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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Primary Biliary Cirrhosis

Intervention / Treatment
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* Drug: budesonide
* Drug: budesonide placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Age ≥ 18 years UDCA treatment for at least 6 months prior to inclusion Liver biopsy compatible with PBC Liver biopsy performed within the last 6 months prior to inclusion 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 Type 2 anti-mitochondrial antibodies > 1:40 by direct immunofluorescence 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: Histologically proven cirrhosis Positive Hepatitis B or C serology Positive HIV serology Primary Sclerosing Cholangitis Wilson's-Disease Celiac Disease (blood tests and/or oesophago-gastro-duodenoscopy with histological examination to be performed) α1-anti-Trypsin-deficiency Haemochromatosis 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 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 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 Sonographic or endoscopic signs of portal hypertension Ascites or history of ascites Hepatic encephalopathy or history of hepatic encephalopathy Total bilirubin > 3.0 mg/dl (> 50 µmol/L) Albumin < 36 g/L Prothrombin ratio < 70% Platelet count < 135.000/mm3 Osteoporosis proven by bone densitometry Diabetes mellitus, defined as B-Glucose > 125 mg/dl on an empty stomach (even when controlled) Hypertension, defined as persistent raised blood pressure > 140/90 mmHg Suspected non-compliance of the patient (suspected difficulties to comply with the study period of 36 months) Severe co-morbidity substantially reducing life expectancy Known intolerance/hypersensitivity/resistance to study drugs or drugs of similar chemical structure or pharmacological profile Existing or intended pregnancy or breast-feeding Participation in another clinical trial within the last 30 days, simultaneous participation in another clinical trial, or previous participation in this trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 |