Biliary Atresia
Conditions
Keywords
biliary atresia, hepatoportoenterostomy, corticosteroids
Brief summary
The Children Liver Disease Research and Education Network (ChiLDREN) is conducting a clinical trial to evaluate whether long-term treatment with corticosteroids improves the outcome of the Kasai or gall-bladder Kasai in infants with biliary atresia. In this clinical trial, ChiLDREN is testing whether corticosteroid therapy following the Kasai will improve bile drainage and long term outcome in infants with biliary atresia. Subjects in this trial must start treatment within 72 hours of the Kasai procedure and be part of a prospective study of the natural history of biliary atresia also being conducted by ChiLDREN (http://www.clinicaltrials.gov/ct/show/NCT00061828?order=3).
Detailed description
This is a multi-center randomized, double-blinded, placebo-controlled trial to prospectively determine the efficacy of corticosteroids on the outcome of infants with biliary atresia. The trial will be conducted by the NIDDK-funded network of 15 clinical centers comprising the Biliary Children Liver Disease Research and Education Network (ChiLDREN), whose goal is to study the etiology, pathogenesis, diagnosis, and treatment of infants with biliary atresia. For the trial, our overall hypothesis is that therapy with corticosteroids following portoenterostomy (including gall bladder Kasai procedure) will improve bile drainage and long-term outcome in infants with biliary atresia. This hypothesis will be tested through the following specific aims and hypotheses: Aim 1: To determine whether corticosteroid therapy decreases serum bilirubin concentration after portoenterostomy. Aim 2: To determine whether corticosteroid treatment after portoenterostomy will improve outcome as defined by survival without transplantation at 24 months of age. Aim 3: To determine whether corticosteroid treatment after portoenterostomy will improve growth of infants with biliary atresia. Aim 4: To determine whether corticosteroid treatment improves biochemical indicators of each of the fat-soluble vitamins after supplementation with standard doses. Aim 5: To determine whether corticosteroid treatment after portoenterostomy will decrease the incidence of persistent ascites or ascites that requires medical treatment. The significance of the proposed trial is that it will determine whether corticosteroids are an effective medical treatment to improve bile drainage and long-term outcome, and whether its use reduces the need for liver transplantation in infants with biliary atresia. Subjects will be recruited from patients enrolled in the ChiLDREN prospective observational database study who undergo portoenterostomy or portochelecystostomy (gall bladder Kasai) for biliary atresia. The Primary outcome measure is the percentage of patients with serum total bilirubin \<1.5 mg/dL and with native liver at 6 months after portoenterostomy. Secondary outcome measures are: 1. Serum total bilirubin concentration (and also at 3 months after portoenterostomy) 2. Survival with native liver at 24 months of age 3. Growth 1. Weight for age Z-score (in patients without ascites) 2. Height for age Z score 4. Serum biomarkers of sufficiency of fat-soluble vitamins 1. Vitamin A: molar ratio of serum retinol/retinol binding protein 2. Vitamin D: serum level of 25-hydroxy vitamin D 3. Vitamin E: ratio of serum vitamin E/total lipids 4. Vitamin K: International Normalized Ratio (INR) 5. Presence of ascites All measurements will be made at 12 and 24 months of age (unless noted otherwise):
Interventions
DRUGCorticosteroids
Schedule and dosing of corticosteroids following portoenterostomy in infants with biliary atresia are listed below. Days 1-3: Methylprednisolone, IV-4mg/kg/day, divided BID Days 4-7: Prednisolone, PO-4mg/kg/day, divided BID Week 2: 4 mg/kg/day, divided BID Week 3: 2 mg/kg/day, divided BID Week 4: 2 mg/kg/day, divided BID Week 5: 1 mg/kg/day, once a day Week 6: 1 mg/kg/day, once a day Week 7: 0.8 mg/kg/day, once a day Week 8: 0.6 mg/kg/day, once a day Week 9: 0.4 mg/kg/day, once a day Week 10: 0.2 mg/kg/day, once a day Week 11: 0.1 mg/kg/day, once a day Week 12-13: 0.1 mg/kg/day, every other day Week 14: Stop
DRUGPlacebo
Schedule and dosing of placebo following portoenterostomy in infants with biliary atresia: Days 1-3: IV - normal saline 4 mg/kg/day, divided BID Days 4-7: PO placebo 4 mg/kg/day, divided BID Week 2: PO placebo 4 mg/kg/day, divided BID Week 3: PO placebo 2 mg/kg/day, divided BID Week 4: PO placebo 2 mg/kg/day, divided BID Week 5: PO placebo 1 mg/kg/day, once a day Week 6: PO placebo 1 mg/kg/day, once a day Week 7: PO placebo 0.8 mg/kg/day, once a day Week 8: PO placebo 0.6 mg/kg/day, once a day Week 9: PO placebo 0.4 mg/kg/day, once a day Week 10: PO placebo 0.2 mg/kg/day, once a day Week 11: PO placebo 0.1 mg/kg/day, once a day Week 12-13: PO placebo 0.1 mg/kg/day, once a day every other day Week 14: Stop
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 6 Months
Healthy volunteers
No
Inclusion criteria
* Portoenterostomy or gall bladder Kasai operation for biliary atresia within the previous 72 hours * Post-conception age ≥ 36 weeks * Weight at enrolment ≥ 2000 gm * Written informed consent to participate in the study obtained prior to or within 72 hours of completion of portoenterostomy. (Note: Families of potential subjects may be approached prior to the portoenterostomy.)
Exclusion criteria
* Known immunodeficiency * Diabetes mellitus * Presence of significant systemic hypertension for age (persistent systolic blood pressure ≥112 mmHg) * A serum indirect (unconjugated) bilirubin ≥ 5 mg/dL for infants under 4 weeks of age or ≥ 7 mg/dL for infants between 4 and 8 weeks of age * Known sensitivity to corticosteroids * Documented bacteremia or other tissue infection which is felt to be clinically relevant * Known congenital infection or disease with herpes simplex virus, toxoplasmosis, or cytomegalovirus inclusion disease of the liver * Infants whose mother is known to have human immunodeficiency virus infection * Infants whose mother is known to be HBsAg or hepatitis C virus positive * Infants with other severe concurrent illnesses such as neurological, cardiovascular, pulmonary, metabolic, endocrine, and renal disorders that would interfere with the conduct and results of the study * Any other clinical condition that is a contraindication to the use of corticosteroid (e.g., bowel perforation) * Infants who have received the live attenuated rotavirus vaccine (e.g., Rotateq) within 5 days prior to proposed administration of study drug
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Percentage of Patients With Serum Total Bilirubin <1.5 mg/dL and With Native Liver at 6 Months After Portoenterostomy | Measurements will be made at 6 months after portoenterostomy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Bilirubin Concentration at 12 Months | 12 Months post HPE | — |
| Weight Z-Score | HPE until 24 months of age | weight for age Z-score (in subjects without ascites) over the course of the study |
| Height Z-Score | HPE to age 24 Months | Height by Age Z-score over the course of the study |
| Presence of Ascites at 12 Months | 12 Months | — |
| Presence of Ascites at 24 Months | 24 Months | — |
| Survival With Native Liver at 24 Months of Age | Measurements will be made at 24 months of age | — |
| Serum Total Bilirubin Concentration | Measurements will be made at 3 months after portoenterostomy | — |
| Total Bilirubin Concentration at 24 Months of Age | At 24 Months of Age | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin D | 24 Months | Vitamin D sufficiency is measured by the serum level of 25-hydroxy vitamin D |
| Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin A | 24 months | Vitamin A sufficiency is defined as the molar ratio of serum retinol/retinol binding protein |
| Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin E | 24 Months | Vitamin E sufficiency is measured as the ratio of serum vitamin E/total lipids |
| Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin K | 24 Months | Vitamin K sufficiency is measured by INR (international normalized ratio) |
Countries
United States
Participant flow
Pre-assignment details
One patient was enrolled but not randomized. Therefore, the overall number enrolled is 141, while the number randomized and starting participant flow is 140.
Participants by arm
| Arm | Count |
|---|---|
| Corticosteroids Corticosteroids: Schedule and dosing of corticosteroids following portoenterostomy in infants with biliary atresia are listed below.
Days 1-3: Methylprednisolone, IV-4mg/kg/day, divided BID Days 4-7: Prednisolone, PO-4mg/kg/day, divided BID Week 2: 4 mg/kg/day, divided BID Week 3: 2 mg/kg/day, divided BID Week 4: 2 mg/kg/day, divided BID Week 5: 1 mg/kg/day, once a day Week 6: 1 mg/kg/day, once a day Week 7: 0.8 mg/kg/day, once a day Week 8: 0.6 mg/kg/day, once a day Week 9: 0.4 mg/kg/day, once a day Week 10: 0.2 mg/kg/day, once a day Week 11: 0.1 mg/kg/day, once a day Week 12-13: 0.1 mg/kg/day, every other day Week 14: Stop | 70 |
| Placebo Placebo: Schedule and dosing of placebo following portoenterostomy in infants with biliary atresia:
Days 1-3: IV - normal saline 4 mg/kg/day, divided BID Days 4-7: PO placebo 4 mg/kg/day, divided BID Week 2: PO placebo 4 mg/kg/day, divided BID Week 3: PO placebo 2 mg/kg/day, divided BID Week 4: PO placebo 2 mg/kg/day, divided BID Week 5: PO placebo 1 mg/kg/day, once a day Week 6: PO placebo 1 mg/kg/day, once a day Week 7: PO placebo 0.8 mg/kg/day, once a day Week 8: PO placebo 0.6 mg/kg/day, once a day Week 9: PO placebo 0.4 mg/kg/day, once a day Week 10: PO placebo 0.2 mg/kg/day, once a day Week 11: PO placebo 0.1 mg/kg/day, once a day Week 12-13: PO placebo 0.1 mg/kg/day, once a day every other day Week 14: Stop | 70 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 8 |
Baseline characteristics
| Characteristic | Corticosteroids | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 2.3 Months STANDARD_DEVIATION 0.93 | 2.3 Months STANDARD_DEVIATION 0.89 | 2.3 Months STANDARD_DEVIATION 0.84 |
| Biliary atresia splenic malformation (BASM) BASM | 2 participants | 5 participants | 3 participants |
| Biliary atresia splenic malformation (BASM) Not BASM | 68 participants | 135 participants | 67 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 36 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 55 Participants | 103 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Length Z Score | -0.7 Z-Score STANDARD_DEVIATION 1.35 | -0.65 Z-Score STANDARD_DEVIATION 1.35 | -0.6 Z-Score STANDARD_DEVIATION 1.35 |
| OHI Main Type I | 5 participants | 13 participants | 8 participants |
| OHI Main Type II | 1 participants | 5 participants | 4 participants |
| OHI Main Type III | 64 participants | 121 participants | 57 participants |
| OHI Main Type Missing | 0 participants | 1 participants | 1 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 19 Participants | 11 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 | 16 Participants | 31 Participants | 15 Participants |
| Race (NIH/OMB) White | 46 Participants | 90 Participants | 44 Participants |
| Sex: Female, Male Female | 32 Participants | 72 Participants | 40 Participants |
| Sex: Female, Male Male | 38 Participants | 68 Participants | 30 Participants |
| Total Bilirubin | 7.5 mg/dL STANDARD_DEVIATION 2.6 | 7.7 mg/dL STANDARD_DEVIATION 2.7 | 7.9 mg/dL STANDARD_DEVIATION 2.8 |
| Weight Z Score | -0.8 Z-Score STANDARD_DEVIATION 1.07 | -0.8 Z-Score STANDARD_DEVIATION 1.07 | -0.8 Z-Score STANDARD_DEVIATION 1.06 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 70 | 0 / 70 |
| serious Total, serious adverse events | 57 / 70 | 56 / 70 |
Outcome results
Primary
The Percentage of Patients With Serum Total Bilirubin <1.5 mg/dL and With Native Liver at 6 Months After Portoenterostomy
Time frame: Measurements will be made at 6 months after portoenterostomy
Population: Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Corticosteroids | The Percentage of Patients With Serum Total Bilirubin <1.5 mg/dL and With Native Liver at 6 Months After Portoenterostomy | 58.6 percentage of participants |
| Placebo | The Percentage of Patients With Serum Total Bilirubin <1.5 mg/dL and With Native Liver at 6 Months After Portoenterostomy | 48.6 percentage of participants |
Comparison: RR greater than one indicates benefit of steriods and a P value of treatment success from a log-binomial model with these covariates: Treatment group, age a HPE, BASM as fixed effects, and site as a random effect.p-value: 0.4395% CI: [0.83, 1.57]Log binomial
Secondary
Height Z-Score
Height by Age Z-score over the course of the study
Time frame: HPE to age 24 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Corticosteroids | Height Z-Score | -0.7 Z-score | Standard Error 0.16 |
| Placebo | Height Z-Score | -0.6 Z-score | Standard Error 0.16 |
p-value: 0.2801Mixed Models Analysis
Secondary
Presence of Ascites at 12 Months
Time frame: 12 Months
Population: Participants with their native liver at 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Corticosteroids | Presence of Ascites at 12 Months | 5 participants |
| Placebo | Presence of Ascites at 12 Months | 3 participants |
p-value: 0.4195% CI: [0.62, 3.14]Log Binomial
Secondary
Presence of Ascites at 24 Months
Time frame: 24 Months
Population: Participants with their native liver at 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Corticosteroids | Presence of Ascites at 24 Months | 1 participants |
| Placebo | Presence of Ascites at 24 Months | 3 participants |
p-value: 0.2995% CI: [0.03, 2.92]Log Binomial
Secondary
Serum Total Bilirubin Concentration
Time frame: Measurements will be made at 3 months after portoenterostomy
Population: Intent to treat patients with 3 month bilirubin available are analyzed. There are no imputations for unobserved data. Patients with missing data are simply not included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Corticosteroids | Serum Total Bilirubin Concentration | 3.5 mg/dL | Standard Deviation 5.32 |
| Placebo | Serum Total Bilirubin Concentration | 5.1 mg/dL | Standard Deviation 6.15 |
Comparison: LS Mean difference reported as steroid minus placebo (negative values mean larger average values of total bilirubin in placebo).p-value: 0.097395% CI: [-3.49, 0.3]Mixed Models Analysis
Secondary
Survival With Native Liver at 24 Months of Age
Time frame: Measurements will be made at 24 months of age
Population: Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Corticosteroids | Survival With Native Liver at 24 Months of Age | 58.7 percentage of participants |
| Placebo | Survival With Native Liver at 24 Months of Age | 59.4 percentage of participants |
p-value: 0.9995% CI: [0.6, 1.8]Regression, Cox
Secondary
Total Bilirubin Concentration at 12 Months
Time frame: 12 Months post HPE
Population: Intent to treat patients with 12 month bilirubin available are analyzed. There are no imputations for unobserved data. Patients with missing data are simply not included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Corticosteroids | Total Bilirubin Concentration at 12 Months | 1.7 mg/dL | Standard Deviation 3.63 |
| Placebo | Total Bilirubin Concentration at 12 Months | 3.7 mg/dL | Standard Deviation 6.63 |
Comparison: LS Mean difference of steroid minus placebo (negative values indicate larger average values of bilirubin in placebo)p-value: 0.055295% CI: [-4.65, 0.05]Mixed Models Analysis
Secondary
Total Bilirubin Concentration at 24 Months of Age
Time frame: At 24 Months of Age
Population: Intent to treat patients with 24 month bilirubin available are analyzed. There are no imputations for unobserved data. Patients with missing data are simply not included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Corticosteroids | Total Bilirubin Concentration at 24 Months of Age | 1.3 mg/dL | Standard Deviation 3.37 |
| Placebo | Total Bilirubin Concentration at 24 Months of Age | 1.6 mg/dL | Standard Deviation 3.73 |
Comparison: LS Mean difference of steroid minus placebo (negative values indicate larger average bilirubin in placebo)p-value: 0.660795% CI: [-2.16, 1.38]Mixed Models Analysis
Secondary
Weight Z-Score
weight for age Z-score (in subjects without ascites) over the course of the study
Time frame: HPE until 24 months of age
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Corticosteroids | Weight Z-Score | -0.8 Z-score | Standard Error 0.13 |
| Placebo | Weight Z-Score | -0.8 Z-score | Standard Error 0.13 |
p-value: 0.1603Mixed Models Analysis
Other Pre-specified
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin A
Vitamin A sufficiency is measured by the molar ratio of serum retinol/retinol binding protein
Time frame: 12 months
Population: Although the protocol specified analyses of serum biomarkers as secondary outcomes, the intent was to only perform these analyses if the primary endpoint showed sufficient efficacy. Given the lack of efficacy of steroids (vs placebo), the analyses of fat-soluble vitamins were not performed; thus, data are not summarized for this assessment.
Other Pre-specified
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin A
Vitamin A sufficiency is defined as the molar ratio of serum retinol/retinol binding protein
Time frame: 24 months
Population: Although the protocol specified analyses of serum biomarkers as secondary outcomes, the intent was to only perform these analyses if the primary endpoint showed sufficient efficacy. Given the lack of efficacy of steroids (vs placebo), the analyses of fat-soluble vitamins were not performed; thus, data are not summarized for this assessment.
Other Pre-specified
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin D
Vitamin D sufficiency is measured by the serum level of 25-hydroxy vitamin D
Time frame: 24 Months
Population: Although the protocol specified analyses of serum biomarkers as secondary outcomes, the intent was to only perform these analyses if the primary endpoint showed sufficient efficacy. Given the lack of efficacy of steroids (vs placebo), the analyses of fat-soluble vitamins were not performed; thus, data are not summarized for this assessment.
Other Pre-specified
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin D
Vitamin D sufficiency is measured by the serum level of 25-hydroxy vitamin D
Time frame: 12 Months
Population: Although the protocol specified analyses of serum biomarkers as secondary outcomes, the intent was to only perform these analyses if the primary endpoint showed sufficient efficacy. Given the lack of efficacy of steroids (vs placebo), the analyses of fat-soluble vitamins were not performed; thus, data are not summarized for this assessment.
Other Pre-specified
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin E
Vitamin E sufficiency is measured as the ratio of serum vitamin E/total lipids
Time frame: 24 Months
Population: Although the protocol specified analyses of serum biomarkers as secondary outcomes, the intent was to only perform these analyses if the primary endpoint showed sufficient efficacy. Given the lack of efficacy of steroids (vs placebo), the analyses of fat-soluble vitamins were not performed; thus, data are not summarized for this assessment.
Other Pre-specified
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin E
Vitamin E sufficiency is measured as the ratio of serum vitamin E/total lipids
Time frame: 12 Months
Population: Although the protocol specified analyses of serum biomarkers as secondary outcomes, the intent was to only perform these analyses if the primary endpoint showed sufficient efficacy. Given the lack of efficacy of steroids (vs placebo), the analyses of fat-soluble vitamins were not performed; thus, data are not summarized for this assessment.
Other Pre-specified
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin K
Vitamin K sufficiency is measured by INR (international normalized ratio)
Time frame: 12 Months
Population: Although the protocol specified analyses of serum biomarkers as secondary outcomes, the intent was to only perform these analyses if the primary endpoint showed sufficient efficacy. Given the lack of efficacy of steroids (vs placebo), the analyses of fat-soluble vitamins were not performed; thus, data are not summarized for this assessment.
Other Pre-specified
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin K
Vitamin K sufficiency is measured by INR (international normalized ratio)
Time frame: 24 Months
Population: Although the protocol specified analyses of serum biomarkers as secondary outcomes, the intent was to only perform these analyses if the primary endpoint showed sufficient efficacy. Given the lack of efficacy of steroids (vs placebo), the analyses of fat-soluble vitamins were not performed; thus, data are not summarized for this assessment.