Liver Cirrhosis, BiliaryPhase 3NCT00006168
Ursodiol-Methotrexate for Primary Biliary Cirrhosis
A Phase 3 study testing Methotrexate in people with Liver Cirrhosis, Biliary, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 12 sites in United States.
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. Read more about this study
- Who is it for?
- Ages 20 to 69 years
- Conditions the study is for
- Liver Cirrhosis, Biliary
- What is being tested?
- Methotrexate
- How many people
- Not given
- Where
- 12 sitesUnited States
- Study dates
- Jan 1994to Mar 2004
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 69 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 16Show fewer
- 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).
Trial locations and contacts
12 sites in 1 country.
12 sites in 1 country
United States12 sites
Emory University School of Medicine
Atlanta, Georgia, 30322
Cleveland Clinic
Cleveland, Ohio, 44195
UT Southwestern Medical Center at Dallas
Dallas, Texas, 75235-9151
Keck School of Medicine at U.S.C.
Los Angeles, California, 90033
Yale University School of Medicine
New Haven, Connecticut, 06520-8019
University of Nebraska Medical Center
Omaha, Nebraska, 68198-3285
Albert Einstein Medical Center
Philadelphia, Pennsylvania, 19141
Oregon Health Sciences University
Portland, Oregon, 97201
Medical College of Virginia
Richmond, Virginia, 23298-0711
U California Medical Center
San Francisco, California, 94143
University of Washington Medical Center
Seattle, Washington, 98195
Saint Louis University
St Louis, Missouri, 63104
About this study
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.
Read the 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
- Being tested
- Methotrexate
- Keywords
- primary biliary cirrhosis, Ursodeoxycholic acid, UDCA, MTX, Hepatology, methotrexate, liver
- Medical subject headings
- Liver Cirrhosis, Biliary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethotrexateDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Aug 2000 (estimated)
- Study startJan 1994
- Study completionMar 2004
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for Liver Cirrhosis, BiliaryStudies of the same condition, open and under way.
- More trials run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Masking
- Double blind
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00006168
- Sponsor's protocol ID
- PUMPS (completed)
- Other IDs
- 5R01DK046602
- Status last verified
- Jan 2010
- First submitted
- 8 Aug 2000
- Last updated
- 13 Jan 2010
- Results posted
- No
Publications
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.
PubMed 1674105Heathcote 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.
PubMed 8175136Lindor 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.
PubMed 8174890Combes 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.
PubMed 7657280Kaplan 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.
PubMed 3408057Kaplan MM. Methotrexate treatment of chronic cholestatic liver diseases: friend or foe? Q J Med. 1989 Aug;72(268):757-61. No abstract available.
PubMed 2532375Kaplan 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.
PubMed 1936805Bergasa 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.
PubMed 8607496Buscher 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.
PubMed 8101853
Study at a glance
From the registry record, last updated by the sponsor on 13 Jan 2010. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Ursodiol-Methotrexate for Primary Biliary Cirrhosis
- ClinicalTrials.gov ID
- NCT00006168
- Acronym / sponsor ID
- PUMPS (completed)
- Conditions
- Liver Cirrhosis, Biliary
- Keywords
- primary biliary cirrhosis, Ursodeoxycholic acid, UDCA, MTX, Hepatology, methotrexate, liver
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Lead sponsor
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)US National Institutes of Health
- Study start
- Jan 1994
- Study completion
- Mar 2004
- First posted
- 9 Aug 2000 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Masking
- Double blind
Who may qualify
- Ages
- 20 to 69 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (16 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Methotrexate | Drug | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jan 2010.
- Background: PubMed 1674105Poupon 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.
- Background: PubMed 8175136Heathcote 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.
- Background: PubMed 8174890Lindor 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.
- Background: PubMed 7657280Combes 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.
- Background: PubMed 3408057Kaplan 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.
- Background: PubMed 2532375Kaplan MM. Methotrexate treatment of chronic cholestatic liver diseases: friend or foe? Q J Med. 1989 Aug;72(268):757-61. No abstract available.
- Background: PubMed 1936805Kaplan 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.
- Background: PubMed 8607496Bergasa 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.
- Background: PubMed 8101853Buscher 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.
Related trials for Liver Cirrhosis, Biliary
Not yet recruitingObservational study
A Study of Fatigue, Itching and Daily Activities in People With Primary Biliary Cholangitis Starting Elafibranor
Primary Biliary Cholangitis (PBC)
RecruitingPhase 3
Fenofibrate for Patients With Primary Biliary Cirrhosis Who Had An Inadequate Response to Ursodeoxycholic Acid
Primary Biliary Cirrhosis
RecruitingPhase 2/3
Fenofibrate in Patients With Primary Biliary Cholangitis (PBC)
Primary Biliary Cholangitis
Enrolling by invitationPhase 2/3
A Multicenter, Randomized, Controlled Trial of Prednisone Combined With Ursodeoxycholic Acid in the Treatment of Primary Biliary Cholangitis With Moderate to Severe Interface Hepatitis Characteristics
Primary Biliary Cholangitis (PBC)
Active, not recruitingPhase 2/3
Fenofibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cholangitis
Primary Biliary Cholangitis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
12 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Methotrexate in people with Liver Cirrhosis, Biliary, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 12 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Jan 2010. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00006168, which also lists 9 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jan 2010.