Ursodiol-Methotrexate for Primary Biliary Cirrhosis

Liver Cirrhosis, Biliary Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00006168
• Other study ID #: PUMPS (completed)
• Secondary ID: 5R01DK046602
• Status: Completed
• Phase: Phase 3
• First received: August 8, 2000
• Last updated: January 12, 2010
• Start date: January 1994
• Est. completion date: March 2004

Study information

• Verified date: January 2010
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 0
• Est. completion date: March 2004
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years to 69 Years

Eligibility

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).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Liver Cirrhosis
• Liver Cirrhosis, Biliary

Intervention

Drug:
• Methotrexate

Locations

Country	Name	City	State
United States	Emory University School of Medicine	Atlanta	Georgia
United States	Cleveland Clinic	Cleveland	Ohio
United States	UT Southwestern Medical Center at Dallas	Dallas	Texas
United States	Keck School of Medicine at U.S.C.	Los Angeles	California
United States	Yale University School of Medicine	New Haven	Connecticut
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Albert Einstein Medical Center	Philadelphia	Pennsylvania
United States	Oregon Health Sciences University	Portland	Oregon
United States	Medical College of Virginia	Richmond	Virginia
United States	U California Medical Center	San Francisco	California
United States	University of Washington Medical Center	Seattle	Washington
United States	Saint Louis University	St. Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (9)

Bergasa NV, Jones A, Kleiner DE, Rabin L, Park Y, Wells MC, Hoofnagle JH. Pilot study of low dose oral methotrexate treatment for primary biliary cirrhosis. Am J Gastroenterol. 1996 Feb;91(2):295-9. — View Citation

Buscher HP, Zietzschmann Y, Gerok W. Positive responses to methotrexate and ursodeoxycholic acid in patients with primary biliary cirrhosis responding insufficiently to ursodeoxycholic acid alone. J Hepatol. 1993 Apr;18(1):9-14. — View Citation

Combes B, Carithers RL Jr, Maddrey WC, Lin D, McDonald MF, Wheeler DE, Eigenbrodt EH, Muñoz SJ, Rubin R, Garcia-Tsao G, et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1995 Sep;22(3):759-66. — View Citation

Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM, Ghent CN, Michieletti P, Minuk GY, Pappas SC, Scully LJ, et al. The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1994 May;19(5):1149-56. — View Citation

Kaplan MM, Knox TA, Arora SA. Primary biliary cirrhosis treated with low-dose oral pulse methotrexate. Ann Intern Med. 1988 Sep 1;109(5):429-31. — View Citation

Kaplan MM, Knox TA. Treatment of primary biliary cirrhosis with low-dose weekly methotrexate. Gastroenterology. 1991 Nov;101(5):1332-8. — View Citation

Kaplan MM. Methotrexate treatment of chronic cholestatic liver diseases: friend or foe? Q J Med. 1989 Aug;72(268):757-61. — View Citation

Lindor KD, Dickson ER, Baldus WP, Jorgensen RA, Ludwig J, Murtaugh PA, Harrison JM, Wiesner RH, Anderson ML, Lange SM, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology. 1994 May;106(5):1284-90. — View Citation

Poupon RE, Balkau B, Eschwège E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med. 1991 May 30;324(22):1548-54. — View Citation