Double-blind, randomised, placebo-controlled, phase IIb trial on the efficacy and safety of norursodeoxycholic acid tablets in patients with non-alcoholic steatohepatitis (NASH)

Up until now, the treatment of patients with non-alcoholic steatohepatitis
(NASH) remains a challenge. NASH is a type of non-alcoholic fatty liver
disease. It is often called a *silent* disease because most patients do not
know they have it. NASH includes both a fatty liver and liver inflammation.
Although the disease remains without symptoms most of the time, it can slowly
progress to end stage liver disease such as liver cancer and liver failure. It
will probably be the most common indication of liver transplantation in the
future.
There is not yet any accepted standard treatment that is able to stop or
reverse the progression of NASH. Current treatment options include life-style
modifications such as physical exercise, diet change, blood fat control and
optimal diabetes mellitus control.
For medical treatment, only a few clinical investigations have been carried out
to date. Long-term data on safety and efficacy on drugs tested are still
missing.
By carrying out this clinical trial, the efficacy, safety and tolerability of
two different dosages of norursodeoxycholic acid (norUDCA) tablets will be
investigated.

Primary objective:*
To evaluate the efficacy of norursodeoxycholic acid (norUDCA) 1500 mg vs.
norUDCA 1000 mg vs. placebo for the treatment of NASH
Secondary objective
To study safety and tolerability (adverse events [AEs], laboratory parameters)
of norUDCA

This is a double-blind, randomised, multi-centre, placebo-controlled,
comparative, phase IIb trial. The trial will be conducted with three treatment
groups in the form of a parallel group comparison and will serve to compare
oral treatment with either 1500 mg/d or 1000 mg/d norUDCA tablets vs. placebo
tablets for the treatment of NASH (in patients with and without diabetes
mellitus type 2 [T2DM]).

Double-blind, randomised (1:1:1) treatment phase:

Patients with NASH (with and without T2DM) will be randomised to receive a
72-week, double-blind treatment with:
- Group A: Norursodeoxycholic acid 1500 mg once daily (OD)
3 norUDCA tablets à 500 mg
- Group B: Norursodeoxycholic acid 1000 mg OD
2 norUDCA tablets à 500 mg AND 1 placebo tablet
- Group C: 3 placebo tablets OD

Blinding is achieved by the application of the same number of tablets (verum
and/or placebo) to each patient, i.e. each patient will receive a total of 3
tablets.

The trial medication are tablets for oral use. 3 tablets should be taken every
day in the morning during the treatment phase of 72 weeks (about 18 months).
Laboratory evaluations will be performed.
Liver biopsy assessment will be performed at the start of the study and at the
end of the study.
Additionally, following optional assessments can be performed at indicated
visits: Fibroscan, ARFI, MRI/MRS, vascular ultrasound, gut microbiota analysis
of stool sample.

The time and events schedule summarizes the frequency and timing of the various
measurments and can be found in the protocol V4.0
(pages 13 and 14).

The procedures performed as part of this clinical trial may be associated with
risks or lead to discomforts: blood sampling, ECG, liver biopsy and ultrasound.

Medication should be taken during the treatment phase of 72 weeks (about 18
months). The medication concerns 3 tablets which should be taken each day in
the morning.
Questionnaires should be completed at visits indicated in the time and events
schedule in the protocol V4.0 on page 13 and 14.
No patient diary will need to be completed.

Diagnostic procedures and examinations exercised in this clinical trial are
mostly routine or non-invasive procedures. Only at screening and end of
treatment visits, liver biopsies will be taken for histological assessment.
According to the current European Association of the Liver (EASL) guideline for
the management of NAFLD, liver biopsy is essential for the diagnosis of NASH
and is the only procedure that reliably differentiates fatty liver from NASH.
The histological assessments will enhance the evidence of the trial and support
the prognostic validity of other efficacy endpoints which are based on
non-invasive techniques like serum-based inflammation and fibrosis markers or
liver stiffness measured by elastography. Accordingly, a potential risk
associated with liver biopsy sampling seems to be justified with regard to the
patient population studied.
Due to the lack of an available standard therapy, it seems justified to
introduce a placebo-arm in this clinical trial.