Investigation of efficacy and safety of three dose levels of subcutaneous semaglutide once daily versus placebo in subjects with non-alcoholic steatohepatitis.

Currently, no drugs are approved for the treatment of NASH. First-line
treatment is lifestyle intervention to achieve weight loss and treatment of
comorbidities (e.g. hyperlipidaemia, hypertension and diabetes). In the case of
progression to cirrhosis and liver failure, liver transplantation is the only
treatment option. The current sparse epidemiological information on progression
rates and predictive factors has limited the ability to calculate risk and
possible benefit of treatments

Primary objective:
To compare the effect of semaglutide subcutaneous (s.c.) once daily versus
placebo on histological resolution of non-alcoholic steatohepatitis (NASH).

Secondary efficacy objectives
To investigate the dose-response relationship of three dose levels of
semaglutide s.c. once daily (0.1 mg/day, 0.2 mg/day and 0.4 mg/day) on
histological resolution of NASH.
To compare the effects of semaglutide s.c. once daily to placebo on
liver-related histological parameters and biomarkers of NASH disease.
To investigate the effects of semaglutide s.c. once daily versus placebo in
subjects with NASH on:
* Weight-related parameters
* Glucose metabolism related parameters
* Cardiovascular risk factors
* Patient reported outcomes

Secondary safety objectives
To evaluate the safety and tolerability of three dose levels of semaglutide
s.c. once daily in subjects with NASH.

This is a 72-week, randomised, double-blind, placebo-controlled, six-armed,
parallel group, multi-centre, multi-national trial comparing once daily
administration of semaglutide s.c. in three different doses (0.1 mg, 0.2 mg and
0.4 mg) with placebo in subjects with NASH. Subjects will be randomised in a
3:3:3:1:1:1 manner to receive daily dosing of semaglutide s.c. 0.1 mg, 0.2 mg,
0.4 mg or corresponding injection volumes of placebo once daily. To avoid bias
in the assessment of the different semaglutide doses, the trial will be
double-blinded within dose levels. The dose levels will not be blinded between
each other because of different dose escalations and different target doses and
volumes required.
The total trial duration for the individual subject will be up to 85 weeks
(maximum).
Randomisation will be stratified in five strata based on region (Japanese or
non-Japanese) and, within the non-Japanese group, based on diabetes status at
screening (with or without type 2 diabetes) and fibrosis stage for baseline
liver biopsy (F1, F2 or F3).

Daily administration of semaglutide/Placebo subcutaneous in 0.1 mg, 0.2 mg or
0.4 mg.

It is concluded that the potential benefits from participating in the trial
outweigh the potential risks including the risk related to the liver biopsy.
The safety profile of semaglutide generated from the clinical and nonclinical
development programme in T2D has not revealed any safety issues that would
prohibit administration of once weekly doses of 0.5 mg or 1.0 mg semaglutide.
Based on the nature and frequency of the AEs in the T2D trials, it appears to
be safe to investigate daily doses of up to 0.4 mg as in the current trial.
Additional safety surveillance will be instituted in all treatment arms during
the dose escalation period until 4 weeks after last target dose is reached
(steady state). It is concluded that the risk to the subjects in this trial is
low and acceptable in view of the potential benefits a long-acting GLP-1
analogue would provide subjects with NASH.