Not provided
Not provided
Not provided
Not provided
Not provided
Target enrollment was not reached because the medication, pentoxifylline, has a taste that is not well tolerated by infants. The study team decided to end the study before meeting the enrollment goal because of the medication taste.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The purpose of this study is to determine whether pentoxifylline reduces liver damage in infants with biliary atresia.
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pentoxifylline | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pentoxifylline | Drug | 20 mg/kg/day divided in 3 doses, given orally for 90 days |
|
| 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 |
| 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. |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Sanjiv Harpavat, MD PhD | Baylor College of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Texas Children's Hospital and Baylor College of Medicine | Houston | Texas | 77030 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12029613 | Background | Perlmutter DH, Shepherd RW. Extrahepatic biliary atresia: a disease or a phenotype? Hepatology. 2002 Jun;35(6):1297-304. doi: 10.1053/jhep.2002.34170. No abstract available. | |
| 17661405 | Background | 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. doi: 10.1002/hep.21790. |
Not provided
Not provided
The data for subjects will be shared in aggregate.
Not provided
Not provided
Not provided
Not provided
Not provided
All newly-diagnosed biliary atresia patients fulfilling the study's inclusion criteria (those who received the Kasai portoenterostomy are in Group 1 and those diagnosed too late for the Kasai portoenterostomy are in Group 2)
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Pentoxifylline - Group 1 (Treatment Starts 3-5 Days After Kasai Portoenterostomy) | 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. Pentoxifylline: 20 mg/kg/day divided in 3 doses, given orally for 90 days |
| FG001 | Pentoxifylline - Group 2 (Patient Diagnosed Too Late for Kasai Portoenterostomy) | 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. Pentoxifylline: 20 mg/kg/day divided in 3 doses, given orally for 90 days |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Pentoxifylline Group 1 | 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. Pentoxifylline: 20 mg/kg/day divided in 3 doses, given orally for 90 days |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Count of Participants | Participants | 12 weeks after starting therapy |
|
Adverse event (AE) data was collected for 12 weeks after the Kasai portoenterostomy (duration of time when patient received medication during the study). Note: Some secondary outcomes were collected at age 2 years, but AEs (included all-cause mortality) were collected for 12 weeks after Kasai portoenterostomy to capture those AEs that could possibly be related to treatment.
Serious AEs were any AEs requiring hospitalization.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Pentoxifylline - Group 1 (Treatment Starts 3-5 Days After Kasai Portoenterostomy) | 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. Pentoxifylline: 20 mg/kg/day divided in 3 doses, given orally for 90 days |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Failure to thrive | Gastrointestinal disorders | Systematic Assessment | Hospital admission for nutrition optimization (expected with biliary atresia) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| ALT >2.5X baseline | Hepatobiliary disorders | Systematic Assessment | ALT levels 2.5X above level at Kasai portoenterostomy |
Because of early termination, this study did not reach the target number of participants needed to achieve target power and statistically reliable results.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Sanjiv Harpavat | Baylor College of Medicine and Texas Children's Hospital | 832-824-2099 | 2144 | harpavat@bcm.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 7, 2022 | Apr 22, 2023 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D001656 | Biliary Atresia |
| D005355 | Fibrosis |
| ID | Term |
|---|---|
| D001649 | Bile Duct Diseases |
| D001660 | Biliary Tract Diseases |
| D004066 | Digestive System Diseases |
| D004065 | Digestive System Abnormalities |
Not provided
Not provided
| ID | Term |
|---|---|
| D010431 | Pentoxifylline |
| ID | Term |
|---|---|
| D013805 | Theobromine |
| D014970 | Xanthines |
| D011688 | Purinones |
| D011687 | Purines |
| D006574 |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| 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. Range of normal values: 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 |
| 22595595 | Background | 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. |
| 16647406 | Background | 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. doi: 10.1016/j.jpeds.2005.12.054. |
| 14722530 | Background | Weerasooriya VS, White FV, Shepherd RW. Hepatic fibrosis and survival in biliary atresia. J Pediatr. 2004 Jan;144(1):123-5. doi: 10.1016/j.jpeds.2003.09.042. |
| 22716212 | Background | 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. |
| 19944210 | Background | 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. |
| 21748765 | Background | 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. doi: 10.1002/hep.24544. Epub 2011 Aug 24. |
| 21037437 | Background | 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. |
| 20102716 | Background | 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. doi: 10.1053/j.gastro.2010.01.040. Epub 2010 Jan 25. |
| 21975745 | Background | 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. |
| 21869674 | Background | 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. |
| 2702835 | Background | Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9. |
| 24944359 | Background | Best BM, Burns JC, DeVincenzo J, Phelps SJ, Blumer JL, Wilson JT, Capparelli EV, Connor JD; Pediatric Pharmacology Research Unit Network. Pharmacokinetic and tolerability assessment of a pediatric oral formulation of pentoxifylline in kawasaki disease. Curr Ther Res Clin Exp. 2003 Feb;64(2):96-115. doi: 10.1016/S0011-393X(03)00018-3. |
| 18362634 | Background | 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. |
| BG001 | Pentoxifylline Group 2 | 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. Pentoxifylline: 20 mg/kg/day divided in 3 doses, given orally for 90 days |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Age at Kasai portoenterostomy (Group 1) or Age at Presentation (Group 2) | Mean | Standard Deviation | days |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Pentoxifylline - Group 2 |
For Group 2: Infants not receiving the KP will be given PTX for 12 weeks, and the number whose CB levels stabilize (within 10% of starting level) will be calculated. Historically, ~10% of such infants have stable CB levels after 12 weeks. The study will determine whether PTX improves this percentage. |
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | 12 weeks after starting therapy |
|
|
|
| Secondary | 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. Range of normal values: 14-45 U/L, with a higher level indicating a worse outcome. | No patient in Group 2 survived with their native liver to 2 years of age. | Posted | Mean | Standard Deviation | U/L | 2 years of age |
|
|
|
| Secondary | 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. | No patient in Group 2 survived with their native liver to 2 years of age. | Posted | Mean | Standard Deviation | cm | 2 years of age |
|
|
|
| Secondary | Time to Liver Transplant | The investigators will track time to liver transplant. The shorter time to liver transplant indicates a worse outcome. | Posted | Mean | Standard Deviation | days | Baseline and up to two years after therapy finishes |
|
|
|
| Secondary | 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. | No patient in Group 2 survived with their native liver to 2 years of age. | Posted | Mean | Standard Deviation | 10^3 Platelets/μL | 2 years of age |
|
|
|
| 0 |
| 8 |
| 6 |
| 8 |
| 4 |
| 8 |
| EG001 | Pentoxifylline - Group 2 (Patient Diagnosed Too Late for Kasai Portoenterostomy) | 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. Pentoxifylline: 20 mg/kg/day divided in 3 doses, given orally for 90 days | 0 | 1 | 1 | 1 | 1 | 1 |
|
| Cholangitis | Hepatobiliary disorders | Systematic Assessment | Hospital admission for cholangitis (expected with biliary atresia) |
|
| Ascites | Hepatobiliary disorders | Systematic Assessment | Hospital admission for ascites management (expected with biliary atresia) |
|
| Bile leak | Hepatobiliary disorders | Systematic Assessment | Hospital admission for bile leak (can happen with biliary atresia) |
|
|
| Bc >2.5X baseline | Hepatobiliary disorders | Systematic Assessment | Conjugated bilirubin levels 2.5X above level at Kasai portoenterostomy |
|
| Platelets <150,000/ul | Blood and lymphatic system disorders | Systematic Assessment | Thrombocytopenia (sign of portal hypertension) |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment | Vomiting from feeds and/or mediations, requiring change in feeding or medication regimen |
|
| Stopped medication before 12 week period | Product Issues | Systematic Assessment | Stopped medication before the study end period because of vomiting |
|
Not provided
Not provided
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |