusoidal + portal, periportal only; - 3 Bridging fibrosis; - 4 Cirrhosis. For analysis purposes no distinction was made between stages 1A, 1B and 1C. Patients are analyzed for this endpoint according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose.
    End point type
    Secondary
    End point timeframe
    At baseline and after 48 weeks of treatment.
    End point values
    		 Survodutide 2.4 mg - planned maintenance treatment Survodutide 4.8 mg - planned maintenance treatment Survodutide 6.0 mg - planned maintenance treatment Placebo - planned maintenance treatment
    Number of subjects analysed
    73
    72
    74
    74
    Units: Percentage of participants
        number (not applicable)
    34.2
    36.1
    33.8
    21.6
    Statistical analysis title
    		 Logistic regression-2.4 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included planned treatment, presence of diabetes of any type and baseline fibrosis score. Firth‘s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 2.4 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [79]
    P-value
    		 = 0.0663 [80]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 4.27
    Notes
    [79] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 2.4 mg" vs. "Placebo".
    [80] - The p−value reported is considered nominal.
    Statistical analysis title
    		 Logistic regression-4.8 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included planned treatment, presence of diabetes of any type and baseline fibrosis score. Firth‘s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 4.8 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other [81]
    P-value
    		 = 0.0672 [82]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 4.23
    Notes
    [81] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 4.8 mg" vs. "Placebo".
    [82] - The p−value reported is considered nominal.
    Statistical analysis title
    		 Logistic regression-6.0 mg Survodutide vs. Placebo
    Statistical analysis description
    The logistic regression model included planned treatment, presence of diabetes of any type and baseline fibrosis score. Firth‘s penalized regression was used. The logistic regression model included all 293 treated subjects, not just those allocated to the two compared treatment groups.
    Comparison groups
    Survodutide 6.0 mg - planned maintenance treatment v Placebo - planned maintenance treatment
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 other [83]
    P-value
    		 = 0.0512 [84]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 4.46
    Notes
    [83] - No confirmatory hypothesis testing was performed. Odds Ratio of "Survodutide 6.0 mg" vs. "Placebo".
    [84] - The p−value reported is considered nominal.

    Secondary: Absolute change from baseline in NAS after 48 weeks of treatment assessed by liver biopsy - actual maintenance treatment

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    End point title
    		 Absolute change from baseline in NAS after 48 weeks of treatment assessed by liver biopsy - actual maintenance treatment
    End point description
    Absolute change from baseline in NAS after 48 weeks of treatment assessed by liver biopsy is reported. The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) represents the sum of subscores for steatosis (scored from 0-3), lobular inflammation (scored from 0-3) and ballooning (scored from 0-2), and the total score ranges from 0 to 8 with higher scores representing worsening of the disease. Patients are analyzed according to the actual treatment they received at the start of the dose maintenance period (for patients who reached the maintenance period) or the next maintenance dose up from the dose at treatment discontinuation (for patients who discontinued treatment prior to the maintenance period). Number of patients analyzed reflects the number of patients included in the analysis model.
    End point type
    Secondary
    End point timeframe
    At baseline and 48 weeks of treatment.
    End point values
    		 Survodutide 2.4 mg - actual maintenance treatment Survodutide 4.8 mg - actual maintenance treatment Survodutide 6.0 mg - actual maintenance treatment Placebo - actual maintenance treatment
    Number of subjects analysed
    56
    53
    44
    66
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.8 ( 1.8 )
    -3.2 ( 1.8 )
    -3.3 ( 2.0 )
    -0.4 ( 1.6 )
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in NAS after 48 weeks of treatment assessed by liver biopsy - planned maintenance treatment

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    End point title
    		 Absolute change from baseline in NAS after 48 weeks of treatment assessed by liver biopsy - planned maintenance treatment
    End point description
    Absolute change from baseline in NAS after 48 weeks of treatment assessed by liver biopsy is reported. The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) represents the sum of subscores for steatosis (scored from 0-3), lobular inflammation (scored from 0-3) and ballooning (scored from 0-2), and the total score ranges from 0 to 8 with higher scores representing worsening of the disease. Patients are analyzed for this endpoint according to the planned treatment (planned maintenance dose strength) they were assigned at randomisation even if patients did not reach the maintenance period at all, and therefore did not "settle" on any maintenance dose. Only patients with NAS at baseline and at 48 weeks after treatment are included in the analysis.
    End point type
    Secondary
    End point timeframe
    At baseline and 48 weeks of treatment.
    End point values
    		 Survodutide 2.4 mg - planned maintenance treatment Survodutide 4.8 mg - planned maintenance treatment Survodutide 6.0 mg - planned maintenance treatment Placebo - planned maintenance treatment
    Number of subjects analysed
    53
    55
    48
    63
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.8 ( 1.8 )
    -3.2 ( 1.8 )
    -3.3 ( 1.9 )
    -0.2 ( 1.5 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    [All-Cause Mortality], [Serious Adverse Events], [Other Adverse Events]: From first study drug administration until last study drug administration plus 28 days of residual effect period (REP), up to 365 days.
    Adverse event reporting additional description
    Adverse events are reported according to the actual treatment the patents received at the start of the dose maintenance phase (for patients who reached the maintenance period) or the next maintenance dose up from the dose at treatment discontinuation (for patients who discontinued treatment prior to the maintenance period).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Survodutide 2.4 mg - actual maintenance treatment
    Reporting group description
    		 This arm includes patients who were treated with 2.4 mg of survodutide administered weekly at the start of the maintenance period, for patients who reached the maintenance period, regardless of whether this was the randomised (planned) dose or not, and regardless of whether the patient stayed on that dose throughout the maintenance period. This arm includes also those patients for whom the next maintenance dose up from the dose at treatment discontinuation was 2.4 mg of survodutide administered weekly, for patients who discontinued treatment prior to the maintenance period, regardless of the reason for the treatment discontinuation.

    Reporting group title
    Placebo
    Reporting group description
    		 This arm includes patients who were treated with placebo matching survodutide administered weekly at the start of the maintenance period, for patients who reached the maintenance period, regardless of whether this was the randomised (planned) dose or not, and regardless of whether the patient stayed on that dose throughout the maintenance period. This arm includes also those patients who were receiving placebo matching survodutide administered weekly and who discontinued treatment prior to the maintenance period, regardless of the reason for the treatment discontinuation.

    Reporting group title
    Survodutide 6.0 mg - actual maintenance treatment
    Reporting group description
    		 This arm includes patients who were treated with 6.0 mg of survodutide administered weekly at the start of the maintenance period, for patients who reached the maintenance period, regardless of whether this was the randomised (planned) dose or not, and regardless of whether the patient stayed on that dose throughout the maintenance period. This arm includes also those patients for whom the next maintenance dose up from the dose at treatment discontinuation was 6.0 mg of survodutide administered weekly, for patients who discontinued treatment prior to the maintenance period, regardless of the reason for the treatment discontinuation.

    Reporting group title
    Survodutide 4.8 mg - actual maintenance treatment
    Reporting group description
    		 This arm includes patients who were treated with 4.8 mg of survodutide administered weekly at the start of the maintenance period, for patients who reached the maintenance period, regardless of whether this was the randomised (planned) dose or not, and regardless of whether the patient stayed on that dose throughout the maintenance period. This arm includes also those patients for whom the next maintenance dose up from the dose at treatment discontinuation was 4.8 mg of survodutide administered weekly, for patients who discontinued treatment prior to the maintenance period, regardless of the reason for the treatment discontinuation.

    Serious adverse events
    		 Survodutide 2.4 mg - actual maintenance treatment Placebo Survodutide 6.0 mg - actual maintenance treatment Survodutide 4.8 mg - actual maintenance treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 93 (5.38%)
    5 / 79 (6.33%)
    5 / 52 (9.62%)
    7 / 69 (10.14%)
         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)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 79 (1.27%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Puncture site pain
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 79 (1.27%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Abnormal uterine bleeding
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Combined pulmonary fibrosis and emphysema
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 79 (1.27%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    1 / 52 (1.92%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    1 / 52 (1.92%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    1 / 52 (1.92%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    1 / 52 (1.92%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness transient
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal polyp
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 79 (1.27%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 79 (1.27%)
    1 / 52 (1.92%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    2 / 52 (3.85%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 79 (1.27%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    1 / 52 (1.92%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 79 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 79 (1.27%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    1 / 52 (1.92%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Survodutide 2.4 mg - actual maintenance treatment Placebo Survodutide 6.0 mg - actual maintenance treatment Survodutide 4.8 mg - actual maintenance treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    85 / 93 (91.40%)
    68 / 79 (86.08%)
    49 / 52 (94.23%)
    60 / 69 (86.96%)
    Investigations
    Lipase increased
         subjects affected / exposed
    5 / 93 (5.38%)
    0 / 79 (0.00%)
    1 / 52 (1.92%)
    4 / 69 (5.80%)
         occurrences all number
    7
    0
    1
    10
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    0 / 93 (0.00%)
    5 / 79 (6.33%)
    1 / 52 (1.92%)
    2 / 69 (2.90%)
         occurrences all number
    0
    5
    1
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 93 (22.58%)
    13 / 79 (16.46%)
    6 / 52 (11.54%)
    12 / 69 (17.39%)
         occurrences all number
    60
    25
    13
    22
    Dizziness
         subjects affected / exposed
    11 / 93 (11.83%)
    6 / 79 (7.59%)
    3 / 52 (5.77%)
    5 / 69 (7.25%)
         occurrences all number
    17
    9
    4
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 93 (1.08%)
    5 / 79 (6.33%)
    1 / 52 (1.92%)
    2 / 69 (2.90%)
         occurrences all number
    1
    5
    1
    3
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    3 / 93 (3.23%)
    5 / 79 (6.33%)
    1 / 52 (1.92%)
    3 / 69 (4.35%)
         occurrences all number
    18
    17
    2
    5
    Asthenia
         subjects affected / exposed
    5 / 93 (5.38%)
    1 / 79 (1.27%)
    2 / 52 (3.85%)
    1 / 69 (1.45%)
         occurrences all number
    6
    1
    2
    1
    Early satiety
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 79 (1.27%)
    6 / 52 (11.54%)
    2 / 69 (2.90%)
         occurrences all number
    2
    1
    7
    2
    Fatigue
         subjects affected / exposed
    18 / 93 (19.35%)
    7 / 79 (8.86%)
    8 / 52 (15.38%)
    10 / 69 (14.49%)
         occurrences all number
    56
    12
    12
    13
    Injection site bruising
         subjects affected / exposed
    3 / 93 (3.23%)
    6 / 79 (7.59%)
    1 / 52 (1.92%)
    1 / 69 (1.45%)
         occurrences all number
    4
    21
    5
    3
    Injection site pain
         subjects affected / exposed
    3 / 93 (3.23%)
    6 / 79 (7.59%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    32
    10
    0
    0
    Pyrexia
         subjects affected / exposed
    4 / 93 (4.30%)
    5 / 79 (6.33%)
    2 / 52 (3.85%)
    3 / 69 (4.35%)
         occurrences all number
    5
    5
    2
    5
    Malaise
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 79 (0.00%)
    5 / 52 (9.62%)
    1 / 69 (1.45%)
         occurrences all number
    2
    0
    7
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    15 / 93 (16.13%)
    7 / 79 (8.86%)
    9 / 52 (17.31%)
    10 / 69 (14.49%)
         occurrences all number
    34
    8
    24
    29
    Abdominal pain upper
         subjects affected / exposed
    7 / 93 (7.53%)
    4 / 79 (5.06%)
    1 / 52 (1.92%)
    2 / 69 (2.90%)
         occurrences all number
    13
    6
    4
    3
    Abdominal pain
         subjects affected / exposed
    12 / 93 (12.90%)
    4 / 79 (5.06%)
    5 / 52 (9.62%)
    5 / 69 (7.25%)
         occurrences all number
    15
    4
    5
    9
    Gastrooesophageal reflux disease
         subjects affected / exposed
    8 / 93 (8.60%)
    5 / 79 (6.33%)
    3 / 52 (5.77%)
    7 / 69 (10.14%)
         occurrences all number
    9
    6
    3
    13
    Nausea
         subjects affected / exposed
    60 / 93 (64.52%)
    22 / 79 (27.85%)
    33 / 52 (63.46%)
    46 / 69 (66.67%)
         occurrences all number
    225
    103
    175
    192
    Vomiting
         subjects affected / exposed
    38 / 93 (40.86%)
    6 / 79 (7.59%)
    15 / 52 (28.85%)
    33 / 69 (47.83%)
         occurrences all number
    99
    16
    82
    89
    Eructation
         subjects affected / exposed
    12 / 93 (12.90%)
    2 / 79 (2.53%)
    8 / 52 (15.38%)
    9 / 69 (13.04%)
         occurrences all number
    25
    3
    12
    35
    Dyspepsia
         subjects affected / exposed
    14 / 93 (15.05%)
    3 / 79 (3.80%)
    11 / 52 (21.15%)
    6 / 69 (8.70%)
         occurrences all number
    23
    9
    23
    10
    Diarrhoea
         subjects affected / exposed
    38 / 93 (40.86%)
    20 / 79 (25.32%)
    29 / 52 (55.77%)
    37 / 69 (53.62%)
         occurrences all number
    133
    61
    97
    170
    Constipation
         subjects affected / exposed
    16 / 93 (17.20%)
    14 / 79 (17.72%)
    15 / 52 (28.85%)
    12 / 69 (17.39%)
         occurrences all number
    27
    21
    29
    21
    Flatulence
         subjects affected / exposed
    8 / 93 (8.60%)
    4 / 79 (5.06%)
    8 / 52 (15.38%)
    6 / 69 (8.70%)
         occurrences all number
    23
    6
    14
    36
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 93 (5.38%)
    8 / 79 (10.13%)
    2 / 52 (3.85%)
    1 / 69 (1.45%)
         occurrences all number
    6
    8
    3
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 93 (1.08%)
    3 / 79 (3.80%)
    4 / 52 (7.69%)
    3 / 69 (4.35%)
         occurrences all number
    1
    3
    5
    5
    Alopecia
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 79 (0.00%)
    4 / 52 (7.69%)
    1 / 69 (1.45%)
         occurrences all number
    0
    0
    4
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 93 (0.00%)
    4 / 79 (5.06%)
    1 / 52 (1.92%)
    0 / 69 (0.00%)
         occurrences all number
    0
    4
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 93 (2.15%)
    6 / 79 (7.59%)
    0 / 52 (0.00%)
    2 / 69 (2.90%)
         occurrences all number
    2
    6
    0
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 93 (8.60%)
    7 / 79 (8.86%)
    7 / 52 (13.46%)
    3 / 69 (4.35%)
         occurrences all number
    8
    12
    7
    4
    Arthralgia
         subjects affected / exposed
    4 / 93 (4.30%)
    12 / 79 (15.19%)
    5 / 52 (9.62%)
    4 / 69 (5.80%)
         occurrences all number
    4
    15
    7
    13
    Pain in extremity
         subjects affected / exposed
    1 / 93 (1.08%)
    5 / 79 (6.33%)
    1 / 52 (1.92%)
    3 / 69 (4.35%)
         occurrences all number
    1
    6
    1
    3
    Myalgia
         subjects affected / exposed
    4 / 93 (4.30%)
    5 / 79 (6.33%)
    1 / 52 (1.92%)
    3 / 69 (4.35%)
         occurrences all number
    4
    6
    1
    3
    Infections and infestations
    COVID-19
         subjects affected / exposed
    19 / 93 (20.43%)
    16 / 79 (20.25%)
    5 / 52 (9.62%)
    15 / 69 (21.74%)
         occurrences all number
    23
    16
    5
    16
    Urinary tract infection
         subjects affected / exposed
    7 / 93 (7.53%)
    5 / 79 (6.33%)
    7 / 52 (13.46%)
    1 / 69 (1.45%)
         occurrences all number
    8
    9
    8
    1
    Influenza
         subjects affected / exposed
    2 / 93 (2.15%)
    5 / 79 (6.33%)
    2 / 52 (3.85%)
    2 / 69 (2.90%)
         occurrences all number
    2
    5
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    6 / 93 (6.45%)
    10 / 79 (12.66%)
    4 / 52 (7.69%)
    12 / 69 (17.39%)
         occurrences all number
    6
    13
    4
    13
    Sinusitis
         subjects affected / exposed
    1 / 93 (1.08%)
    5 / 79 (6.33%)
    2 / 52 (3.85%)
    0 / 69 (0.00%)
         occurrences all number
    1
    5
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 93 (7.53%)
    3 / 79 (3.80%)
    2 / 52 (3.85%)
    4 / 69 (5.80%)
         occurrences all number
    10
    4
    3
    5
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    7 / 93 (7.53%)
    2 / 79 (2.53%)
    1 / 52 (1.92%)
    3 / 69 (4.35%)
         occurrences all number
    9
    8
    1
    4
    Hyperglycaemia
         subjects affected / exposed
    1 / 93 (1.08%)
    4 / 79 (5.06%)
    0 / 52 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    1
    6
    0
    1
    Decreased appetite
         subjects affected / exposed
    20 / 93 (21.51%)
    8 / 79 (10.13%)
    8 / 52 (15.38%)
    9 / 69 (13.04%)
         occurrences all number
    23
    11
    10
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2020
    Global protocol amendment No. 1 - Part 1: Regular self-monitoring blood glucose (SMBG) measurements in type 2 diabetes mellitus (T2DM) patients on antidiabetic medication and safety measures in case of hypoglycaemic events were added at request from Health Authority. Dispensation of SMBG device was implemented as an additional safety measure. Unplanned data monitoring committee (DMC) meeting and unblinded safety assessment by DMC at the occurrence of adverse events that might lead to trial discontinuation were added at request from Health Authority regarding trial stopping criteria and process. Inclusion criterion body mass index (BMI) cut-off increased to 25 kg/m2 to homogenously include overweight patients of all ethnicities. The previous BMI cut-off included normal weight Caucasians or overweight Asians. Exclusion criteria modified: Estimated glomerular filtration rate (eGFR) cut-off increased to 60 mL/min/1.73m2 (at request from Health Authority). Exclusion of patients with history of organ transplantation except for corneal transplantation (at request from Health Authority). For patients with history of major depressive disorder in the past 2 years, the criterion “requiring inpatient treatment or escalation of care” was added for identification of patients with history of major depressive disorder.
    18 Dec 2020
    Global protocol amendment No. 1 - Part 2: Trial treatment discontinuation criteria modified: Occurrence of an adverse event (AE) Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 related to trial treatment added to the trial treatment discontinuation criteria for individual patients. Information regarding close monitoring and medical review of all AEs CTCAE Grade 3 and higher added as triggers for discontinuation of trial treatment for all patients. Minimum requirement for collection of liver biopsy specimen (i.e. size of biopsy needle, size of biopsy specimen) added to define the quality standards for an accurate histology evaluation Clarification added to exclude patients from sites in China for collection of blood samples for exploratory biomarkers, but Fib-4 index and aspartate amino transferase (AST) to platelet ratio index (APRI) were to be calculated. Guidelines for removal of individual patients in case of increased liver enzymes revised, and trial treatment discontinuation criteria defined for individual patients in the event of drug-induced liver injury, at request from Health Authority.
    14 May 2021
    Global protocol amendment No. 2: Cap for patients from sites in China removed: Definition of full analysis set amended to omit the reference to China. Sensitivity analysis of the primary endpoint including patients from sites in China removed. Description of interim analysis modified to include patients from sites in China. Screening period extended to 10 weeks, as central assessments might take longer than 8 weeks. Vital signs at Visit 1a became optional, as measurement at the primary site on the day of the screening biopsy might not be always possible. Requirement to perform imaging assessments at the same time of the day removed. Urine pregnancy test at Follow-Up Visit added, pregnancy test should be performed at the end of the relevant systemic exposure. Exclusion criteria modified: Fasting condition was no longer required for blood samples collection at any visit. However, serum triglycerides might be retested at fasting condition during screening if the levels at Visit 1 exceeded 500 mg/dL (5.65 mmol/L). Congestive heart failure New York Heart Association (NYHA) class III-IV added to align with trials using the same compound. Treatment discontinuation criteria modified: Torsade de Pointes and any major adverse cardiovascular events added at request from Health Authority. Clinically significant elevation of liver enzymes and tolerance issues added for completeness (this information was already mentioned in other sections). Information from toxicology studies relevant to selection of 6 mg dose added at request from Health Authority. Paper Instructions for Use, paper diary, and paper PRO questionnaires added as a backup solution in case electronic documents were not available. Option to conduct safety laboratory tests in local laboratories added to ensure trial continuity while maintaining patient safety in the event of disruptive circumstances.
    24 May 2022
    Global Protocol amendment No. 3 - Part 2: Sodium-Glucose Co-Transporter 2 (SGLT-2) inhibitors removed from the list of restricted concomitant medications, there are no clinical justifications for complete exclusion of T2DM patients treated with SGLT-2 inhibitors. Medications known to significantly prolong the QT/QTc interval added as restricted concomitant medications, to align with exclusion criterion #15. Requirement to repeat FibroScan® and MR imaging at re-screening removed, if the initial screening was performed within a month, to reduce burden for patients. Guidelines for removal of individual patients in case of increased liver enzymes revised, to align with the consensus guidelines including provisions for patients with Gilbert’s syndrome. Note: upon submission of CTP version 4.0 dated 24 May 2022 Boehringer Ingelheim (BI) received advice from the FDA to: (1) implement non-invasive tests and/or imaging tools in non-cirrhotic subjects with low platelet count in order to exclude portal hypertension, and (2) exclude patients who recently started treatment with an SGLT-2 inhibitor. As the trial was in the final stage of recruitment and the implementation of additional tests and tools would require more time than the remaining time for recruitment, it was decided that clinical trial protocol (CTP) version 4.0 dated 24 May 2022 was not implemented.
    24 May 2022
    Global Protocol amendment No. 3 - Part 1: Inclusion criterion modified: liver biopsy findings should always be the primary assessment if histology and non-invasive assessments differed, as liver biopsy is more accurate in staging and grading NASH and liver fibrosis than FibroScan® and Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF). Screening period extended if logistical issues caused delays for results of liver biopsy from central vendor(s). Eligible patients could be considered for trial participation even if results were received more than 10 weeks after Visit 1 (ethical aspect). Exclusion criteria: eGFR cut-off modified to include patients with mild or moderate renal impairment, as recent findings indicated no safety concerns for these patients. Platelet count cut-off modified: liver cirrhosis was ruled out by histology, therefore patients without any sign of liver cirrhosis and a platelet count >110 x 10^9/L assumably have a non-significant risk of portal hypertension. Stopping rules of the trial modified: instead of stopping the trial treatment in all patients, enrolment of new patients was to be stopped pending DMC recommendation, as sudden stop and possible restart of the trial treatment in all patients might lead to drug tolerability issues in many patients. Criteria for Grade 3 CTCAE AEs of nausea, vomiting, diarrhoea, constipation, or anorexia specified: evaluation the CTCAE grading was put into a more clinically meaningful context to be considered for stopping enrolment of new patients and potentially stopping the trial following DMC recommendation.
    04 Aug 2022
    Global Protocol amendment No. 4: Platelet count cut-off changed back to the original level, as the trial was in the final stage of recruitment and implementation of alternative non-invasive tests and/or imaging tools for the exclusion of portal hypertension as requested by Health Authority would require more time than the remaining recruitment time. Patients recently started on SGLT-2 inhibitors excluded as recommended by Health Authority.
    27 Jul 2023
    Global Protocol amendment No. 5: Information on purpose of the interim analysis and access to unblinded data from the interim analysis modified, as data on liver fat reduction and liver benefits from this trial were essential for developing the Phase III program for Survodutide in chronic weight management.

    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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