Double-blind, randomised, placebo-controlled, phase II dose-finding study comparing different doses of norucholic acid tablets with placebo in the treatment of primary biliary cholangitis in patients with an inadequate response to ursodeoxycholic acid

• Signed informed consent, • Male or female patients >= 18 and <= 74 years at
screening, • PBC verified by at least 2 out of the following 3 criteria at
screening: - Chronic cholestatic disease of at least 12 months duration, -
Positive anti-mitochondrial antibody (AMA) titer or, if AMA negative or in low
titer (< 1:80), presence of PBC-specific antibodies (anti-GP210 and/or
anti-SP100 and/or antibodies against the major M2 components [PDC-E2,
2-oxo-glutaric acid dehydrogenase complex]), - Liver biopsy available for
review and compatible with the diagnosis of non-cirrhotic PBC, •
Ursodeoxycholic acid (UDCA) treatment for at least 12 months (with a stable
dose for >= 3 months) prior to screening, • Women of childbearing potential
agreeing to use a highly effective method of birth control during the entire
duration of the trial and for 4 weeks following the last dose of trial
treatment, defined as those which result in a low failure rate (i.e., less than
1% per year) when used consistently and correctly such as implants,
injectables, combined oral contraceptive methods, some intrauterine devices
(IUD), sexual abstinence, or vasectomized partner. Women of non-childbearing
potential (surgically sterile [e.g., hysterectomy, bilateral salpingectomy,
bilateral oophorectomy], or postmenopausal with at least two years without
spontaneous menses) may be included. The investigator is responsible for
determining whether the patient has adequate birth control for trial
participation.

1. History or presence of other relevant concomitant liver diseases, including
(list not exhaustive):
• Positive hepatitis B or C serology: hepatitis B surface antigen (HBsAg+),
antibodies against hepatitis B core antigen (anti-HBc+), antibodies against
hepatitis C virus (anti-HCV+) at screening. Note: Patients with anti-HBc+ only
and negative hepatitis B virus- deoxyribonucleic acid as well as patients with
anti-HCV+ only and negative HCV-ribonucleic acid may be included.
• Primary Sclerosing Cholangitis,
• Wilson*s Disease,
• Hemochromatosis
• Definite autoimmune hepatitis or overlap syndrome,
• Nonalcoholic steatohepatitis (NASH),
• Alcoholic steatohepatitis (ASH),
• Cholangiocarcinoma,
• Drug-induced liver disease,
• Suspected or proven liver cancer,
2. Treatment with any of the following drugs within the last 4 weeks prior to
screening: any glucocorticosteroids, azathioprine or other immunosuppressive
drugs (e.g., cyclophosphamide, cyclosporine, methotrexate, tacrolimus,
6-mercaptopurine, colchicine), pentoxyfylline, biologics (e.g., anti-tumor
necrosis factor-* therapy),
NOTE: Treatment with dermal, inhalative, or nasal topical glucocorticosteroids
for up to 10 days within the last 4 weeks prior to screening or as planned
concomitant treatment for up to 10 days/4 weeks is allowed.
3. Treatment with farnesoid X receptor-agonists within the last 8 weeks prior
to screening,
4. Starting treatment with fibrates within the last 8 weeks prior to screening,
5. Liver cirrhosis. NOTE: Patients with compensated cirrhosis and a Child-Pugh
Score <8 are allowed to participate,
6. History or presence of hepatic decompensation (e.g., variceal bleeding,
international normalised ratio [INR] > 1.3), hepatic encephalopathy or poorly
controlled ascites (serum albumin less than 3.2 g/dl),
7. Total bilirubin > 2x ULN at screening visit, unless due to Gilbert*s
syndrome,
8. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5x ULN
at screening visit,
9. Any known relevant infectious disease (e.g., active tuberculosis, acquired
immunodeficiency syndrome [AIDS]-defining diseases),
10. Abnormal renal function (glomerular filtration rate estimated from cystatin
C
< 30 ml/min) at screening visit,
11. Thyroid-stimulating hormone (TSH) > ULN at screening (elevated levels [4.2-
10 µU/mL] are acceptable if fT4 is measured and within the normal range),
12. Current history of significant alcohol consumption (> 30 g/d in men, > 20
g/d in women on average) for a period of more than 3 consecutive months within
1 year prior to screening,
13. Inability to reliably quantify alcohol consumption as judged by the
investigator,
14. Any illness or medical conditions that are unstable or could jeopardize the
safety of the patient or his/her compliance in the trial or might interfere
with the interpretability of the trial results,
15. Previous or concurrent cancer except cervical carcinoma in situ, treated
basal cell carcinoma, or any cancer curatively treated < 3 years before
screening,
16. Known intolerance/hypersensitivity to the Investigational Medicinal Product
(IMP) or its excipients, or to drugs of similar chemical structure or
pharmacological profile,
17. Well-founded doubt about the patient*s cooperation, e.g., because of
addiction to alcohol or drugs,
18. Existing or intended pregnancy or breast-feeding,
19. Participation in another clinical trial and having received investigational
medicinal product (IMP) within the last 30 days or <= 5 terminal elimination
half-lives of previous IMP, whichever is longer, prior to screening visit,
simultaneous participation in another clinical trial, or previous participation
in this trial and having received IMP,
20. Dependency (as an employee or relative) on the sponsor or investigator,
21. Commitment to an institution by virtue of an order issued either by the
judicial or the administrative authorities,
22. Legal incapacity or limited legal capacity.