Trial Outcomes & Findings for A Research Study on How Semaglutide Works in People With Fatty Liver Disease and Liver Damage (NCT NCT03987451)

The trial was conducted at 38 sites in 5 countries as follows (number of sites that screened subjects/ number of sites that randomised subjects): United States (24/19); United Kingdom (4/3); Germany (3/2); France (5/3); Spain (2/2).

Participants were randomised in a 2:1 ratio to receive once-weekly either semaglutide or placebo subcutaneously as an adjunct to a reduced-calorie diet and increased physical activity.

A Research Study on How Semaglutide Works in People With Fatty Liver Disease and Liver Damage

NASH resolution defined by NASH clinical research network (CRN) as lobular inflammation of 0 or 1; hepatocellular ballooning reduced to 0; both criteria were necessary conditions. Hepatocellular ballooning ranges from 0-2; lobular inflammation ranges from 0-3, higher scores indicating more severe hepatocellular ballooning/lobular inflammation. Worsening of NASH defined by NASH CRN as increase of at least 1 stage of either lobular inflammation, hepatocyte ballooning or steatosis. Worsening of fibrosis defined by increase in fibrosis at least 1 stage of Kleiner fibrosis classification: fibrosis stages range from 0-4, higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in liver fat content (measured as percentage) from baseline to week 48 is presented as ratio to baseline. Liver fat content was assessed via MRI-PDFF technique and results were measured in percentage. MRI-PDFF utilized a gradient echo sequence with low flip angle to minimize T1 bias, corrected T2\* decay (due to iron overload) via modeling of the fat signal as a superposition of multiple frequency components from 5 different lipid types, and was applied in each of the 9 Couinaud segments. This technique improved fat quantification accuracy for the entire liver permitting quantification of small differences/changes following pharmacological intervention. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in Liver Stiffness from baseline to week 48 is presented as ratio to baseline. Liver stiffness was measured in kilopascal using MRE. MRE is a technology that uses MRI imaging with low-frequency vibrations to create a visual map (elastogram) that shows stiffness of the liver. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

NASH resolution defined by NASH clinical research network as lobular inflammation of 0 or 1 and hepatocellular ballooning reduced to 0; both criteria were necessary conditions. Hepatocellular ballooning ranges from 0-2; lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. Worsening of fibrosis defined by an increase in fibrosis at least one stage of Kleiner fibrosis classification: fibrosis stages range from 0-4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in fibrosis-4 score from baseline to week 48 is presented as ratio to baseline. Fibrosis-4 is the ratio of age in years and aminotransferase to platelet count. It is a non-invasive hepatic fibrosis index score combining standard biochemical values, platelets, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and age that was calculated using formula: Fibrosis-4 = (Age \[years\] x AST \[units per liter (U/L)\]) / (platelets \[10\^9 cells/L\] x (square root of ALT \[U/L\])). A Fibrosis-4 index of \< 1.45 indicated no or moderate fibrosis and an index of \> 3.25 indicated extensive fibrosis/cirrhosis. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Percentage of participants who had worsened, improved or had no change in total NAS from baseline to week 48 or missing data is presented. Worsening was defined as an increase of at least 1 in the NAS; Improvement was defined as a decrease of at least 1 in the NAS; while no change corresponds to no change in NAS and missing refers to participants with missing outcomes for NAS from baseline to week 48. NAS was calculated as the sum of scores for steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocyte ballooning (0 to 2). Therefore, it is assessed on a scale of 0-8, with higher scores indicating more severe disease. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Percentage of participants who had improved, worsened, or had no change in fibrosis stage from baseline to week 48 or missing data is presented. The degree of fibrosis was described by the Kleiner fibrosis staging system, ranging from F0 (absence of fibrosis), F1 (portal/perisinusoidal fibrosis), F2 (perisinusoidal and portal/periportal fibrosis), F3 (septal or bridging fibrosis) through F4 (cirrhosis). Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Percentage of participants who had improved, worsened, or had no change in hepatocyte ballooning from baseline to week 48 or missing data is presented. Hepatocyte ballooning was assessed on a scale of 0-2, with higher scores indicating more severe disease. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Percentage of participants who had improved, worsened, or had no change in lobular inflammation from baseline to week 48 or missing data is presented. Lobular inflammation was assessed on a scale of 0-3, with higher scores indicating more severe lobular inflammation. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Percentage of participants who had improved, worsened, or had no change in steatosis from baseline to week 48 or missing data is presented. Steatosis was assessed on a scale of 0-3, with higher scores indicating more severe steatosis. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Percentage of participants who had improved, worsened, or had no change in the activity component of the SAF score from baseline to week 48 or missing data is presented. SAF score was assessed on a scale of 0-4, with higher scores indicating more severe disease. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Percentage of participants who had improved, worsened, or had no change in the Ishak fibrosis score from baseline to week 48 or missing data is presented. Ishak fibrosis score was assessed on a scale of 0-6, with higher scores indicating more severe disease. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in hepatic collagen from baseline to week 48 was analysed. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Improvement is defined as at least one stage decrease from baseline to week 48 in Kleiner fibrosis classification. The degree of fibrosis was described by the Kleiner fibrosis staging system, ranging from F0 (absence of fibrosis), F1 (portal/perisinusoidal fibrosis), F2 (perisinusoidal and portal/periportal fibrosis), F3 (septal or bridging fibrosis) through F4 (cirrhosis). Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Improvement is defined as at least one stage decrease from baseline to week 48 in hepatocyte ballooning clinical research network (CRN) score. Hepatocyte ballooning was assessed on a scale of 0-2, with higher scores indicating more severe disease. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Improvement is defined as at least one stage decrease from baseline to week 48 in lobular inflammation CRN score. Lobular inflammation was assessed on a scale of 0-3, with higher scores indicating more severe lobular inflammation. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Improvement is defined as at least one stage decrease from baseline to week 48 in steatosis CRN score. Steatosis was assessed on a scale of 0-3, with higher scores indicating more severe steatosis. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Improvement is defined as at least one stage decrease from baseline to week 48 in NAS. NAS was calculated as the sum of scores for steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocyte ballooning (0 to 2). Therefore, it is assessed on a scale of 0-8, with higher scores indicating more severe disease. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Improvement is defined as at least one stage decrease from baseline to week 48 in SAF score. SAF score was assessed on a scale of 0-4, with higher scores indicating more severe disease. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Improvement is defined as at least one stage decrease from baseline to week 48 in Ishak fibrosis score. Ishak fibrosis score was assessed on a scale of 0-6, with higher scores indicating more severe disease. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in body weight from baseline to week 48 is presented. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Relative change in body weight (measured as kg) from baseline to week 48 is presented. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in waist circumference from baseline to week 48 is presented. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in BMI from baseline to week 48 is presented. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Percentage of participants with weight loss of greater than or equal to (≥) 5% of baseline body weight at 48 weeks is presented. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Percentage of participants with weight loss of ≥ 10% of baseline body weight at 48 weeks is presented. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in HbA1c from baseline to week 48 is presented. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in FPG from baseline to week 48 is presented. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in fasting C-peptide \[measured as nanomoles per litre (nmol/L)\] from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in systolic and diastolic blood pressure from baseline to week 48 is presented. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in total cholesterol (measured as mmol/L) from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in LDL cholesterol (measured as mmol/L) from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in HDL cholesterol (measured as mmol/L) from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in VLDL cholesterol (measured as mmol/L) from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in triglycerides (measured as mmol/L) from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in free fatty acids (measured as mmol/L) from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in hsCRP (measured as milligrams per liter) from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in ALT (measured as units per liter) from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in AST (measured as units per liter) from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in GGT (measured as units per liter) from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in albumin \[measured as grams per deciliter (g/dL)\] from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in thrombocytes \[measured as 10\^9 cells per liter\] from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in INR from baseline to week 48 is presented as ratio to baseline. INR is the ratio of measured prothrombin time over normal prothrombin time and it evaluates the extrinsic coagulation pathway (vitamin K dependent clotting factors II; V, VII, IX and X). These clotting factors are synthesised in the liver, thus INR is used as a marker of liver synthesis function. The therapeutic INR range varies, most commonly an INR 2-3 goal, but ranging from 1.5-4.0. Bleeding complications are more likely to occur above an INR value of 4.0. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in direct bilirubin \[measured as micromoles per liter (umol/L)\] from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

Change in total bilirubin \[measured as umol/L\] from baseline to week 48 is presented as ratio to baseline. Outcome measure was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with participant (for participants lost to follow-up); 4) death.

An adverse event (AE) was any untoward medical occurrence in a clinical trial participant administered or using a medicinal product, whether or not considered related to the medicinal product or usage. All AEs reported here are TEAEs. TEAE is defined as an event that had onset date during the on-treatment period. Outcome measure was evaluated based on data from on-treatment period which started on the date of first administration of trial product and ended on the date of whatever comes first of: a) last dose of trial product + 49 days (7 half-lives of semaglutide), b) follow-up visit (week 55), or c) end of the in-trial period.

Hypoglycaemic episode (blood glucose less than or equal to (\<=) 3.9 mmol/L \[70 milligrams per decilitre (mg/dL)\] Or greater than (\>) 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms) is defined as treatment emergent if the onset of the episode occurs during the on-treatment period. Outcome measure was evaluated based on data from on-treatment period which started on the date of first administration of trial product and ended on the date of whatever comes first of: a) last dose of trial product + 49 days (7 half-lives of semaglutide), b) follow-up visit (week 55), or c) end of the in-trial period.

Change in pulse from baseline to week 48 is presented. Outcome measure was evaluated based on data from on-treatment period which started on the date of first administration of trial product and ended on the date of whatever comes first of: a) last dose of trial product + 49 days (7 half-lives of semaglutide), b) follow-up visit (week 55), or c) end of the in-trial period.