Ursodiol-Methotrexate for Primary Biliary Cirrhosis

Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

Overall Status

Completed

CT.gov ID

NCT00006168

Collaborator

(none)

Locations

122

Duration (Months)

Study Details

Study Description

Brief Summary

The major thrust is to determine whether treatment of patients with Primary Biliary Cirrhosis (PBC) with Ursodiol (Ursodeoxycholic Acid-UDCA) plus methotrexate (MTX) is more effective than treatment with UDCA alone.

Condition or Disease	Intervention/Treatment	Phase
Liver Cirrhosis, Biliary	Drug: Methotrexate	Phase 3

Detailed Description

PBC is a chronic cholestatic liver disease, predominantly of women, in which interlobular and septal bile ducts undergo inflammation and destruction. Once initiated, the disease persists and progresses at varying rates. Neither the initiating nor perpetuating mechanisms are well understood. Current concepts of pathogenesis include (1) destruction of bile ducts is maintained and perhaps initiated by autoimmune mechanisms; (2) hydrophobic bile acids which accumulate in serum and liver cause functional and cytotoxic liver injury; (3) cytokines and lymphokines released at sites of inflammation may contribute to cell damage and fibrosis. A considerable body of evidence indicates that UDCA when fed orally leads to improvement in liver tests, in pruritus and in liver histology. There exist differences in opinion as to whether development of complications of liver disease, liver transplantation or transplant-free survival is affected. UDCA, a relatively non-toxic bile acid, when administered orally, alters the composition of the bile acid pool in factor of its enrichment with UDCA and appears to protect against the cytotoxic effects of endogenous bile acids that accumulate as a result of bile acid destruction. MTX is being shown to improve liver tests, symptoms and liver histology in a small number of precirrhotic patients with PBC. The mechanism of action is unknown but felt to be related to anti-inflammatory immunosuppressive effects of MTX. The current trial explores whether MTX improves the therapeutic effects of UDCA in PBC. Patients with PBC whose serum bilirubin is less than 3 mg%, who have been on UDCA for at least 6 months, and who satisfy a series of inclusion and exclusion criteria are stratified into 2 groups on the basis of liver histologic stage (Ludwig classification), i.e., early (Stages I and II) versus late (Stages III or IV). They are then randomized to receive either methotrexate or its placebo as a second drug while continuing to receive UDCA. The relative value of the two treatment arms is assessed by comparing their effects on symptoms, results of laboratory tests, development of complications of liver disease, histologic changes in liver, liver transplantation, and on transplant-free survival. The safety of each therapeutic regimen is also being determined.

Study Design

Study Type:

Interventional

Allocation:

Randomized

Masking:

Double

Primary Purpose:

Treatment

Study Start Date :

Jan 1, 1994

Study Completion Date :

Mar 1, 2004

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 69 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Chronic cholestatic liver disease of at least 6 months' duration.
Serum alkaline phosphatase levels at least 1.5 times the upper limit of normal prior to treatment with UDCA.
Serum bilirubin less than 3.0 mg% prior to treatment with UDCA.
Serum albumin of 3.0 gram% or greater prior to treatment with UDCA.
Positive antimitochondrial antibody test
Liver biopsy within the previous 6 months after at least 6 months on UDCA (available for review, and at least 2 cm long if cirrhosis not detected) compatible with the diagnosis of PBC.
Ultrasound, computed tomography (CT) or cholangiography of the biliary tree which excludes biliary obstruction.

Exclusion Criteria:

Treatment with immunosuppressive agents including azathioprine, chlorambucil, colchicine, corticosteroids, or d-penicillamine in the preceding 3 months; or with cyclosporine, FK-506 or methotrexate in the preceding 6 months.
Treatment with rifampin in the preceding 3 months.
Serum bilirubin of 3.0 mg% or greater.
Serum albumin less than 3.0 gm%.
WBC 2,500 mm3; granulocytes 1,500 mm3; platelets 80,000mm3.
Ascites, hepatic encephalopathy, variceal bleed.
Findings by clinical, serologic and histologic evidence of liver disease of other etiology (such as chronic hepatitis B or C, autoimmune chronic active hepatitis, alcoholic liver disease, sclerosing cholangitis, drug-induced liver disease, symptomatic or obstructive gallstones).
Pregnancy, or if not pregnant and in the reproductive period, unwillingness to utilize an adequate form of birth control.
Age less than 20 or greater than 69 years.
Epilepsy requiring use of dilantin.
Malignant disease within the past 5 years (except skin cancer)
Anti-HIV positive. Major illnesses that could limit life span.
History of alcoholism during the previous 2 years.
Creatinine clearance less than 60 ml per minute.
Severe lung disease, defined as a diffusion capacity or vital capacity of less than 50 percent of predicted.
Patients who are both asymptomatic and have Stage I histology on liver biopsy (Ludwig classification).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Keck School of Medicine at U.S.C.	Los Angeles	California	United States	90033
2	U California Medical Center	San Francisco	California	United States	94143
3	Yale University School of Medicine	New Haven	Connecticut	United States	06520-8019
4	Emory University School of Medicine	Atlanta	Georgia	United States	30322
5	Saint Louis University	St. Louis	Missouri	United States	63104
6	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-3285
7	Cleveland Clinic	Cleveland	Ohio	United States	44195
8	Oregon Health Sciences University	Portland	Oregon	United States	97201
9	Albert Einstein Medical Center	Philadelphia	Pennsylvania	United States	19141
10	UT Southwestern Medical Center at Dallas	Dallas	Texas	United States	75235-9151
11	Medical College of Virginia	Richmond	Virginia	United States	23298-0711
12	University of Washington Medical Center	Seattle	Washington	United States	98195