Ursodiol-Methotrexate for Primary Biliary Cirrhosis

NCT ID: NCT00006168

Last Updated: 2010-01-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Study Classification: INTERVENTIONAL
• Study Start Date: 1994-01-31
• Study Completion Date: 2004-03-31

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.

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.

Conditions

Liver Cirrhosis, Biliary

Study Design

• Allocation Method: RANDOMIZED
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Interventions

Methotrexate

Intervention Type: DRUG

Eligibility Criteria

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).

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 69 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

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

NIH

Sponsor Role: lead

Locations

Keck School of Medicine at U.S.C.

Los Angeles, California, United States

U California Medical Center

San Francisco, California, United States

Yale University School of Medicine

New Haven, Connecticut, United States

Emory University School of Medicine

Atlanta, Georgia, United States

Saint Louis University

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Cleveland Clinic

Cleveland, Ohio, United States

Oregon Health Sciences University

Portland, Oregon, United States

Albert Einstein Medical Center

Philadelphia, Pennsylvania, United States

UT Southwestern Medical Center at Dallas

Dallas, Texas, United States

Medical College of Virginia

Richmond, Virginia, United States

University of Washington Medical Center

Seattle, Washington, United States

Countries

United States

References

Poupon RE, Balkau B, Eschwege 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. doi: 10.1056/NEJM199105303242204.

Reference Type: BACKGROUND

PMID: 1674105 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 8175136 (View on PubMed)

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. doi: 10.1016/0016-5085(94)90021-3.

Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Kaplan MM. Methotrexate treatment of chronic cholestatic liver diseases: friend or foe? Q J Med. 1989 Aug;72(268):757-61. No abstract available.

Reference Type: BACKGROUND

PMID: 2532375 (View on PubMed)

Kaplan MM, Knox TA. Treatment of primary biliary cirrhosis with low-dose weekly methotrexate. Gastroenterology. 1991 Nov;101(5):1332-8. doi: 10.1016/0016-5085(91)90085-y.

Reference Type: BACKGROUND

PMID: 1936805 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 8607496 (View on PubMed)

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. doi: 10.1016/s0168-8278(05)80004-2.

Reference Type: BACKGROUND

PMID: 8101853 (View on PubMed)

Other Identifiers

5R01DK046602

Identifier Type: NIH

Identifier Source: secondary_id

View Link

PUMPS (completed)

Identifier Type: -

Identifier Source: org_study_id