Pentoxifylline Therapy in Biliary Atresia - Full Text View

Purpose

The purpose of this study is to determine whether pentoxifylline reduces liver damage in infants with biliary atresia.

Condition	Intervention	Phase
Biliary Atresia	Drug: Pentoxifylline	Phase 2

Study Type:	Interventional
Study Design:	Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase II Trial of Pentoxifylline in Newly-Diagnosed Biliary Atresia

Resource links provided by NLM:

MedlinePlus related topics: Liver Transplantation

Drug Information available for: Pentoxifylline

U.S. FDA Resources

Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:

Change in serum conjugated bilirubin [ Time Frame: Baseline and after 90 days of therapy ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change in Weight [ Time Frame: Baseline and after 90 days of therapy ] [ Designated as safety issue: No ]
Change in serum markers [ Time Frame: Baseline and up to two years after therapy finishes ] [ Designated as safety issue: No ]
The investigators will track the change in serum liver markers and platelets over the course of two years in patients receiving 90 days of PTX therapy.
Change in liver imaging [ Time Frame: Baseline and up to two years after therapy finishes ] [ Designated as safety issue: No ]
The investigators will track liver ultrasound changes, including liver and spleen size.
Time to liver transplant [ Time Frame: Baseline and up to two years after therapy finishes ] [ Designated as safety issue: No ]

Estimated Enrollment:	60
Study Start Date:	January 2013
Estimated Study Completion Date:	January 2017
Estimated Primary Completion Date:	January 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Pentoxifylline All newly-diagnosed biliary atresia patients fulfilling the study's inclusion criteria will receive oral pentoxifylline, 20 mg/kg/day divided in three doses for a total of 90 days. The hospital pharmacy will create a 20 mg/ml oral pentoxifylline solution using 400 mg pentoxifylline tablets and established compounding recipes.	Drug: Pentoxifylline 20 mg/kg/day divided in 3 doses, given orally for 90 days Other Name: Trental

Detailed Description:

Biliary atresia (BA) is a devastating liver disease of infancy of unknown etiology, characterized by bile duct obstruction, live fibrosis, and cirrhosis. BA has no known medical treatments. The only proven treatment is a surgical portoenterostomy (the Kasai procedure, or KP) which can achieve bile drainage and improve outcomes in some cases. The KPs success is variable depending on several factors including age of the infant, experience of the surgeon, and extent of liver fibrosis at the time of KP.

In this study, the investigators conduct a phase II trial of a potential new medical therapy for BA: pentoxifylline (PTX). PTX is a methylxanthine derivative closely related to caffeine that has been used safely in infants with other diseases such as sepsis. In adults, PTX has been shown to have a number of properties beneficial to the liver, including preventing liver fibrosis, improving liver regeneration, and reducing cirrhosis-related complications.

The trial's objective is to determine whether PTX has sufficient biological activity against BA to warrant further study. PTX will be administered orally for 90 days as an adjunct to standard therapy (i.e. KP if appropriate). The primary outcome will measure the change in serum conjugated bilirubin levels after 90 days. Secondary outcomes include changes in body weight, serum markers, liver imaging, and time to liver transplant in infants with BA.

Eligibility

Ages Eligible for Study:	up to 180 Days
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

0-180 days old
Diagnosed with biliary atresia through liver biopsy and/or intra-operative cholangiogram
No previous Kasai portoenterostomy performed at another institution
Able to take medications orally
Legal guardian signs consent after understanding risks and investigational nature of study

Exclusion Criteria:

Infants greater than 180 days old
Infants receiving a Kasai portoenterostomy at another institution
Infants unable to take medications orally

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01774487

Contacts

Contact: Sanjiv Harpavat, MD PhD	832-824-2099 ext 2144	harpavat@bcm.edu
Contact: Ross Shepherd, MD	832-824-2099 ext 1223	Ross.Shepherd@bcm.edu

Locations

United States, Texas
Texas Children's Hospital and Baylor College of Medicine	Recruiting
Houston, Texas, United States, 77030
Contact: Sanjiv Harpavat, MD PhD 832-824-2099 ext 2144 harpavat@bcm.edu
Contact: Ross Shepherd, MD 832-824-2099 ext 1223 Ross.Shepherd@bcm.edu
Principal Investigator: Sanjiv Harpavat, MD PhD
Principal Investigator: Ross Shepherd, MD
Sub-Investigator: Mary Brandt, MD
Sub-Investigator: Shelly Kim, PharmD
Sub-Investigator: Charles Minard, PhD
Sub-Investigator: Paula Hertel, MD
Sub-Investigator: Milton Finegold, MD

Sponsors and Collaborators

Baylor College of Medicine

Texas Children's Hospital

Investigators

Principal Investigator:	Sanjiv Harpavat, MD PhD	Baylor College of Medicine
Principal Investigator:	Ross Shepherd, MD	Baylor College of Medicine

More Information

Publications:

Perlmutter DH, Shepherd RW. Extrahepatic biliary atresia: a disease or a phenotype? Hepatology. 2002 Jun;35(6):1297-304. Review.

Sokol RJ, Shepherd RW, Superina R, Bezerra JA, Robuck P, Hoofnagle JH. Screening and outcomes in biliary atresia: summary of a National Institutes of Health workshop. Hepatology. 2007 Aug;46(2):566-81. Review.

Garcia AV, Cowles RA, Kato T, Hardy MA. Morio Kasai: a remarkable impact beyond the Kasai procedure. J Pediatr Surg. 2012 May;47(5):1023-7. doi: 10.1016/j.jpedsurg.2012.01.065.

Shneider BL, Brown MB, Haber B, Whitington PF, Schwarz K, Squires R, Bezerra J, Shepherd R, Rosenthal P, Hoofnagle JH, Sokol RJ; Biliary Atresia Research Consortium. A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatr. 2006 Apr;148(4):467-474.

Weerasooriya VS, White FV, Shepherd RW. Hepatic fibrosis and survival in biliary atresia. J Pediatr. 2004 Jan;144(1):123-5.

Zhang D, Jiang H, Wang Y, Ma J. Pentoxifylline inhibits hepatic stellate cells proliferation via the Raf/ERK pathway. APMIS. 2012 Jul;120(7):572-81. doi: 10.1111/j.1600-0463.2011.02868.x. Epub 2012 Jan 19.

Andrade Wde C, Tannuri U, da Silva LF, Alves VA. Effects of the administration of pentoxifylline and prednisolone on the evolution of portal fibrogenesis secondary to biliary obstruction-an experimental study in growing animals. J Pediatr Surg. 2009 Nov;44(11):2071-7. doi: 10.1016/j.jpedsurg.2009.05.020.

Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, McCullough AJ. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology. 2011 Nov;54(5):1610-9. Epub 2011 Aug 24.

Petrowsky H, Breitenstein S, Slankamenac K, Vetter D, Lehmann K, Heinrich S, DeOliveira ML, Jochum W, Weishaupt D, Frauenfelder T, Graf R, Clavien PA. Effects of pentoxifylline on liver regeneration: a double-blinded, randomized, controlled trial in 101 patients undergoing major liver resection. Ann Surg. 2010 Nov;252(5):813-22. doi: 10.1097/SLA.0b013e3181fcbc5e.

Lebrec D, Thabut D, Oberti F, Perarnau JM, Condat B, Barraud H, Saliba F, Carbonell N, Renard P, Ramond MJ, Moreau R, Poynard T; Pentocir Group. Pentoxifylline does not decrease short-term mortality but does reduce complications in patients with advanced cirrhosis. Gastroenterology. 2010 May;138(5):1755-62. Epub 2010 Jan 25.

Haque KN, Pammi M. Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD004205. doi: 10.1002/14651858.CD004205.pub2. Review.

Superina R, Magee JC, Brandt ML, Healey PJ, Tiao G, Ryckman F, Karrer FM, Iyer K, Fecteau A, West K, Burns RC, Flake A, Lee H, Lowell JA, Dillon P, Colombani P, Ricketts R, Li Y, Moore J, Wang KS; Childhood Liver Disease Research and Education Network. The anatomic pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival. Ann Surg. 2011 Oct;254(4):577-85. doi: 10.1097/SLA.0b013e3182300950.

Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10.

Davenport M, Caponcelli E, Livesey E, Hadzic N, Howard E. Surgical outcome in biliary atresia: etiology affects the influence of age at surgery. Ann Surg. 2008 Apr;247(4):694-8. doi: 10.1097/SLA.0b013e3181638627.

Responsible Party:	Sanjiv Harpavat, Assistant Professor, Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine
ClinicalTrials.gov Identifier:	NCT01774487 History of Changes
Other Study ID Numbers:	BCM/TCH-H-31387
Study First Received:	January 22, 2013
Last Updated:	January 23, 2013
Health Authority:	United States: Institutional Review Board

Keywords provided by Baylor College of Medicine:

Biliary Atresia
Pentoxifylline
Trental
Serum bilirubin

Conjugated bilirubin
Liver transplantation
Fibrosis

Additional relevant MeSH terms:

Biliary Atresia
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Digestive System Abnormalities
Congenital Abnormalities
Pentoxifylline
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

Platelet Aggregation Inhibitors
Hematologic Agents
Therapeutic Uses
Radiation-Protective Agents
Protective Agents
Physiological Effects of Drugs
Vasodilator Agents
Cardiovascular Agents
Free Radical Scavengers
Antioxidants

ClinicalTrials.gov processed this record on May 16, 2013