Study of Combivir for Patients With Primary Biliary Cirrhosis

Randomized Controlled Pilot Study of Combivir for Patients With Primary Biliary Cirrhosis

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

Study Overview

• Status: Completed
• Conditions: Primary Biliary Cirrhosis
• Intervention / Treatment: Drug: Placebo; Drug: Combination antiviral therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T5N 1Y9
      • University of Alberta
  • Quebec
    • Montreal, Quebec, Canada, H3C 3J7
      • University of Montreal
• United Kingdom
  • England
    • Birmingham, England, United Kingdom, B15 2TH
      • University of Birmingham
• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • St Louis, Missouri, United States, 63103
      • St Louis University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 1; blinded placebo control	Drug: Placebo; placebo BID for 6 months
Active Comparator: 2; Antiretroviral therapy	Drug: Combination antiviral therapy; Zidovudine 300mg and lamivudine 150mg BID for 6 months; Other Names: Combivir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The percentage of patients with either (i) normalized alkaline phosphatase, (ii) normalized AST and ALT or (iii) normal alkaline phosphatase, AST and ALT will be recorded.	During the 6 months of therapy

Secondary Outcome Measures

Outcome Measure	Time Frame
50% improvement towards baseline for alkaline phosphatase, AST and ALT, changes in symptoms using an objective graded clinical parameter scale, serum AMA titers, quantitative immunoglobulins and virologic parameters.	During the 6 months of therapy

Collaborators and Investigators

• Sponsor: University of Alberta
• Collaborators: GlaxoSmithKline; Axcan Pharma
• Investigators: Principal Investigator: Andrew L Mason, MBBS MRCPI, University of Alberta; Principal Investigator: Bruce Bacon, MD, St. Louis University; Principal Investigator: Keith Lindor, MD, Mayo Clinic Foundation; Principal Investigator: James Neuberger, MD FRCP, University of Birmingham; Principal Investigator: Catherine Vincent, MD FRCPC, Université de Montréal

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2004
• Study Completion (Actual): April 1, 2007

Study Registration Dates

• First Submitted: June 21, 2007
• First Submitted That Met QC Criteria: June 21, 2007
• First Posted (Estimate): June 25, 2007

Study Record Updates

• Last Update Posted (Estimate): November 1, 2007
• Last Update Submitted That Met QC Criteria: October 31, 2007
• Last Verified: October 1, 2007

More Information

Terms related to this study

• Keywords: primary biliary cirrhosis C06.552.630.400; retroviral infection C02.782.815
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Cholestasis; Fibrosis; Liver Cirrhosis; Liver Cirrhosis, Biliary; Anti-Infective Agents; Antiviral Agents
• Other Study ID Numbers: Col40296