Ursodeoxycholic Acid Plus Budesonide Versus Ursodeoxycholic Acid Alone in Primary Biliary Cirrhosis (PBC)

Inclusion Criteria:

1. Signed informed consent

2. Age ≥ 18 years

3. UDCA treatment for at least 6 months prior to inclusion

4. Liver biopsy compatible with PBC

5. Liver biopsy performed within the last 6 months prior to inclusion

6. PBC patients at risk of disease progression based on one or more of the followingcriteria:

• Serum alkaline phosphatase ≥ 3 times the upper limit of normal at any time sincediagnosis of PBC and ALT ≥ 2 times upper limit of normal or

• Total Bilirubin ≥ 1.0 mg/dl (≥ 17 µmol/L) or

• Moderate to severe periportal or periseptal lymphocytic interface hepatitis or

• Periportal and portal fibrosis with numerous septa (Ludwig stage III) withoutcirrhosis

7. Type 2 anti-mitochondrial antibodies > 1:40 by direct immunofluorescence

8. Women of child-bearing potential have to apply appropriate contraceptive methods,e.g., hormonal contraception, intrauterine device (IUD), double-barrier method ofcontraception (e.g., use of a condom and spermicide), partner has undergone vasectomyand subject is in monogamous relationship. The investigator is responsible fordetermining whether the subject has adequate birth control for study participation

Exclusion Criteria:

1. Histologically proven cirrhosis

2. Positive Hepatitis B or C serology

3. Positive HIV serology

4. Primary Sclerosing Cholangitis

5. Wilson's-Disease

6. Celiac Disease (blood tests and/or oesophago-gastro-duodenoscopy with histologicalexamination to be performed)

7. α1-anti-Trypsin-deficiency

8. Haemochromatosis

9. Autoimmune-Hepatitis (AIH; defined by an Alvarez score > 15 without treatment or ≥ 17with treatment); Note: PBC/AIH overlap disease, treated insufficiently with UDCAmonotherapy may be enrolled

10. Treatment with any of the following drugs within the last 3 months prior to inclusion:colchicine, corticosteroids, azathioprine or other immunosuppressive drugs (e.g.cyclosporine, methotrexate), chlorambucil, D-penicillamine, fibrates, orantihyperlipidemic drugs

11. Treatment with ketoconazole or other CYP3A inhibitors within the last 4 weeks beforebaseline; rifampicin (up to 600 mg/d) is allowed to treat pruritus until baseline

12. Sonographic or endoscopic signs of portal hypertension

13. Ascites or history of ascites

14. Hepatic encephalopathy or history of hepatic encephalopathy

15. Total bilirubin > 3.0 mg/dl (> 50 µmol/L)

16. Albumin < 36 g/L

17. Prothrombin ratio < 70%

18. Platelet count < 135.000/mm3

19. Osteoporosis proven by bone densitometry

20. Diabetes mellitus, defined as B-Glucose > 125 mg/dl on an empty stomach (even whencontrolled)

21. Hypertension, defined as persistent raised blood pressure > 140/90 mmHg

22. Suspected non-compliance of the patient (suspected difficulties to comply with thestudy period of 36 months)

23. Severe co-morbidity substantially reducing life expectancy

24. Known intolerance/hypersensitivity/resistance to study drugs or drugs of similarchemical structure or pharmacological profile

25. Existing or intended pregnancy or breast-feeding

26. Participation in another clinical trial within the last 30 days, simultaneousparticipation in another clinical trial, or previous participation in this trial