Study of Combivir for Patients With Primary Biliary Cirrhosis

NCT ID: NCT00490620

Last Updated: 2007-11-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 59 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-01-31
• Study Completion Date: 2007-04-30

Brief Summary

This is a proof of principal study to determine whether combination anti-viral therapy with Combivir impacts on hepatic biochemistry in patients with primary biliary cirrhosis

Detailed Description

A novel human retrovirus has been cloned from a cDNA library derived from biliary epithelia cells extracted from patients with Primary Biliary Cirrhosis. Although there is no formal proof that this virus is etiologically related to the disease, we have found evidence for viral infection in the majority of patients with PBC using standard serologic and hybridization assays. In order to address the hypotheses that PBC is etiologically related to a retrovirus infection and that anti-retroviral therapy may be beneficial for patients with PBC, we have conducted 2 pilot studies using lamivudine and Combivir (lamivudine 150mg and Zidovudine 300mg). On the whole, little clinical improvement was observed in patients on lamivudine therapy alone, whereas those on Combivir had significant reductions of hepatic biochemistry studies and histologic improvement. Moreover, 4 of 10 Combivir patients completely normalized their liver function tests and the anti-viral therapy was well tolerated. We now propose a larger randomized trial to assess the short term (6 months) safety and efficacy of Combivir for patients with PBC. Efficacy in this study will be defined using both liver biochemistries and virologic endpoints.

Conditions

Primary Biliary Cirrhosis

Keywords

primary biliary cirrhosis C06.552.630.400; retroviral infection C02.782.815

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

1

blinded placebo control

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

placebo BID for 6 months

2

Antiretroviral therapy

Group Type: ACTIVE_COMPARATOR

Combination antiviral therapy

Intervention Type: DRUG

Zidovudine 300mg and lamivudine 150mg BID for 6 months

Interventions

Combination antiviral therapy

Zidovudine 300mg and lamivudine 150mg BID for 6 months

Intervention Type: DRUG

Placebo

placebo BID for 6 months

Intervention Type: DRUG

Other Intervention Names

Combivir

Eligibility Criteria

Inclusion Criteria

• Patients 18 years old of either sex will be recruited for this study.
• Persistently elevated alkaline phosphatase or serum aminotransferases of at least 1.5 times normal after a minimum of 6 months UDCA therapy.
• Positive serum AMA (titer > 1:20).
• Liver biopsy histology compatible with PBC obtained at any time prior to study.
• Maintained on UDCA at a dose of 13-15 mg/kg for 6 or more months.
• Patients must read and sign informed consent form.

Exclusion Criteria

• Patients treated with immunosuppressive or anti-inflammatory agents such as colchicine, methotrexate, D-penicillamine, cyclosporine, tacrolimus, mycophenolate mofetil, corticosteroid therapy will be excluded but may enter the study after a 3 month period off immunosuppressive and anti-inflammatory therapy.
• Advanced liver disease: Childs Pugh class B or C cirrhosis, recurrent variceal hemorrhage, spontaneous encephalopathy, diuretic resistant ascites, need for liver transplantation within the year.
• Patients with a secondary hepatic diagnosis such as viral hepatitis, drug induced liver injury, extrahepatic biliary obstruction, primary sclerosing cholangitis, metabolic liver diseases or alcoholic liver disease.
• Regular use of more than 30 g of alcohol per day in the last year.
• Patients with a predicted survival of less than 3 years from malignant or other potentially life threatening disease.
• Creatinine clearance less than < 70 mL/min using the Cockcroft Gault equation:
• Clinically apparent pancreatitis.
• Serum amylase > 3 x upper limit of normal (patients with sicca syndrome and salivary gland disease may have elevated amylase levels)
• Pregnancy or breast-feeding a child.
• Sexually active patients of child bearing age and not using effective contraception.
• Allergic reaction to Combivir like drugs
• Clinical evidence of myositis
• Weight of < 50 Kg

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: collaborator

Axcan Pharma

INDUSTRY

Sponsor Role: collaborator

University of Alberta

OTHER

Sponsor Role: lead

Principal Investigators

Andrew L Mason, MBBS MRCPI

Role: PRINCIPAL_INVESTIGATOR

University of Alberta

Bruce Bacon, MD

Role: PRINCIPAL_INVESTIGATOR

St. Louis University

Keith Lindor, MD

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic Foundation

James Neuberger, MD FRCP

Role: PRINCIPAL_INVESTIGATOR

University of Birmingham

Catherine Vincent, MD FRCPC

Role: PRINCIPAL_INVESTIGATOR

Université de Montréal

Locations

Mayo Clinic

Rochester, Minnesota, United States

St Louis University

St Louis, Missouri, United States

University of Alberta

Edmonton, Alberta, Canada

University of Montreal

Montreal, Quebec, Canada

University of Birmingham

Birmingham, England, United Kingdom

Countries

United States; Canada; United Kingdom

References

Mason AL, Farr GH, Xu L, Hubscher SG, Neuberger JM. Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis. Am J Gastroenterol. 2004 Dec;99(12):2348-55. doi: 10.1111/j.1572-0241.2004.40741.x.

Reference Type: BACKGROUND

PMID: 15571581 (View on PubMed)

Mason A, Nair S. Primary biliary cirrhosis: new thoughts on pathophysiology and treatment. Curr Gastroenterol Rep. 2002 Feb;4(1):45-51. doi: 10.1007/s11894-002-0037-8.

Reference Type: BACKGROUND

PMID: 11825541 (View on PubMed)

Xu L, Shen Z, Guo L, Fodera B, Keogh A, Joplin R, O'Donnell B, Aitken J, Carman W, Neuberger J, Mason A. Does a betaretrovirus infection trigger primary biliary cirrhosis? Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8454-9. doi: 10.1073/pnas.1433063100. Epub 2003 Jun 27.

Reference Type: BACKGROUND

PMID: 12832623 (View on PubMed)

Other Identifiers

Col40296

Identifier Type: -

Identifier Source: org_study_id