Non-alcoholic Steatohepatitis (NASH)
Conditions
Brief summary
This study is open for men and women with a liver disease called nonalcoholic steatohepatitis (NASH) and liver fibrosis. The purpose of the study is to find out whether a medicine called BI 456906 helps patients with NASH and liver fibrosis. The study tests 3 different doses of BI 456906 to find the dose that helps best. Participants are put into 4 groups randomly, which means by chance. There are 3 groups that each receive a different dose of BI 456906 and there is 1 group that receives placebo. BI 456906 and placebo are given as an injection under the skin once per week. The placebo injection looks like the BI 456906 injection but does not contain any medicine. Participants are in the study for a little over 1 year (60 weeks). During this time, they visit the study site several times and have some video calls in addition. At the visits, the study doctors take different measurements. To see whether the treatment works, the doctors take a very small sample of liver tissue (biopsy) from each participant at the start and at the end of the study. They also examine the liver by ultrasound and MRI. The doctors also regularly check the general health of the participants.
Interventions
DRUGSurvodutide
Survodutide
DRUGPlacebo
Placebo
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female patients ≥ 18 years (or who are of legal age in countries where that is greater than 18 years) and ≤ 80 years of age at time of consent. 2. Diagnosis of non-alcoholic steatohepatitis (NASH) (Non-alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) ≥ 4, with at least 1 point in inflammation and ballooning each) and fibrosis stage F1-F3 proven by a biopsy conducted during the screening period or by a historical biopsy conducted within the last 6 months prior to randomization and stable body weight defined as less than 5% self-reported change in body weight between the historical biopsy and randomization, if a historical biopsy is used. 3. Liver fat fraction ≥ 8% measured by Magnetic Resonance Imaging (MRI)-Proton Density Fat Fraction (PDFF) and liver stiffness \> 6.0 kPa measured by FibroScan® at Visit 1 (if biopsy is scheduled during the screening period MRI-PDFF and FibroScan® assessments have to be performed prior to the biopsy). However, the diagnosis of NASH and fibrosis at liver biopsy (including historical biopsy) is the primary assessment to establish patient eligibility. 4. Patients willing and able to undergo liver biopsies per protocol as judged by the Investigator. 5. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial. 6. Women of childbearing potential (WOCBP)1 must be willing and able to use two forms of effective contraception where at least one form is highly effective methods of birth control per International Council on Harmonisation (ICH) M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. Further inclusion criteria apply.
Exclusion criteria
1. Current or history of significant alcohol consumption (defined as intake of \> 210 g/ week in males and \> 140 g/ week in females on average over a consecutive period of more than 3 months) or inability to reliably quantify alcohol consumption based on Investigator judgement within the last 5 years. 2. Intake of medications historically associated with liver injury, hepatic steatosis or steatohepatitis within 12 weeks prior to Visit 1. Intake of restricted medications or any medications considered likely to interfere with the safe conduct of the trial. 3. History of other forms of chronic liver disease (e.g., viral hepatitis, autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilson's disease, hemochromatosis, Alpha-1 Antitrypsin (A1At) deficiency, history of liver transplantation). Hepatitis B and C testing will be done at Visit 1. Patients with positive Hepatitis B surface antigen (HBsAg) should be excluded. Patients treated for hepatitis C must have a negative RNA test at screening and also be Hepatitis C Virus (HCV) RNA negative for at least 3 years prior to screening in order to be eligible for the trial. 4. Suspicion, diagnosis, or history of hepatocellular carcinoma (HCC), or any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix. 5. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, manifest hypo- or hyperthyroidism at Visit 1. 6. History of chronic or acute pancreatitis or elevation of serum lipase/amylase \> 2x ULN or fasting serum triglyceride levels of \> 500 mg/dL (\> 5.65 mmol/L) at screening. 7. Known history of HIV (Human Immunodeficiency Virus) infection and/or tuberculosis and/or an acute COVID-19 infection at Visit 1 (confirmed by SARS CoV-2 RT-PCR test). Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | At baseline and at 48 weeks. | 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. The 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. The total score for the fibrosis stage ranges from 0 to 4 with higher score indication worsening of the disease. Patients without post-baseline data were considered non-responders. |
| 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 | At baseline and after 48 weeks of treatment. | 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. The 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. The total score for the fibrosis stage ranges from 0 to 4 with higher score indication worsening of the disease. Patients without post-baseline data were considered non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment | 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. | 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. |
| Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment | 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. | 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. |
| Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment | 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. | 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. |
| Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment | 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. | 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. |
| 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 | At baseline and after 48 weeks. | 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. |
| 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 | At baseline and after 48 weeks of treatment. | 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, perisinusoidal, 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. |
| Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Actual Maintenance Treatment | At baseline and 48 weeks of treatment. | 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. |
| Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Planned Maintenance Treatment | At baseline and 48 weeks of treatment. | 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. |
| 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 | At baseline and after 48 weeks of treatment. | 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, perisinusoidal, 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. |
| 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 | At baseline and at 48 weeks. | 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. |
Countries
Australia, Austria, Belgium, Canada, China, Czechia, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Malaysia, Netherlands, New Zealand, Poland, Portugal, Singapore, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This was a 48 weeks, multi-centre, randomised, dose-ranging, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy, safety and tolerability of multiple subcutaneous (s.c.) doses of survodutide (BI 456906) 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 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.
Participants by arm
| Arm | Count |
|---|---|
| Survodutide 2.4 mg - Planned Maintenance Treatment 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).
Participants 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. | 73 |
| Survodutide 4.8 mg - Planned Maintenance Treatment 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).
Participants 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. | 72 |
| Survodutide 6.0 mg - Planned Maintenance Treatment 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).
Participants 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. | 74 |
| Placebo - Planned Maintenance Treatment 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). | 74 |
| Total | 293 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Dose Escalation Period | Adverse Event | 8 | 9 | 12 | 2 |
| Dose Escalation Period | Burden of study procedures | 1 | 0 | 0 | 0 |
| Dose Escalation Period | Change of residence | 0 | 0 | 0 | 1 |
| Dose Escalation Period | Not treated with trial medication | 0 | 1 | 1 | 0 |
| Dose Escalation Period | Other reasons than listed | 2 | 0 | 2 | 1 |
| Dose Escalation Period | Perceived lack of efficacy | 0 | 0 | 0 | 1 |
| Dose Escalation Period | Protocol Violation | 0 | 0 | 3 | 1 |
| Maintenance Period | Adverse Event | 4 | 5 | 5 | 0 |
| Maintenance Period | Burden of study procedures | 1 | 0 | 0 | 0 |
| Maintenance Period | Change of residence | 0 | 1 | 3 | 0 |
| Maintenance Period | Other than listed | 4 | 2 | 0 | 3 |
| Maintenance Period | Perceived lack of efficacy | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Survodutide 2.4 mg - Planned Maintenance Treatment | Total | Placebo - Planned Maintenance Treatment | Survodutide 6.0 mg - Planned Maintenance Treatment | Survodutide 4.8 mg - Planned Maintenance Treatment |
|---|---|---|---|---|---|
| Age, Continuous | 49.6 years STANDARD_DEVIATION 13.7 | 50.8 years STANDARD_DEVIATION 12.8 | 53.0 years STANDARD_DEVIATION 11.5 | 50.4 years STANDARD_DEVIATION 13.1 | 50.2 years STANDARD_DEVIATION 12.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 81 Participants | 22 Participants | 26 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 59 Participants | 212 Participants | 52 Participants | 48 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| NAS score at baseline | 5.2 score on a scale STANDARD_DEVIATION 1 | 5.2 score on a scale STANDARD_DEVIATION 1 | 5.2 score on a scale STANDARD_DEVIATION 1.1 | 5.1 score on a scale STANDARD_DEVIATION 1 | 5.3 score on a scale STANDARD_DEVIATION 1.1 |
| Number of participants at each category of liver fibrosis stage at baseline Stage 1A | 0 Participants | 8 Participants | 2 Participants | 3 Participants | 3 Participants |
| Number of participants at each category of liver fibrosis stage at baseline Stage 1B | 17 Participants | 47 Participants | 9 Participants | 14 Participants | 7 Participants |
| Number of participants at each category of liver fibrosis stage at baseline Stage 1C | 3 Participants | 15 Participants | 3 Participants | 6 Participants | 3 Participants |
| Number of participants at each category of liver fibrosis stage at baseline Stage 2 | 30 Participants | 120 Participants | 30 Participants | 24 Participants | 36 Participants |
| Number of participants at each category of liver fibrosis stage at baseline Stage 3 | 23 Participants | 103 Participants | 30 Participants | 27 Participants | 23 Participants |
| Number of participants in each category of diabetes at baseline No | 44 Participants | 176 Participants | 45 Participants | 44 Participants | 43 Participants |
| Number of participants in each category of diabetes at baseline Yes | 29 Participants | 117 Participants | 29 Participants | 30 Participants | 29 Participants |
| Number of patients in each category of NAS score 0 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of patients in each category of NAS score 1 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of patients in each category of NAS score 2 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of patients in each category of NAS score 3 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of patients in each category of NAS score 4 | 21 Participants | 89 Participants | 22 Participants | 26 Participants | 20 Participants |
| Number of patients in each category of NAS score 5 | 27 Participants | 93 Participants | 28 Participants | 17 Participants | 21 Participants |
| Number of patients in each category of NAS score 6 | 17 Participants | 73 Participants | 8 Participants | 26 Participants | 22 Participants |
| Number of patients in each category of NAS score 7 | 8 Participants | 37 Participants | 16 Participants | 5 Participants | 8 Participants |
| Number of patients in each category of NAS score 8 | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Number of patients in each category of the NAS sub-scores (ballooning) 0 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of patients in each category of the NAS sub-scores (ballooning) 1 | 55 Participants | 212 Participants | 49 Participants | 53 Participants | 55 Participants |
| Number of patients in each category of the NAS sub-scores (ballooning) 2 | 18 Participants | 81 Participants | 25 Participants | 21 Participants | 17 Participants |
| Number of patients in each category of the NAS sub-scores (steatosis and lobular inflammation) Lobular inflammation 0 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of patients in each category of the NAS sub-scores (steatosis and lobular inflammation) Lobular inflammation 1 | 32 Participants | 136 Participants | 37 Participants | 36 Participants | 31 Participants |
| Number of patients in each category of the NAS sub-scores (steatosis and lobular inflammation) Lobular inflammation 2 | 38 Participants | 146 Participants | 32 Participants | 36 Participants | 40 Participants |
| Number of patients in each category of the NAS sub-scores (steatosis and lobular inflammation) Lobular inflammation 3 | 3 Participants | 11 Participants | 5 Participants | 2 Participants | 1 Participants |
| Number of patients in each category of the NAS sub-scores (steatosis and lobular inflammation) Steatosis 0 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of patients in each category of the NAS sub-scores (steatosis and lobular inflammation) Steatosis 1 | 6 Participants | 10 Participants | 3 Participants | 1 Participants | 0 Participants |
| Number of patients in each category of the NAS sub-scores (steatosis and lobular inflammation) Steatosis 2 | 38 Participants | 168 Participants | 43 Participants | 49 Participants | 38 Participants |
| Number of patients in each category of the NAS sub-scores (steatosis and lobular inflammation) Steatosis 3 | 29 Participants | 115 Participants | 28 Participants | 24 Participants | 34 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 24 Participants | 80 Participants | 17 Participants | 17 Participants | 22 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 46 Participants | 205 Participants | 56 Participants | 56 Participants | 47 Participants |
| Sex: Female, Male Female | 36 Participants | 155 Participants | 44 Participants | 41 Participants | 34 Participants |
| Sex: Female, Male Male | 37 Participants | 138 Participants | 30 Participants | 33 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 93 | 0 / 69 | 0 / 52 | 0 / 79 |
| other Total, other adverse events | 85 / 93 | 60 / 69 | 49 / 52 | 68 / 79 |
| serious Total, serious adverse events | 5 / 93 | 7 / 69 | 5 / 52 | 5 / 79 |
Outcome results
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
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. The 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. The total score for the fibrosis stage ranges from 0 to 4 with higher score indication worsening of the disease. Patients without post-baseline data were considered non-responders.
Time frame: At baseline and at 48 weeks.
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Survodutide 2.4 mg - Actual Maintenance Treatment | 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 | 38.7 Percentage of participants |
| Survodutide 4.8 mg - Actual Maintenance Treatment | 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 | 63.8 Percentage of participants |
| Survodutide 6.0 mg - Actual Maintenance Treatment | 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 | 55.8 Percentage of participants |
| Placebo - Actual Maintenance Treatment | 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 | 15.2 Percentage of participants |
Comparison: The logistic regression model included actual treatment, presence of diabetes of any type and Baseline Fibrosis Score. Firth's penalized regression was used.p-value: 0.00195% CI: [1.66, 7.25]Regression, Logistic
Comparison: The logistic regression model included actual treatment, presence of diabetes of any type and Baseline Fibrosis Score. Firth's penalized regression was used.p-value: <0.000195% CI: [4.35, 20.85]Regression, Logistic
Comparison: The logistic regression model included actual treatment, presence of diabetes of any type and Baseline Fibrosis Score. Firth's penalized regression was used.p-value: <0.000195% CI: [3.1, 16.16]Regression, Logistic
Comparison: 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).p-value: <0.0001MCP-Mod linear model fit
Comparison: 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).p-value: <0.0001MCP-Mod exponential-1 model fit
Comparison: 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).p-value: 0.0008MCP-Mod exponential -2 model fit
Comparison: 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).p-value: <0.0001MCP-Mod Emax1 model fit
Comparison: 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).p-value: <0.0001MCP-Mod Emax2 model fit
Comparison: 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).p-value: <0.0001MCP-Mod quadratic model fit
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
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. The 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. The total score for the fibrosis stage ranges from 0 to 4 with higher score indication worsening of the disease. Patients without post-baseline data were considered non-responders.
Time frame: At baseline and after 48 weeks of treatment.
Population: Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Survodutide 2.4 mg - Actual Maintenance Treatment | 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 | 46.6 percentage of participants |
| Survodutide 4.8 mg - Actual Maintenance Treatment | 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 | 62.5 percentage of participants |
| Survodutide 6.0 mg - Actual Maintenance Treatment | 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 | 43.2 percentage of participants |
| Placebo - Actual Maintenance Treatment | 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 | 13.5 percentage of participants |
Comparison: The logistic regression model includes planned treatment, presence of diabetes of any type and Baseline Fibrosis Score. Firth's penalized regression was used.p-value: <0.000195% CI: [2.46, 12.28]Regression, Logistic
Comparison: The logistic regression model includes planned treatment, presence of diabetes of any type and Baseline Fibrosis Score. Firth's penalized regression was used.p-value: <0.000195% CI: [4.49, 22.87]Regression, Logistic
Comparison: The logistic regression model includes planned treatment, presence of diabetes of any type and Baseline Fibrosis Score. Firth's penalized regression was used.p-value: 0.000195% CI: [2.18, 10.91]Regression, Logistic
Comparison: 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).p-value: 0.0001MCPMod linear model fit
Comparison: 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).p-value: 0.0115MCPMod exponential-1 model fit
Comparison: 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).p-value: 0.2204MCP-Mod exponential-2 model fit
Comparison: 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).p-value: <0.0001MCP-Mod Emax1 model fit
Comparison: 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).p-value: <0.0001MCP-Mod Emax2
Comparison: 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).p-value: <0.0001MCP-Mod quadratic model fit
Secondary
Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Actual Maintenance Treatment
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.
Time frame: At baseline and 48 weeks of treatment.
Population: 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). Only patients with NAS data at baseline and at 48 weeks after treatment are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Survodutide 2.4 mg - Actual Maintenance Treatment | Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Actual Maintenance Treatment | -2.8 units on a scale | Standard Deviation 1.8 |
| Survodutide 4.8 mg - Actual Maintenance Treatment | Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Actual Maintenance Treatment | -3.2 units on a scale | Standard Deviation 1.8 |
| Survodutide 6.0 mg - Actual Maintenance Treatment | Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Actual Maintenance Treatment | -3.3 units on a scale | Standard Deviation 2 |
| Placebo - Actual Maintenance Treatment | Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Actual Maintenance Treatment | -0.4 units on a scale | Standard Deviation 1.6 |
Secondary
Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Planned Maintenance Treatment
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.
Time frame: At baseline and 48 weeks of treatment.
Population: Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. 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 data at baseline and at 48 weeks after treatment are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Survodutide 2.4 mg - Actual Maintenance Treatment | Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Planned Maintenance Treatment | -2.8 units on a scale | Standard Deviation 1.8 |
| Survodutide 4.8 mg - Actual Maintenance Treatment | Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Planned Maintenance Treatment | -3.2 units on a scale | Standard Deviation 1.8 |
| Survodutide 6.0 mg - Actual Maintenance Treatment | Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Planned Maintenance Treatment | -3.3 units on a scale | Standard Deviation 1.9 |
| Placebo - Actual Maintenance Treatment | Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Planned Maintenance Treatment | -0.2 units on a scale | Standard Deviation 1.5 |
Secondary
Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment
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.
Time frame: 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.
Population: 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). The reported number of participants analyzed reflects the number of participants in the analysis model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Survodutide 2.4 mg - Actual Maintenance Treatment | Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment | -10.48 percentage of liver fat content |
| Survodutide 4.8 mg - Actual Maintenance Treatment | Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment | -12.80 percentage of liver fat content |
| Survodutide 6.0 mg - Actual Maintenance Treatment | Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment | -12.96 percentage of liver fat content |
| Placebo - Actual Maintenance Treatment | Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment | -1.89 percentage of liver fat content |
Comparison: 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.p-value: <0.000195% CI: [-10.59, -6.6]MMRM
Comparison: 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.p-value: <0.000195% CI: [-12.96, -8.86]MMRM
Comparison: 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.p-value: <0.000195% CI: [-13.23, -8.92]MMRM
Secondary
Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment
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.
Time frame: 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.
Population: Treated set - planned maintenance treatment. 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. The reported number of participants analyzed reflects the number of participants in the analysis model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Survodutide 2.4 mg - Actual Maintenance Treatment | Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment | -10.73 percentage of liver fat content |
| Survodutide 4.8 mg - Actual Maintenance Treatment | Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment | -12.40 percentage of liver fat content |
| Survodutide 6.0 mg - Actual Maintenance Treatment | Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment | -12.48 percentage of liver fat content |
| Placebo - Actual Maintenance Treatment | Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment | -1.61 percentage of liver fat content |
Comparison: 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.p-value: <0.000195% CI: [-11.21, -7.03]MMRM
Comparison: 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.p-value: <0.000195% CI: [-12.85, -8.73]MMRM
Comparison: 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.p-value: <0.000195% CI: [-13, -8.73]MMRM
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
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, perisinusoidal, 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.
Time frame: At baseline and after 48 weeks of treatment.
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Survodutide 2.4 mg - Actual Maintenance Treatment | 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 | 30.1 Percentage of participants |
| Survodutide 4.8 mg - Actual Maintenance Treatment | 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 | 34.8 Percentage of participants |
| Survodutide 6.0 mg - Actual Maintenance Treatment | 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 | 44.2 Percentage of participants |
| Placebo - Actual Maintenance Treatment | 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 | 21.5 Percentage of participants |
Comparison: The logistic regression model included actual treatment, presence of diabetes of any type and baseline fibrosis score. Firth's penalized regression was used.p-value: 0.189495% CI: [0.79, 3.26]Regression, Logistic
Comparison: The logistic regression model included actual treatment, presence of diabetes of any type and baseline fibrosis score. Firth's penalized regression was used.p-value: 0.068595% CI: [0.95, 4.2]Regression, Logistic
Comparison: The logistic regression model included actual treatment, presence of diabetes of any type and baseline fibrosis score. Firth's penalized regression was used.p-value: 0.002895% CI: [1.52, 7.45]Regression, Logistic
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
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, perisinusoidal, 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.
Time frame: At baseline and after 48 weeks of treatment.
Population: Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Survodutide 2.4 mg - Actual Maintenance Treatment | 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 | 34.2 Percentage of participants |
| Survodutide 4.8 mg - Actual Maintenance Treatment | 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 | 36.1 Percentage of participants |
| Survodutide 6.0 mg - Actual Maintenance Treatment | 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 | 33.8 Percentage of participants |
| Placebo - Actual Maintenance Treatment | 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 | 21.6 Percentage of participants |
Comparison: The logistic regression model included planned treatment, presence of diabetes of any type and baseline fibrosis score. Firth's penalized regression was used.p-value: 0.066395% CI: [0.95, 4.27]Regression, Logistic
Comparison: The logistic regression model included planned treatment, presence of diabetes of any type and baseline fibrosis score. Firth's penalized regression was used.p-value: 0.067295% CI: [0.95, 4.23]Regression, Logistic
Comparison: The logistic regression model included planned treatment, presence of diabetes of any type and baseline fibrosis score. Firth's penalized regression was used.p-value: 0.051295% CI: [1, 4.46]Regression, Logistic
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
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.
Time frame: At baseline and after 48 weeks.
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Survodutide 2.4 mg - Actual Maintenance Treatment | 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 | 50.5 Percentage of participants |
| Survodutide 4.8 mg - Actual Maintenance Treatment | 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 | 66.7 Percentage of participants |
| Survodutide 6.0 mg - Actual Maintenance Treatment | 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 | 76.9 Percentage of participants |
| Placebo - Actual Maintenance Treatment | 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 | 16.5 Percentage of participants |
Comparison: 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.p-value: <0.000195% CI: [2.47, 10.4]Regression, Logistic
Comparison: 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.p-value: <0.000195% CI: [4.36, 20.51]Regression, Logistic
Comparison: 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.p-value: <0.000195% CI: [6.69, 38.73]Regression, Logistic
Comparison: 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).p-value: <0.0001MCP-Mod linear model fit
Comparison: 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).p-value: <0.0001MCP-Mod exponential-1 model fit
Comparison: 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).p-value: <0.0001MCP-Mod exponential-2 model fit
Comparison: 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).p-value: <0.0001MCP-Mod Emax1 model fit
Comparison: 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).p-value: <0.0001MCP-Mod Emax2 model fit
Comparison: 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).p-value: <0.0001MCP-Mod quadratic model fit
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
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.
Time frame: At baseline and at 48 weeks.
Population: Treated set - planned maintenance treatment: included all patients that were administered survodutide or placebo matching survodutide. 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Survodutide 2.4 mg - Actual Maintenance Treatment | 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 | 63.0 Percentage of participants |
| Survodutide 4.8 mg - Actual Maintenance Treatment | 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 | 66.7 Percentage of participants |
| Survodutide 6.0 mg - Actual Maintenance Treatment | 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 | 56.8 Percentage of participants |
| Placebo - Actual Maintenance Treatment | 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 | 13.5 Percentage of participants |
Comparison: 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.p-value: <0.000195% CI: [4.6, 23.45]Regression, Logistic
Comparison: 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.p-value: <0.000195% CI: [5.3, 27.45]Regression, Logistic
Comparison: 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.p-value: <0.000195% CI: [3.66, 18.5]Regression, Logistic
Comparison: 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).p-value: <0.0001MCP-Mod linear model fit
Comparison: 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).p-value: 0.0031MCP-Mod exponential-1 model fit
Comparison: 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).p-value: 0.0925MCP-Mod exponential-2 model fit
Comparison: 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).p-value: <0.0001MCP-Mod Emax1 model fit
Comparison: 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).p-value: <0.0001MCP-Mod Emax2 model fit
Comparison: 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).p-value: <0.0001MCP-Mod quadratic model fit
Secondary
Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment
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.
Time frame: 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.
Population: 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). The reported number of participants analyzed reflects the number of participants in the analysis model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Survodutide 2.4 mg - Actual Maintenance Treatment | Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment | -50.92 percent change of liver fat content |
| Survodutide 4.8 mg - Actual Maintenance Treatment | Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment | -62.79 percent change of liver fat content |
| Survodutide 6.0 mg - Actual Maintenance Treatment | Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment | -64.30 percent change of liver fat content |
| Placebo - Actual Maintenance Treatment | Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment | -7.28 percent change of liver fat content |
Comparison: 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.p-value: <0.000195% CI: [-53.49, -33.79]MMRM
Comparison: 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.p-value: <0.000195% CI: [-65.61, -45.42]MMRM
Comparison: 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.p-value: <0.000195% CI: [-67.66, -46.39]MMRM
Secondary
Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment
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.
Time frame: 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.
Population: Treated set - planned maintenance treatment: all patients that administered survodutide or placebo matching survodutide. 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.~The reported number of participants analyzed reflects the number of participants in the analysis model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Survodutide 2.4 mg - Actual Maintenance Treatment | Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment | -52.20 percent change of liver fat content |
| Survodutide 4.8 mg - Actual Maintenance Treatment | Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment | -60.82 percent change of liver fat content |
| Survodutide 6.0 mg - Actual Maintenance Treatment | Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment | -61.97 percent change of liver fat content |
| Placebo - Actual Maintenance Treatment | Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment | -5.71 percent change of liver fat content |
Comparison: 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.p-value: <0.000195% CI: [-56.74, -36.25]MMRM
Comparison: 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.p-value: <0.000195% CI: [-65.25, -44.98]MMRM
Comparison: 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.p-value: <0.000195% CI: [-66.76, -45.77]MMRM