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

Double-blind, Randomised, Placebo-controlled, Multi-centre Phase III Clinical Study Comparing the Combination of Ursodeoxycholic Acid Capsules Plus Budesonide Capsules to Ursodeoxycholic Acid Capsules Plus Placebo in the Treatment of Primary Biliary Cirrhosis

The study is aimed to compare the efficacy and tolerability of a combination therapy with ursodeoxycholic acid (12-16 mg/kg body weight (BW)/d) plus budesonide (9 mg/d) vs. ursodeoxycholic acid (12-16 mg/kg BW/d) plus placebo in the treatment of PBC. Depending on ALT values 6 mg/d budesonide are allowed. The study population will be patients with PBC at risk for disease progression. It is assumed that the combination therapy will result in a decrease of treatment failures after 3 years of treatment.

Study Overview

• Status: Terminated
• Conditions: Primary Biliary Cirrhosis
• Intervention / Treatment: Drug: budesonide; Drug: budesonide placebo

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75571
    • Hôpital Saint-Antoine
• Germany
  • NRW
    • Bonn, NRW, Germany, 53105
      • Universitätsklinikum Bonn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 following criteria:

   • Serum alkaline phosphatase ≥ 3 times the upper limit of normal at any time since diagnosis 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) without cirrhosis
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 of contraception (e.g., use of a condom and spermicide), partner has undergone vasectomy and subject is in monogamous relationship. The investigator is responsible for determining 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 histological examination to be performed)
7. α1-anti-Trypsin-deficiency
8. Haemochromatosis
9. Autoimmune-Hepatitis (AIH; defined by an Alvarez score > 15 without treatment or ≥ 17 with treatment); Note: PBC/AIH overlap disease, treated insufficiently with UDCA monotherapy 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, or antihyperlipidemic drugs
11. Treatment with ketoconazole or other CYP3A inhibitors within the last 4 weeks before baseline; 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 when controlled)
21. Hypertension, defined as persistent raised blood pressure > 140/90 mmHg
22. Suspected non-compliance of the patient (suspected difficulties to comply with the study period of 36 months)
23. Severe co-morbidity substantially reducing life expectancy
24. Known intolerance/hypersensitivity/resistance to study drugs or drugs of similar chemical structure or pharmacological profile
25. Existing or intended pregnancy or breast-feeding
26. Participation in another clinical trial within the last 30 days, simultaneous participation in another clinical trial, or previous participation in this trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; One budesonide 3 mg capsule TD or one budesonide 3 mg capsule BD and 12-16 mg ursodeoxycholic acid/kg BW/d	Drug: budesonide; One budesonide 3 mg capsule TD or one budesonide 3 mg capsule BD and 12-16 mg ursodeoxycholic acid/kg BW/d for 3 years
Active Comparator: B; One placebo capsule TD or One placebo capsule BD and 12-16 mg ursodeoxycholic acid/kg BW/d	Drug: budesonide placebo; One placebo capsule TD or One placebo capsule BD and 12-16 mg ursodeoxycholic acid/kg BW/d for 3 years

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Rate of patients without treatment failure after 3 years of treatment	3 years, LOCF

Secondary Outcome Measures

Outcome Measure	Time Frame
course of pruritus	3 years, LOCF
course of fatigue	3 years, LOCF
course of Mayo Risk score	3 years, LOCF
bone mineral density	3 years, LOCF

Collaborators and Investigators

• Sponsor: Dr. Falk Pharma GmbH
• Investigators: Principal Investigator: Raoul Poupon, Professor, Hôpital Saint-Antoine, 75571 Paris, France

Publications and helpful links

General Publications

• Mousa HS, Lleo A, Invernizzi P, Bowlus CL, Gershwin ME. Advances in pharmacotherapy for primary biliary cirrhosis. Expert Opin Pharmacother. 2015 Apr;16(5):633-43. doi: 10.1517/14656566.2015.998650. Epub 2014 Dec 29.
• Hirschfield GM, Beuers U, Kupcinskas L, Ott P, Bergquist A, Farkkila M, Manns MP, Pares A, Spengler U, Stiess M, Greinwald R, Prols M, Wendum D, Drebber U, Poupon R. A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA. J Hepatol. 2021 Feb;74(2):321-329. doi: 10.1016/j.jhep.2020.09.011. Epub 2020 Sep 17.

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): October 1, 2019
• Study Completion (Actual): October 1, 2019

Study Registration Dates

• First Submitted: September 3, 2008
• First Submitted That Met QC Criteria: September 3, 2008
• First Posted (Estimate): September 4, 2008

Study Record Updates

• Last Update Posted (Actual): January 28, 2020
• Last Update Submitted That Met QC Criteria: January 27, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Cholestasis; Fibrosis; Liver Cirrhosis; Liver Cirrhosis, Biliary; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Budesonide
• Other Study ID Numbers: BUC-56/PBC; 2007-004040-70