Study of Combivir for Patients With Primary Biliary Cirrhosis

Primary Biliary Cirrhosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00490620
• Other study ID #: Col40296
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: June 21, 2007
• Last updated: October 31, 2007
• Start date: January 2004
• Est. completion date: April 2007

Study information

• Verified date: October 2007
• Source: University of Alberta
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health CanadaUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 59
• Est. completion date: April 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Liver Cirrhosis
• Liver Cirrhosis, Biliary
• Primary Biliary Cirrhosis

Intervention

Drug:
• Combination antiviral therapy
Zidovudine 300mg and lamivudine 150mg BID for 6 months
• Placebo
placebo BID for 6 months

Locations

Country	Name	City	State
Canada	University of Alberta	Edmonton	Alberta
Canada	University of Montreal	Montreal	Quebec
United Kingdom	University of Birmingham	Birmingham	England
United States	Mayo Clinic	Rochester	Minnesota
United States	St Louis University	St Louis	Missouri

Sponsors (3)

Lead Sponsor	Collaborator
University of Alberta	Axcan Pharma, GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Canada,  United Kingdom, 

References & Publications (3)

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

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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