Primary sclerosing cholangitis (PSC) is a progressive chronic cholestatic liver disease of unknown etiology that is commonly associated with chronic colitis. PSC usually leads to advanced liver disease and liver failure, and as such, is an important indication for liver transplantation. Unfortunately, no effective medical therapy currently exists for PSC. Ursodeoxycholic acid (UDCA) used at a dose of 13-15 mg/kg/d in patients with PSC led to biochemical improvement but did not affect other clinically important endpoints in a previous study that we performed. Pilot data from another study we performed suggested that higher doses of UDCA (28-30 mg/kg/d) may have not only more effect on liver tests but may be expected to improve clinical outcome. These data were supported by data from another group showing in a small, randomized trial that high-dose ursodeoxycholic acid led to biochemical, histologic, and cholangiographic improvement compared to placebo at two years. We have successfully completed enrollment into this placebo-controlled trial of high-dose ursodeoxycholic acid (28-30 mg/kg/d) for PSC. In this submission, we propose to complete the large-scale multi-center placebo-controlled randomized trial with a minimum follow-up of five years for 150 patients with primary sclerosing cholangitis. Our group of investigators has a long track record of experience with clinical trials in cholestatic liver disease and seems ideally suited to complete this important study. Primary endpoints of the study will include histologic progression to cirrhosis, documentation of esophageal or gastric varices, development of cholangiocarcinoma, need for liver transplantation, and death. Secondary endpoints will include measurements of the effects of ursodeoxycholic acid (28-30 mg/kg/d) on liver biochemistries, histologic stage, cholangiographic features, Mayo risk score, and quality of life using validated questionnaires. This study will be among the largest ever conducted in PSC, and the follow-up will be the most extensive. This study will provide an invaluable resource for studying the natural history of this disease. As part of this study we will also continue to collect serum, cells for extraction of DNA, bile, and tissue from the liver and colon as a resource for future studies. The multicentered nature of this trial allowed recruitment of patients into this study from a diverse patient population, representative of the gender and racial distribution of this disease. Successful completion of this study is dependent on the continued excellent retention of the enrolled subjects in this trial which will be enhanced by the longstanding track record in clinical trials in cholestatic liver disease established bv this group of investigators.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056924-10
Application #
8117547
Study Section
Special Emphasis Panel (ZDK1-GRB-W (J4))
Program Officer
Sherker, Averell H
Project Start
1999-12-01
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2011
Total Cost
$641,283
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Eaton, John E; Gossard, Andrea A; Talwalkar, Jayant A (2014) Recall processes for biliary cytology in primary sclerosing cholangitis. Curr Opin Gastroenterol 30:287-94
Eaton, John E; Talwalkar, Jayant A (2013) Primary Sclerosing Cholangitis: Current and Future Management Strategies. Curr Hepat Rep 12:28-36
Singh, Siddharth; Talwalkar, Jayant A (2013) Primary sclerosing cholangitis: diagnosis, prognosis, and management. Clin Gastroenterol Hepatol 11:898-907
Eaton, John E; Talwalkar, Jayant A; Lazaridis, Konstantinos N et al. (2013) Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology 145:521-36
Li, Yu; Kowdley, Kris V (2012) Method for microRNA isolation from clinical serum samples. Anal Biochem 431:69-75
Li, Yu; Kowdley, Kris V (2012) MicroRNAs in common human diseases. Genomics Proteomics Bioinformatics 10:246-53
Razumilava, Nataliya; Gores, Gregory J; Lindor, Keith D (2011) Cancer surveillance in patients with primary sclerosing cholangitis. Hepatology 54:1842-52
Stanich, Peter P; Bjornsson, Einar; Gossard, Andrea A et al. (2011) Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis. Dig Liver Dis 43:309-13
Eaton, John E; Silveira, Marina G; Pardi, Darrell S et al. (2011) High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol 106:1638-45
Imam, M H; Sinakos, E; Gossard, A A et al. (2011) High-dose ursodeoxycholic acid increases risk of adverse outcomes in patients with early stage primary sclerosing cholangitis. Aliment Pharmacol Ther 34:1185-92

Showing the most recent 10 out of 14 publications