Pentoxifylline Therapy in Biliary Atresia

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

Detailed Description
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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.

Official Title
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A Phase II Trial of Pentoxifylline in Newly-Diagnosed Biliary Atresia

Conditions
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Biliary Atresia

Intervention / Treatment
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* Drug: Pentoxifylline


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 180 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pentoxifylline<br>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<br>* 20 mg/kg/day divided in 3 doses, given orally for 90 days<br>* Other names: Trental;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Normal Serum Conjugated Bilirubin Levels 12 Weeks After Starting PTX (Pentoxifylline) Therapy | The investigators will track the serum conjugated bilirubin (CB) levels over the course of therapy in patients receiving 90 days of PTX (this laboratory test is drawn as part of routine care). Normal CB is 0.0-0.3 mg/dL, with a higher number of patients meeting this indicating a better outcome. | 12 weeks after starting therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Zero or Positive Weight Z-scores 12 Weeks After Starting PTX Therapy | The investigators will track the weight of patients over the course of therapy in patients receiving 90 days of PTX (this is recorded as part of routine clinical care). The weight will then be compared to standards to calculate a z-score. Normal weight Z-score is greater than or equal to 0, with a higher number of patients meeting this indicating a better outcome. | 12 weeks after starting therapy | 
| Alanine Amino Transferase (ALT) Levels at 2 Years of Life | The investigators will record the ALT levels at age two years, in patients who had previously been treated with PTX therapy and still have their native liver. Scale 14-45 U/L, with a higher level indicating a worse outcome. | 2 years of age | 
| Spleen Size at 2 Years of Age | The investigators will measure spleen size by ultrasound at 2 years of age, in patients who had received PTX therapy earlier and still have their native liver. Normal spleen size range (10th-90th percentile) at this age is 6.4-8.6 cm, with a value exceeding this range indicating a worse outcome. | 2 years of age | 
| Time to Liver Transplant | The investigators will track time to liver transplant. The shorter time to liver transplant indicates a worse outcome. | Baseline and up to two years after therapy finishes | 
| Platelet Levels at 2 Years of Life | The investigators will record platelet levels at age two years, in patients who had previously been treated with PTX therapy and still have their native liver. Scale 189-403*10^3 Platelets/μL, with a lower level indicating a worse outcome. | 2 years of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biliary Atresia, Pentoxifylline, Trental, Serum bilirubin, Conjugated bilirubin, Liver transplantation, Fibrosis