Clinical trial NCT00006168: Ursodiol-Methotrexate for Primary Biliary Cirrhosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Liver Cirrhosis, Biliary
Keywords: primary biliary cirrhosis
Ursodeoxycholic acid
UDCA
MTX
Hepatology
methotrexate
liver
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
First posted: 2000-08-09
Sex: ALL
Minimum age (years): 20
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Keck School of Medicine at U.S.C.
state: California
city: San Francisco
country: United States
facility: U California Medical Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: St. Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: Albert Einstein Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center at Dallas
state: Texas
city: Richmond
country: United States
facility: Medical College of Virginia
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
Study officials:
References:
citation: 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.
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.
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. doi: 10.1016/0016-5085(94)90021-3.
citation: Combes B, Carithers RL Jr, Maddrey WC, Lin D, McDonald MF, Wheeler DE, Eigenbrodt EH, Munoz 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.
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. doi: 10.7326/0003-4819-109-5-429. No abstract available.
citation: Kaplan MM. Methotrexate treatment of chronic cholestatic liver diseases: friend or foe? Q J Med. 1989 Aug;72(268):757-61. No abstract available.
citation: 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.
citation: 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.
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. doi: 10.1016/s0168-8278(05)80004-2.