Study of Combivir for Patients With Primary Biliary Cirrhosis - Full Text View

Sponsor:	University of Alberta
Collaborators:	GlaxoSmithKline Axcan Pharma
Information provided by:	University of Alberta
ClinicalTrials.gov Identifier:	NCT00490620

Purpose

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

Condition	Intervention	Phase
Primary Biliary Cirrhosis	Drug: Combination antiviral therapy Drug: Placebo	Phase II Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Randomized Controlled Pilot Study of Combivir for Patients With Primary Biliary Cirrhosis

Resource links provided by NLM:

Genetics Home Reference related topics: North American Indian childhood cirrhosis progressive familial intrahepatic cholestasis

MedlinePlus related topics: Cirrhosis

Drug Information available for: Combivir

U.S. FDA Resources

Further study details as provided by University of Alberta:

Primary Outcome Measures:

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. [ Time Frame: During the 6 months of therapy ]

Secondary Outcome Measures:

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. [ Time Frame: During the 6 months of therapy ]

Enrollment:	59
Study Start Date:	January 2004
Study Completion Date:	April 2007

Arms	Assigned Interventions
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 Name: Combivir

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.

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00490620

Locations

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

Sponsors and Collaborators

University of Alberta

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	University of Montreal

More Information

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.

Mason A, Nair S. Primary biliary cirrhosis: new thoughts on pathophysiology and treatment. Curr Gastroenterol Rep. 2002 Feb;4(1):45-51. Review.

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. Epub 2003 Jun 27.

ClinicalTrials.gov Identifier:	NCT00490620 History of Changes
Other Study ID Numbers:	Col40296
Study First Received:	June 21, 2007
Last Updated:	October 31, 2007
Health Authority:	Canada: Health Canada; United States: Food and Drug Administration

Keywords provided by University of Alberta:

primary biliary cirrhosis C06.552.630.400
retroviral infection C02.782.815

Additional relevant MeSH terms:

Liver Cirrhosis, Biliary
Liver Cirrhosis
Fibrosis
Cholestasis, Intrahepatic
Cholestasis
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Liver Diseases
Pathologic Processes
Antiviral Agents

Lamivudine, zidovudine drug combination
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents

ClinicalTrials.gov processed this record on February 09, 2012