Highly Active Antiretroviral Therapy for Patients With Primary Biliary Cirrhosis - Full Text View

Purpose

Patients with primary biliary cirrhosis (PBC) develop progressive liver disease and often require liver transplantation. The cause of disease is unknown. It is thought to occur as a result of an infection in subjects that are more susceptible to disease than others. The investigators found evidence of retrovirus infection in patients with primary biliary cirrhosis. The investigators found that most patients with PBC have evidence of viral infection. Since then the investigators have conducted clinical studies using anti-viral therapy. The investigators found that PBC patients treated with combination anti-retrovirus therapy experienced significant reversal of the disease process. However, the changes were not substantial and the investigators are now looking for better antiviral regimens. Now the investigators have found a mouse model with a similar virus infection that develops a similar biliary disease. Importantly, the investigators found that antiviral therapy blocks the development of the disease in this mouse. The investigators have used this model to find safer and more effective antiviral treatments for patients with PBC. The investigators have now found out that a combination of highly active antiretroviral therapy with Truvada and Kaletra stops disease in the mouse and plan to use this combination to see if it works in patients with PBC.

Condition	Intervention
Primary Biliary Cirrhosis	Drug: Truvada and Kaletra


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Crossover Assignment Masking: Double Blind (Participant, Care Provider, Investigator) Primary Purpose: Treatment
Official Title:	Randomized Controlled Pilot Study of Highly Active Anti-Retroviral Therapy for Patients With Primary Biliary Cirrhosis

Resource links provided by NLM:

Genetics Home Reference related topics: North American Indian childhood cirrhosis

MedlinePlus related topics: Cirrhosis

Drug Information available for: Lopinavir Truvada

Genetic and Rare Diseases Information Center resources: Primary Biliary Cholangitis

U.S. FDA Resources

Further study details as provided by Andrew L. Mason, University of Alberta:

Primary Outcome Measures:

Reduction of ALP to 1.67x ULN [ Time Frame: The outcomes will be measured are from 12 to 24 weeks at the end of the study ]
normalization of bilirubin. [ Time Frame: The outcomes will be measured are from 12 to 24 weeks at the end of the study ]

Secondary Outcome Measures:

Reduction of human betaretrovirus. [ Time Frame: The outcomes will be measured are from 12 to 24 weeks in RCT; and 6 monthly to 2 years for the extension study ]
Symptoms with changes in PBC-40 [ Time Frame: The outcomes will be measured are from 12 to 24 weeks in RCT; and 6 monthly to 2 years for the extension study ]
Changes in AMA and immunoglobulin levels [ Time Frame: The outcomes will be measured are from 12 to 24 weeks in RCT; and 6 monthly to 2 years for the extension study ]
Biochemistry: GGT, AST and ALT [ Time Frame: The outcomes will be measured are from 12 to 24 weeks in RCT; and 6 monthly to 2 years for the extension study ]
Histology in extension study [ Time Frame: The outcomes will be measured are from 12 to 24 weeks in RCT; and 6 monthly to 2 years for the extension study ]


Enrollment:	13
Study Start Date:	June 2012
Study Completion Date:	August 2015
Primary Completion Date:	July 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: Placebo 6 months therapy with blinded placebo followed by 6 months open label therapy with Kaletra and Truvada. Then there is an option for an 18 month follow-up study.	Drug: Truvada and Kaletra one tablet of Truvada a day at standard dose of Tenofovir 300mg and Emtricitabine 200mg and four tablets of Kaletra once a day for a total dose of lopinavir 800mg and ritonavir 200mg for 6 months or less if adverse events occur Other Names: Truvada Tenofovir Emtricitabine Kaletra lopinavir ritonavir
Active Comparator: Truvada and Kaletra Patients will be take Truvada and Kaletra for 6 months with the option of open label for additional 18 months.	Drug: Truvada and Kaletra one tablet of Truvada a day at standard dose of Tenofovir 300mg and Emtricitabine 200mg and four tablets of Kaletra once a day for a total dose of lopinavir 800mg and ritonavir 200mg for 6 months or less if adverse events occur Other Names: Truvada Tenofovir Emtricitabine Kaletra lopinavir ritonavir

Detailed Description:

6 months therapy with blinded Kaletra and Truvada vs. 6 months therapy with blinded placebo followed by 6 months open label therapy with Kaletra and Truvada

18 month extension study with open label Kaletra and Truvada in patients completing 6 months of therapy with Kaletra and Truvada with biochemical endpoint

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients 18 years old of either sex will be recruited for this study.
Elevated ALP after 6 months UDCA therapy ≥ 2 x upper limit of normal or abnormal bilirubin.
Positive serum AMA or Liver biopsy histology compatible with PBC.
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:

Subjects with baseline AST or ALT > 5 x ULN.
Patients who have altered dose of any medications used to treat PBC (such as UDCA) or the use of colchicine, corticosteroids, azathioprine, chlorambucil, methotrexate, or D-penicillamine within the last 6 months.
Advanced liver disease or esophageal varices, INR > 1.2 (upper limit of normal), Albumin < 35 g/L (lower limit of normal), platelets < 120,000/mm3, Childs Pugh class B or C cirrhosis, presence of varices or previous variceal hemorrhage, spontaneous encephalopathy, ascites or need for liver transplantation.
Patients with a secondary diagnosis such as HIV, 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. Clinically apparent pancreatitis or with a predicted survival of less than 3 years from malignant or other potentially life threatening disease.
An ultrasound showing a hepatic mass consistent with hepatocellular carcinoma within the last year in patients with cirrhosis.
Previous allergic reaction to study medications.
Creatinine clearance less than < 70 mL/min using the Cockcroft Gault equation:

Creatinine clearance (mL/min) = (140 - age) x body wt (Kg) x 0.85 (if female)/serum creatinine in mol/l
Pregnancy or breast-feeding a child. Young sexually active patients not using contraception
Young sexually active patients not using contraception.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01614405

Locations


Canada, Alberta
University of Alberta
Edmonton, Alberta, Canada, T6G 2B2

Sponsors and Collaborators

University of Alberta

Abbott

Gilead Sciences

Canadian Institutes of Health Research (CIHR)

Investigators


Principal Investigator:	Andrew Mason	University of Alberta

More Information

Publications:

Schembri G, Schober P. Killing two birds with one stone. Lancet. 2011 Jan 1;377(9759):96. doi: 10.1016/S0140-6736(10)61343-8.


Responsible Party:	Andrew L. Mason, Principal Investigator, University of Alberta
ClinicalTrials.gov Identifier:	NCT01614405 History of Changes
Other Study ID Numbers:	HAART Study
Study First Received:	April 25, 2011
Last Updated:	November 30, 2015

Keywords provided by Andrew L. Mason, University of Alberta:


PBC

Additional relevant MeSH terms:


Fibrosis Liver Cirrhosis Liver Cirrhosis, Biliary Pathologic Processes Liver Diseases Digestive System Diseases Cholestasis, Intrahepatic Cholestasis Bile Duct Diseases Biliary Tract Diseases Ritonavir Lopinavir Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination Tenofovir	Emtricitabine HIV Protease Inhibitors Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Cytochrome P-450 CYP3A Inhibitors Cytochrome P-450 Enzyme Inhibitors Reverse Transcriptase Inhibitors Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on June 28, 2017

Highly Active Antiretroviral Therapy for Patients With Primary Biliary Cirrhosis (HAART)