Biliary Atresia
Conditions
Keywords
Biliary Atresia, Pentoxifylline, Trental, Serum bilirubin, Conjugated bilirubin, Liver transplantation, Fibrosis
Brief summary
The purpose of this study is to determine whether pentoxifylline reduces liver damage in infants with biliary atresia.
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.
Interventions
DRUGPentoxifylline
20 mg/kg/day divided in 3 doses, given orally for 90 days
Sponsors
Baylor College of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 180 Days
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Normal Serum Conjugated Bilirubin Levels 12 Weeks After Starting PTX (Pentoxifylline) Therapy | 12 weeks after starting 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Zero or Positive Weight Z-scores 12 Weeks After Starting PTX Therapy | 12 weeks after starting 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. |
| Alanine Amino Transferase (ALT) Levels at 2 Years of Life | 2 years of age | 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. |
| Spleen Size at 2 Years of Age | 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. |
| Time to Liver Transplant | Baseline and up to two years after therapy finishes | The investigators will track time to liver transplant. The shorter time to liver transplant indicates a worse outcome. |
| Platelet Levels at 2 Years of Life | 2 years of age | 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. |
Countries
United States
Participant flow
Recruitment details
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)
Participants by arm
| Arm | Count |
|---|---|
| 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 | 12 |
| 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 | 5 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not tolerate taste | 4 | 4 |
Baseline characteristics
| Characteristic | Pentoxifylline Group 1 | Pentoxifylline Group 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 12 Participants | 5 Participants | 17 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 49 days STANDARD_DEVIATION 26 | 120 days STANDARD_DEVIATION 30 | 69 days STANDARD_DEVIATION 42 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 2 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 3 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 4 Participants | 13 Participants |
| Sex: Female, Male Female | 8 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 1 |
| other Total, other adverse events | 4 / 8 | 1 / 1 |
| serious Total, serious adverse events | 6 / 8 | 1 / 1 |
Outcome results
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.
Time frame: 12 weeks after starting therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pentoxifylline - Group 1 | Number of Participants With Normal Serum Conjugated Bilirubin Levels 12 Weeks After Starting PTX (Pentoxifylline) Therapy | 6 Participants |
| Pentoxifylline - Group 2 | Number of Participants With Normal Serum Conjugated Bilirubin Levels 12 Weeks After Starting PTX (Pentoxifylline) Therapy | 0 Participants |
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.
Time frame: 2 years of age
Population: No patient in Group 2 survived with their native liver to 2 years of age.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pentoxifylline - Group 1 | Alanine Amino Transferase (ALT) Levels at 2 Years of Life | 160 U/L | Standard Deviation 122 |
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.
Time frame: 12 weeks after starting therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pentoxifylline - Group 1 | Number of Participants Achieving Zero or Positive Weight Z-scores 12 Weeks After Starting PTX Therapy | 0 Participants |
| Pentoxifylline - Group 2 | Number of Participants Achieving Zero or Positive Weight Z-scores 12 Weeks After Starting PTX Therapy | 0 Participants |
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.
Time frame: 2 years of age
Population: No patient in Group 2 survived with their native liver to 2 years of age.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pentoxifylline - Group 1 | Platelet Levels at 2 Years of Life | 208 10^3 Platelets/μL | Standard Deviation 102 |
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.
Time frame: 2 years of age
Population: No patient in Group 2 survived with their native liver to 2 years of age.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pentoxifylline - Group 1 | Spleen Size at 2 Years of Age | 10.0 cm | Standard Deviation 1.8 |
Secondary
Time to Liver Transplant
The investigators will track time to liver transplant. The shorter time to liver transplant indicates a worse outcome.
Time frame: Baseline and up to two years after therapy finishes
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pentoxifylline - Group 1 | Time to Liver Transplant | 317 days | Standard Deviation 95 |
| Pentoxifylline - Group 2 | Time to Liver Transplant | 273 days | — |