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Use of Corticosteroids After Hepatoportoenterostomy for Bile Drainage in Infants With Biliary Atresia The START Randomized Clinical Trial

JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 05/2014; 311(17):1750-9. DOI: 10.1001/jama.2014.2623
Source: PubMed
ABSTRACT
IMPORTANCE Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome. OBJECTIVE To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver. DESIGN, SETTING, AND PATIENTS The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013. INTERVENTIONS Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy. MAIN OUTCOMES AND MEASURES The primary end point (powered to detect a 25% absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events. RESULTS The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% [41/70] of steroids group vs 48.6% [34/70] of placebo group; adjusted relative risk, 1.14 [95% CI, 0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, -10.4% to 27.7%). Transplant-free survival was 58.7% in the steroids group vs 59.4% in the placebo group (adjusted hazard ratio, 1.0 [95% CI, 0.6 to 1.8]; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4% [57/70] of the steroids group and 80.0% [56/70] of the placebo group (P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2% [95% CI, 26.9% to 50.0%] of steroids group vs 19.0% [95% CI, 11.5% to 30.4%] of placebo group; P = .008). CONCLUSIONS AND RELEVANCE Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00294684.

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Use of Corticosteroids After Hepatoportoenterostomy
for Bile Drainage in Infants With Biliary Atresia
The START Randomized Clinical Trial
Jorge A. Bezerra, MD; Cathie Spino, DSc; John C. Magee, MD; Benjamin L. Shneider, MD; Philip Rosenthal, MD; Kasper S. Wang, MD;
Jessi Erlichman, MPH; Barbara Haber, MD; Paula M. Hertel, MD; Saul J. Karpen, MD; Nanda Kerkar, MD; Kathleen M. Loomes, MD; Jean P. Molleston, MD;
Karen F. Murray, MD; Rene Romero, MD; Kathleen B. Schwarz, MD; Ross Shepherd, MD; Frederick J. Suchy, MD; Yumirle P. Turmelle, MD;
Peter F. Whitington, MD; Jeffrey Moore, MS; Averell H. Sherker, MD, FRCP(C); Patricia R. Robuck, PhD, MPH; Ronald J. Sokol, MD;
for the Childhood Liver Disease Research and Education Network (ChiLDREN)
IMPORTANCE
Biliary atresia is the most common cause of end-stage liver disease in children.
Controversy exists as to whether use of steroids after hepatoportoenterostomy improves
clinical outcome.
OBJECTIVE To determine whether the addition of high-dose corticosteroids after
hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and
survival with the native liver.
DESIGN, SETTING, AND PATIENTS The multicenter, double-blind Steroids in Biliary Atresia
Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between
September 2005 and February 2011 in the United States; follow-up ended in January 2013.
INTERVENTIONS Participants were randomized to receive intravenous methylprednisolone
(4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a
tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of
hepatoportoenterostomy.
MAIN OUTCOMES AND MEASURES The primary end point (powered to detect a 25% absolute
treatment difference) was the percentage of participants with a serum total bilirubin level of less
than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary
outcomes included survival with native liver at 24 months of age and serious adverse events.
RESULTS The proportion of participants with improved bile drainage was not statistically
significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% [41/70]
of steroids group vs 48.6% [34/70] of placebo group; adjusted relative risk, 1.14 [95% CI,
0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, −10.4% to
27.7%). Transplant-free survival was 58.7% in the steroids group vs 59.4% in the placebo
group (adjusted hazard ratio, 1.0 [95% CI, 0.6 to 1.8]; P = .99) at 24 months of age. The
percentage of participants with serious adverse events was 81.4% [57/70] of the steroids
group and 80.0% [56/70] of the placebo group (P > .99); however, participants receiving
steroids had an earlier time of onset of their first serious adverse event by 30 days
posthepatoportoenterostomy (37.2% [95% CI, 26.9% to 50.0%] of steroids group vs 19.0%
[95% CI, 11.5% to 30.4%] of placebo group; P = .008).
CONCLUSIONS AND RELEVANCE Among infants with biliary atresia who have undergone
hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in
statistically significant treatment differences in bile drainage at 6 months, although a small
clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of
serious adverse events in children with biliary atresia.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00294684
JAMA. 2014;311(17):1750-1759. doi:10.1001/jama.2014.2623
Supplemental content at
jama.com
Author Affiliations: Author
affiliations are listed at the end of this
article.
Group Information: The Childhood
Liver Disease Research and Education
Network (ChiLDREN) investigators
are listed at the end of the article.
Corresponding Author: Jorge A.
Bezerra, MD, Cincinnati Children’s
Hospital Medical Center, 3333 Burnet
Ave, Cincinnati, OH 45229
(jorge.bezerra@cchmc.org).
Research
Original Investigation
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B
iliary atresia occurs in 1:5000 to 1:18 000 live births and
progresses to end-stage cirrhosis in more than 70% of
affected children.
1
It is the leading indication for pedi-
atric liver transplantation in the world, accounting for about
50% of transplants in children and about 10% of transplants
at any age.
1
The disease results from an inflammatory and rap-
idly fibrosing cholangiopathy that obstructs the lumen of ex-
trahepatic bile ducts and manifests as cholestatic jaundice in
the first few weeks after birth. At diagnosis, the primary treat-
ment is a hepatoportoenterostomy (the Kasai procedure),
which entails surgical excision of the biliary remnant and cre-
ation of bile drainage via a jejunal Roux-en-Y anastomosis to
the porta hepatis. Hepatoportoenterostomy results in success-
ful bile drainage in only about half of patients with biliary atre-
sia treated in the United States.
2
Even after successful drain-
age, most infants experience progression of intrahepatic
disease, ultimately requiring liver transplantation for survival.
3
This poor outcome underscores the need for adjunct thera-
pies to improve survival without liver transplantation.
Following initial reports of corticosteroids (called ste-
roids hereafter) use following hepatoportoenterostomy or as
short-term pulses to reverse cessation of previously achieved
bile flow after successful hepatoportoenterostomy,
4,5
others
have reported improved clinical outcomes with postopera-
tive steroid therapy for biliary atresia.
6-14
The proposed justi-
fication for use of steroids was to reduce biliary inflamma-
tion and fibrosis and to promote bile flow. These reports were
largely retrospective analyses that used historical controls and
varying doses and durations of treatment, yet they became the
basis for the widespread use of steroids following hepatopor-
toenterostomy in the United States and in other countries.
11,15
Moreover, due to their designs, these studies could not ad-
dress potential adverse consequences of this therapy in young
infants with biliary atresia. A recent meta-analysis
16
was un-
able to determine if steroids improve patient outcomes be-
cause of an insufficient number of well-conducted studies.
Based on these conflicting reports and safety concerns regard-
ing the use of steroids in infants, we conducted the Steroids
in Biliary Atresia Randomized Trial (START) to determine
whether the combination of hepatoportoenterostomy with
high-dose steroid therapy was superior to hepatoportoenter-
ostomy alone.
Methods
Study Design
START was a randomized multicenter, double-blind, placebo-
controlled trial of steroid therapy following hepatoportoen-
terostomy in infants with biliary atresia conducted at 14 clini-
cal sites in the Childhood Liver Disease Research and Education
Network (ChiLDREN) funded by the National Institute of Dia-
betes and Digestive and Kidney Diseases. Institutional re-
view board approval was obtained at each site and at the data
coordinating center; parents or guardians of the children pro-
vided written informed consent. Enrollment began in Sep-
tember 2005 and ended in February 2011, with follow-up com-
pleted in January 2013.
Patient Population
Infants were recruited if they had biliary atresia and had been
enrolled in the ChiLDREN prospective observational data-
base study of cholestasis in infancy (PROBE) and later under-
went hepatoportoenterostomy. Inclusion criteria were age of
180 days or younger, serum direct or conjugated bilirubin level
of 2 mg/dL or higher and greater than 20% of total bilirubin,
postconception age of 36 weeks or older, and weight of 2000
g or greater. Potential participants were excluded from START
if they had undergone previous hepatobiliary surgery or had
known immunodeficiency, diabetes mellitus, or significantsys-
temic hypertension for age (the complete inclusion and ex-
clusion criteria appear in eTable 1 in Supplement).
Study Intervention and Randomization
Eligible participants were randomized with equal probability
to a 13-week course of steroid therapy or matching placebo,
which was administered in a double-blind manner starting
within 72 hours after hepatoportoenterostomy. Participants in
the steroids group received intravenous methylprednisolone
(4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for
2 weeks) followed by a tapering protocol for prednisolone for
9 weeks (Table 1). Steroids or placebo were given intrave-
nously for at least 2 postoperative days or until the infant re-
sumed oral or enteral feedings, at which time prednisolone or
placebo was given orally for the remainder of the study. Par-
ticipants in the placebo group received intravenous normal sa-
line or an oral inactive substance that matched the steroid prod-
uct for appearance and taste. The initial dose was chosen based
Table 1. Dosage and Duration of Steroids or Placebo for START
Period Steroids
a
Placebo
Week 1
Days 1-3 Methylprednisolone,
4 mg/kg/d intravenously,
divided twice daily
b
Normal saline intrave-
nously (same volume,
twice daily)
b
Days 4-7 Prednisolone, 4 mg/kg/d
orally, divided twice daily
Placebo with same
appearance as steroid
pill, orally, twice daily
Week 2 Prednisolone, 4 mg/kg/d,
divided twice daily
Placebo, twice daily
Week 3-4 Prednisolone, 2 mg/kg/d,
divided twice daily
Placebo, twice daily
Week 5-6 Prednisolone, 1 mg/kg/d Placebo, once daily
Week 7 Prednisolone, 0.8 mg/kg/d Placebo, once daily
Week 8 Prednisolone, 0.6 mg/kg/d Placebo, once daily
Week 9 Prednisolone, 0.4 mg/kg/d Placebo, once daily
Week 10 Prednisolone, 0.2 mg/kg/d Placebo, once daily
Week 11 Prednisolone, 0.1 mg/kg/d Placebo, once daily
Week
12-13
Prednisolone, 0.1 mg/kg,
every other day
Placebo, every other day
Week 14 Stop use Stop use
Abbreviation: START, Steroids in Biliary Atresia Randomized Trial.
a
Initial dosage was based on the infant’s weight. Subsequent doses were
adjusted based on the infant’s weight measured monthly at each scheduled
outpatient visit.
b
Steroids or placebo were given intravenously for at least 2 postoperative days
or until the infant resumed oral or enteral feedings, at which time
prednisolone or placebo was given orally for the remainder of the study.
High-Dose Corticosteroids for Biliary Atresia Original Investigation Research
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on 2 reports published before the start of the trial,
6,9
one of
which showed improved serum bilirubin levels in 76% of
patients.
6
The data coordinating center generated treatment ran-
domization codes with permuted block sizes of 4 (stratified by
site) and provided the central pharmacy with a list of assign-
ments for each study site. Study medications were labeled and
put into a kit by the central pharmacy and distributed to study
site research pharmacists who were instructed to dispense the
kits to participants enrolled sequentially. Routine clinical care
guidelines for the postoperative care were established for in-
fants enrolled in PROBE and were followed for all partici-
pants in this clinical trial (eTable 2 in Supplement).
Measures
Baseline assessments included the collection of demo-
graphic, medical, and surgical history; physical examination;
presence of biliary atresia splenic malformation (BASM) syn-
drome, which could influence the response to hepatoporto-
enterostomy; laboratory parameters; and anthropometric mea-
surements. Race and ethnicity were self-reported according to
categories set by the US Office of Management and Budget and
are reported to provide descriptive information on these demo-
graphic characteristics. Biochemical and serological tests were
performed at the clinical laboratories of the participating cen-
ters. The assessments were also performed at 2 weeks after
hepatoportoenterostomy; at 1, 2, 3, and 6 months after hepa-
toportoenterostomy; and at 12, 18, and 24 months of age. An-
tibody titers in response to routine infant immunizations were
collected at 18 months of age.
Study Outcomes
The primary end point was defined as successful bile drain-
age (measured as the percentage of participants with serum
total bilirubin level of <1.5 mg/dL; to convert to μmol/L, mul-
tiply by 17.104) with his/her native liver at 6 months after hepa-
toportoenterostomy. Total bilirubin was determined directly
using standard laboratory methods, or calculated by the ad-
dition of conjugated plus unconjugated bilirubin.
17
If these val-
ues were missing at the 6-month time point in participants with
their native liver, successful bile drainage was imputed if the
total bilirubin values were less than 1.5 mg/dL at both time
points immediately prior to and after the 6-month time point
(ie, 3 months posthepatoportoenterostomy and at 12 months
of age), and were considered to have unsuccessful bile drain-
age otherwise.
Secondary outcomes included duration of successful bile
drainage, survival with native liver at 24 months of age, and
the proportion of participants with ascites at 12 and 24 months
of age. The duration of successful bile drainage was defined
as the time (months) between a participant’s first total biliru-
bin level of less than 1.5 mg/dL and the earlier of next re-
corded total bilirubin level of 1.5 mg/dL or greater, liver trans-
plantation, or death. Time until loss to follow-up, withdrawn
from the study, and completion of the study without experi-
encing the event were censored. If a participant never achieved
successful bile drainage (ie, total bilirubin level ≥1.5 mg/dL for
the duration of the study), then duration was set to 0. Unlike
other secondary time-to-event end points, the end point for
the duration of successful bile drainage began when a partici-
pant achieved successful bile drainage instead of the time of
hepatoportoenterostomy.
Survival with the native liver was defined as the time from
the date of hepatoportoenterostomy to the earlier date when
the participant underwent liver transplantation or died
(events), was 24 months of age with native liver, withdrew, or
was lost to follow-up (censored). The occurrence of ascites was
defined as the clinical manifestation of ascites, treatment of
ascites, or detection of ascites by sonographic examination.
Safety outcomes included adverse events (total, ex-
pected, and unexpected), serious adverse events (defined as
death, disability, life-threatening illness, or an event requir-
ing hospitalization), and infectious serious adverse events. The
list of a priori expected adverse events appears in eTable 3 in
Supplement; each expected adverse event was defined in the
START manual of operations. An independent medical moni-
tor reviewed all serious adverse events, providing body sys-
tem classifications and preparing safety narratives that were
reviewed by an independent data and safety monitoring board
that was convened quarterly by the National Institute of Dia-
betes and Digestive and Kidney Diseases to review study con-
duct, adverse events, and serious adverse events.
Statistical Analysis
Seventy participants per group were calculated to provide 80%
power to detect a 25% absolute treatment difference in the pri-
mary end point on the basis of a 2-sample test of proportions,
with a 2-sided significance level of .05 and allowing for 20%
attrition and 2 interim analyses based on the O’Brien-
Fleming spending function. A retrospective study of the level
of serum total bilirubin and survival with the native liver in
children with biliary atresia treated with hepatoportoenter-
ostomy at the participating centers provided our estimate of
50% for the primary end point in the placebo group.
2
The ex-
pectation for steroids to improve the primary outcome to 75%
was based on 2 studies published before the initiation of START
reporting that the use of corticosteroids after hepatoportoen-
terostomy was associated with resolution of jaundice in 76%
to 79% of patients.
6,9
Although planned, no formal interim
analyses of the primary end point were conducted; therefore,
the nominal 2-sided α level used for the final analysis was .05
for the primary end point. All other secondary outcomes were
also tested at the 2-sided level of .05, with no adjustment for
multiplicity; thus, the interpretation of these tests should be
considered exploratory.
The primary analysis was based on a modified intention-
to-treat approach; all randomized participants who received
at least 1 dose of study medication were included. We com-
pared the proportion of participants who had successful bile
drainage at 6 months between the steroids and placebo groups,
using a generalized linear model based on the binomial dis-
tribution with a log link (log-binomial regression),
18
with co-
variates for treatment group, age at hepatoportoenteros-
tomy, and the presence of BASM syndrome as fixed effects and
clinical site as a random effect, providing relative risk (RR) ra-
tios of the treatment effect. The adjusted absolute treatment
Research Original Investigation High-Dose Corticosteroids for Biliary Atresia
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difference and its corresponding 95% confidence interval based
on this model were also calculated in a post hoc analysis. Sen-
sitivity analyses were performed to assess the robustness of
our findings (1) using 2 mg/dL instead of 1.5 mg/dL as the thresh-
old for total bilirubin level
2
; (2) defining successful bile drain-
age based on any time point during the 6-month posthepato-
portoenterostomy period; and (3) using a per-protocol analysis
set, excluding participants with major protocol deviations, in-
adequate study medication exposure, or both (inadequate ex-
posure defined as <80% and >120% of the intended study medi-
cations, independent of adverse events).
We also conducted a post hoc sensitivity analysis of our
imputation method for missing data for the analysis of the pri-
mary end point using multiple imputation methods, which as-
sumes that data were missing at random. Missing total biliru-
bin at 6 months was multiply imputed using a Markov chain
Monte Carlo method that assumes multivariate normality. The
imputation model included treatment, age at the time of hepa-
toportoenterostomy, BASM syndrome, site, total bilirubin val-
ues at all time points, and baseline levels of alkaline phospha-
tase and γ-glutamyltransferase. Then the composite primary
end point was calculated for each participant in each of the 10
imputed data sets, and each data set was analyzed separately
using the same model as that used for the primary analysis.
Results were combined to account for both within- and be-
tween-imputation variance.
An additional post hoc analysis was performed to ad-
dress new information on the use of steroids in children
younger than 70 days of age at hepatoportoenterostomy.
13
We
dichotomized age at the time of hepatoportoenterostomy to
younger than 70 days and 70 days or older and added an in-
teraction term (treatment × age at hepatoportoenterostomy)
to the model used for the primary end point (replacing age at
hepatoportoenterostomy as a continuous variable). We also
performed subgroup analyses using separate models for the 2
age categories.
Duration of successful bile drainage, survival with the na-
tive liver, and other time-to-event outcomes were summa-
rized using Kaplan-Meier methods and tested using Cox pro-
portional hazards models with the same set of covariates as
for the primary end point. Prevalence of ascites and other di-
chotomous efficacy outcomes were analyzed using the same
model as used for the primary end point. For dichotomous
safety outcomes, the Fisher exact test was used; and for safety
outcomes with multiple recurrences per patient, Poisson re-
gression models were used (incorporating an offset for the pe-
riod of observation from the time of study medication for in-
fectious serious adverse events and no offset for positive blood
cultures among infectious serious adverse events). We lim-
ited the number of inferential tests because of the large num-
ber of potential safety parameters and the expected small in-
cidence of most types of specific adverse events. For
continuous safety outcomes, a random-effects model was used
to assess the effect of treatment on the safety outcomes over
time posthepatoportoenterostomy, with participant as a ran-
dom effect, treatment and time posthepatoportoenteros-
tomy as fixed effects, and a spatial power correlation struc-
ture used to model the correlation among safety outcomes over
time for each participant. All analyses were performed using
SAS version 9.2 (SAS Institute Inc).
Results
Study Population
There were 257 patients with biliary atresia assessed for eligi-
bility and 141 patients consented to participate in START; 140
participants were randomized, with 70 beginning treatment
with steroids and 70 with placebo within 72 hours of hepato-
portoenterostomy (1 participant was not randomized be-
cause he developed fever and other symptoms postopera-
tively that raised safety concerns) (Figure 1). Patients who
consented to the study were comparable with those who did
not consent to participate in START with respect to sex, race,
ethnicity, and age at the time of hepatoportoenterostomy
(eTable 4 in Supplement). There was greater than expected
study retention with 92.9% of participants in the steroids group
and 88.6% in the placebo group either completing the final visit
at 2 years of age, undergoing liver transplantation, or dying.
Demographic and baseline characteristics were compa-
rable between the 2 groups (Table 2). Age at hepatoportoen-
terostomy (mean [SD] age, 2.3 [0.9] months in the steroids
group vs 2.3 [0.8] months in the placebo group) and the per-
centage of participants with the clinical subtype of BASM syn-
drome (3% for steroids vs 4% for placebo) were similar in both
groups. The degree of hyperbilirubinemia was well balanced
between the 2 groups (mean [SD] serum total bilirubin level
of7.5[2.6]mg/dLinsteroidsgroupvs7.9[2.8]mg/dLinpla-
cebo group), as were biochemical indicators of liver injury and
synthetic function.
Figure 1. Enrollment, Randomization, and Follow-up of Participants in
START Through 24 Months of Age
257 Individuals assessed for eligibility
117 Excluded
54 Refused to participate
31 Eligible but not recruited
18 Other reasons
14 Did not meet inclusion
criteria
140 Randomized
70 Included in primary analysis 70 Included in primary analysis
70 Randomized to receive steroids
70 Received steroids as randomized
70 Randomized to receive placebo
70 Received placebo as randomized
5 Lost to follow-up
2 Withdrew
3 Other reasons
10 Discontinued steroids
a
5 Adverse events
2 Withdrew
3 Other reasons
8 Lost to follow-up
4 Withdrew
4 Other reasons
4 Discontinued placebo
a
2 Adverse events
1 Withdrew
1 Other reasons
START indicates Steroids in Biliary Atresia Randomized Trial.
a
Defined as participants who did not receive at least 80% of their
protocol-prescribed study medication.
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Primary End Point
In a modified intention-to-treat analysis, treatment with ste-
roids did not increase the proportion of participants that met
the primary end point of serum total bilirubin level of less than
1.5 mg/dL with the native liver 6 months after hepatoporto-
enterostomy compared with placebo (58.6% [41/70] of ste-
roids group vs 48.6% [34/70] of placebo group; adjusted RR,
1.14 [95% CI, 0.83 to 1.57], P =.43;Table 3). The adjusted ab-
solute risk difference was 8.7% (95% CI, −10.4% to 27.7%), with
the upper bound exceeding the a priori minimal clinically im-
portant difference of 25%.
Sensitivity analyses of the primary end point support the
conclusions of the primary analysis. In a per-protocol analy-
sis of 56 participants in the steroids group and 58 in the pla-
cebo group, the percentage of the participants meeting the pri-
mary end point was similar between the 2 groups (62.5% with
steroids and 51.7% with placebo; RR, 1.14 [95% CI, 0.81-1.61],
P = .44). Using multiple imputation methods with 10 im-
puted data sets, there was no statistically significant differ-
ence between treatment groups (RR, 1.14 [95% CI, 0.77-1.51],
P =.46).
There was no statistically differential effect of steroids by
age at hepatoportoenterostomy when younger than 70 days
or when aged 70 days or older (P = .67, eTable 5 in Supple-
ment). In the subgroup analysis of 76 participants younger than
70 days at the time of hepatoportoenterostomy, 71.8% (28/39)
in the steroids group and 56.8% (21/37) in the placebo group
had good bile drainage at 6 months posthepatoportoenteros-
tomy; however, this difference was not statistically signifi-
cant (RR, 1.23 [95% CI, 0.79-1.89], P = .36). There was also no
statistically significant treatment difference in the 64 older pa-
tients.
Secondary End Points
Survival without liver transplantation for participants treated
with steroids was nearly identical to those who received pla-
cebo, with 58.7% of participants receiving steroids and 59.4%
of those receiving placebo surviving with native liver at 2 years
of age (adjusted hazard ratio [HR], 1.0 [95% CI, 0.6-1.8], P = .99;
Figure 2A).
Of those participants who achieved successful bile drain-
age during the study, treatment with steroids did not signifi-
cantly influence the duration of serum total bilirubin level of
less than 1.5 mg/dL throughout the study (Figure 2B), with
49.4% of participants in the steroids group and 39.8% in the
placebo group with their native liver having successful bile
drainage at 2 years of age (adjusted HR, 0.8 [95% CI, 0.5-1.2],
P = .29). Furthermore, comparison of serum total bilirubin lev-
els at earlier time points and greater than 6 months after hepa-
toportoenterostomy (time of the primary end point) showed
no statistically significant differences between the steroids and
placebo groups (eFigure 1 in Supplement).
The prevalence of ascites did not differ statistically be-
tween the 2 treatment groups. At 12 months of age, ascites was
present in 9.6% (5/52) of the steroids group and 6.4% (3/47) of
the placebo group (adjusted RR, 1.40 [95% CI, 0.62-3.14],
P = .41), and in 2.4% (1/42) and 7.0% (3/43), respectively, at 24
months of age (adjusted RR, 0.30 [95% CI, 0.03-2.92], P = .29;
Table 3).
Safety
Premature discontinuation of steroids due to adverse events
was uncommon (5 participants; 7.1%) and similar to placebo
(2 did not receive at least 80% and 1 discontinued after receiv-
ing >80% for a total of 3 participants [4.3%] discontinuing pla-
cebo; P = .72). In contrast, serious adverse events were com-
mon in both treatment groups (81.4% [57/70] for steroids vs
80.0% [56/70] for placebo; P > .99), as were unexpected and
expected adverse events (Table 4 and eTables 6 and 7 in Supple-
Table 2. Participant Characteristics at Enrollment in the Study
No. (%) of Participants
Steroids
(n = 70)
Placebo
(n = 70)
Male sex 38 (54) 30 (43)
Race
a
White 46 (66) 44 (63)
Black 8 (11) 11 (16)
Other 16 (23) 15 (21)
Ethnicity
a
Hispanic 14 (20) 22 (31)
Non-Hispanic 55 (79) 48 (69)
Refused to respond 1 (1) 0
BASM syndrome 2 (3) 3 (4)
Main types of Ohi classification
system
b
I 5 (7) 8 (11)
II 1(1) 4(6)
III 64 (91) 57 (81)
Mean (SD) Values
Age, mo 2.3 (0.93) 2.3 (0.84)
z Score
Weight −0.8 (1.07) −0.8 (1.06)
Length −0.7 (1.35) −0.6 (1.35)
Total bilirubin, mg/dL 7.5 (2.6) 7.9 (2.8)
γ-Glutamyltransferase, U/L 929 (719) 731 (569)
Alkaline phosphatase, U/L 619 (341) 658 (290)
Alanine aminotransferase, U/L 154 (94) 178 (131)
Aspartate aminotransferase, U/L 236 (215) 235 (122)
White blood cell count, /μL 13 200 (4300) 12 900 (4300)
Hemoglobin, g/dL 10.8 (1.9) 10.4 (1.3)
Platelet count, × 10
3
/μL 473 (179) 441 (164)
International normalized ratio 1.0 (0.2) 1.1 (0.4)
Albumin, g/dL 3.6 (0.5) 3.6 (0.5)
Abbreviation: BASM, biliary atresia splenic malformation.
SI conversion factors: To convert alanine aminotransferase, alkaline
phosphatase, aspartate aminotransferase, and γ-glutamyltransferase to μkat/L,
multiply by 0.0167; albumin and hemoglobin to g/L, multiply by 10; bilirubin to
μmol/L, multiply by 17.104.
a
Self-reported according to categories set by the US Office of Management and
Budget.
b
Anatomical classification of biliary atresia based on the visual appearance of
the extrahepatic biliary tree and the results of intraoperative cholangiography.
Type I represents atresia of the common bile duct, type II extends to the
hepatic duct, and type III extends to the porta hepatis.
19
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ment). However, infants treated with steroids experienced their
first serious adverse events earlier than those receiving pla-
cebo; 37.2% (95% CI, 26.9%-50.0%) of the steroids group
experienced a first serious adverse event by 30 days posthepa-
toportoenterostomy compared with 19.0% (95% CI, 11.5%-
30.4%) of the placebo group (P = .008; Figure 3A). Six partici-
pants in the steroids group compared with 1 in the placebo
group experienced a surgical serious adverse event (eTable 8
in Supplement). In contrast, during the study period follow-
ing completion of drug or placebo administration, there were
no statistically significant differences in the time to first seri-
ous adverse event between the groups (P = .33; Figure 3B).
Figure 2. Kaplan-Meier Analysis of Key Secondary End Points by Treatment Group
1.0
0.8
0.6
0.4
0.2
0
No. of participants
Steroids
Placebo
0
70
70
6
60
57
12
49
45
18
43
38
24
0
2
Proportion of Participants
Time After Hepatoportoenterostomy, mo
Steroids
Steroids
Log-rank P
=
.26Log-rank P
=
.93
Placebo
Placebo
Survival with native liver
A
1.0
0.8
0.6
0.4
0.2
0
No. of participants
Steroids
Placebo
0
70
70
6
41
32
12
37
26
18
29
22
24
0
0
Proportion of Participants
Time After Good Bile Drainage, mo
Duration of good bile drainage
a
B
Vertical tick marks indicate censored observations. Participants were censored
at time of earlier withdrawal from the study or at the age of 24 months.
a
Defined as period when total bilirubin level of less than 1.5 mg/dL achieved
for the first time to the first time total bilirubin increased to 1.5 mg/dL
or higher, participants underwent liver transplant, or died. Participants that
never achieved good bile drainage were considered treatment failures
at time 0.
Table 3. Primary and Secondary End Points
No. (%) of Participants
Adjusted RR (95% CI) Adjusted HR (95% CI) P Value
Steroids
(n = 70)
Placebo
(n = 70)
At 6 mo posthepatoportoenterostomy
a
Total bilirubin <1.5 mg/dL and survival with
native liver
41 (58.6) 34 (48.6) 1.14 (0.83-1.57)
b
.43
Total bilirubin <1.5 mg/dL 43 (61.4) 38 (54.3) 1.14 (0.82-1.58)
c
.44
Survival with native liver 55 (78.6) 52 (74.3) 1.06 (0.82-1.36)
c
.66
Alive 68 (97.1) 68 (97.1) 1.00 (0.94-1.06)
c
.98
At 24 mo posthepatoportoenterostomy
d
Survival with native liver and total bilirubin
<1.5 mg/dL
49.4% 39.8% 0.8 (0.5-1.2) .29
Survival with native liver 58.7% 59.4% 1.0 (0.6-1.8) .99
Prevalence of ascites
e
At age 12 mo (n = 52)
5 (9.6)
(n = 47)
3 (6.4)
1.40 (0.62-3.14) .41
At age 24 mo (n = 42)
1 (2.4)
(n = 43)
3 (7.0)
0.30 (0.03-2.92) .29
Abbreviations: HR, hazard ratio; RR, relative risk.
a
Good bile drainage defined as serum total bilirubin level of less than 1.5 mg/dL
in a participant alive with native liver.
b
An RR greater than 1 indicates benefit of steroids and a P value for treatment
success (good bile drainage) from a log-binomial model with these covariates:
treatment group, age of the infant at hepatoportoenterostomy (continuous
variable), and biliary atresia splenic malformation (BASM) syndrome as fixed
effects and site as a random effect.
c
An RR greater than 1 indicates benefit of steroids and a P value for
components of the primary end point from a log-binomial model with
treatment group as a fixed effect and site as a random effect.
d
Estimate at end of study from the Kaplan-Meier method; the HRs
and P values from a Cox proportional hazards model, controlling for
treatment group, BASM syndrome, and age of the infant at
hepatoportoenterostomy (continuous variable) as fixed effects and
site as a random effect.
e
Among participants with their native liver; the RRs and P values from a
log-binomial model with the covariates: treatment group and age of the infant
at hepatoportoenterostomy (continuous variable) as fixed effects and site as a
random effect.
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There were no significant treatment differences in weight
(posttreatment mean z score range, −0.4 to −1.7 for steroids
group vs 0.1 to −1.2 for placebo group, P = .16) and length (post-
treatment mean z score range, −0.6 to −1.3 for steroids group
vs −0.3 to −1.0 for placebo group, P = .28) or in the number of
infectious serious adverse events (P = .40) during the course
Table 4. Adverse Events (AEs) Throughout the Duration of the Study
Type of AE
No. of AEs
a
P Value
b
Steroids
(n = 70)
Placebo
(n = 70)
Serious
c
57 (81.4)
d
56 (80.0)
d
>.99
Total No. 204 162
Per participant 2.91 2.31
Unexpected
e
36 (51.4)
d
36 (51.4)
d
>.99
Dermatological 12 11
Febrile 21 27
Gastrointestinal 19 19
Infectious viral 25 9
Infectious 38 24
Nutritional 0 6
Pulmonary 32 16
Miscellaneous
f
12 17
Expected
g
44 (62.9)
d
40 (57.1)
d
.61
Bacteremia 31 27
Bone fracture 2 5
Cataracts 0 0
Fungemia 5 2
Gastrointestinal bleeding 23 14
Hyperglycemia 1 0
Hypokalemia 9 4
Impaired wound healing 0 0
Pancreatitis events 0 0
Severe irritability events 3 2
Vaccine-preventable infection 0 1
a
Expressed as number of events
unless otherwise indicated. Any
expected or unexpected AE that
qualified as serious was counted as
such. Details of serious and
unexpected AEs are reported in
eTables 6 and 7, respectively, in
Supplement. A participant may have
had more than 1 AE.
b
Calculated using the Fisher exact test.
c
Defined as any untoward medical
occurrence (whether it was plausibly
related to the index surgery) that
resulted in death, was life
threatening, required inpatient
hospitalization, resulted in persistent
or serious disability or incapacity,
resulted in a congenital anomaly or
birth defect, or constituted a
medically important condition.
d
Expressed as No. (%) of participants.
e
Defined as any other untoward
event that did not qualify as an
expected AE.
f
Included hematologic or hepatic in-
jury and immunological, metabolic,
orthopedic, or urinary events.
g
Defined as common events
attributable to the initial surgical
drainage procedure or the
underlying liver disease.
Figure 3. Time to First Serious Adverse Event
1.0
0.8
0.6
0.4
0.2
0
No. of participants
Steroids
Placebo
0
70
70
30
42
56
60
31
46
90
21
36
120
Proportion of Participants
Time After Hepatoportoenterostomy, d
Time to first serious adverse event while receiving treatment
a
A
1.0
0.8
Log-rank P
=
.33Log-rank P
=
.008
0.6
0.4
0.2
0
No. of participants
Steroids
Placebo
0
70
70
6
29
22
3
37
32
12
19
17
9
25
18
21
0
1
18
16
15
15
18
16
24
Proportion of Participants
Time Following Study Drug Period, mo
Time to first serious adverse event after completion of treatment
b
B
Steroids
Steroids
Placebo
Placebo
Vertical tick marks indicate censored observations.
a
Defined as the time from initiation of study medication to the earliest first
serious adverse event or liver transplantation, exit from the study, or last day
taking study medication (censored). Serious adverse events occurred
significantly earlier in participants receiving steroids compared with placebo.
b
Defined as the time from the end of study medication to the earliest first
serious adverse event after completion of study drug or placebo (event) or
liver transplantation, or exit from the study (censored).
Research Original Investigation High-Dose Corticosteroids for Biliary Atresia
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of the study. An analysis of the occurrence of cholangitis, a
known infectious complication following hepatoportoenter-
ostomy, showed similar proportions of participants surviv-
ing with their native livers with no cholangitis episodes at 24
months of age (eFigure 2 in Supplement).
The proportion of patients with inadequate response to
routine childhood immunizations tended to be higher in the
steroids group (51.5%) than in the placebo group (38.5%), but
was not statistically significant (P = .43; eTable 9 in Supple-
ment).
Discussion
We found that the addition of high-dose steroids following
hepatoportoenterostomy did not result in statistically signifi-
cant differences compared with placebo in the proportion of
patients achieving normalization of total serum bilirubin level
6 months posthepatoportoenterostomy, a short-term bio-
marker of achieving successful bile drainage,
2
although we can-
not exclude a small clinical benefit of steroids. We observed
no statistically significant differences between the 2 groups in
the 2-year survival with the native liver or in the levels of se-
rum total bilirubin after hepatoportoenterostomy at any time
point during the duration of the study. Notably, those receiv-
ing steroids had a shorter time to the development of serious
adverse events while receiving the study drug, raising a po-
tential increase in risks associated with steroid therapy.
The results of this trial differ from previous reports of a
benefit of steroid therapy on bile drainage, survival in biliary
atresia, or both.
6-12
The only other prospective, randomized
placebo-controlled trial, which was published after initiation
of this trial, showed no steroid effect in the percentage of
participants achieving normal bilirubin levels
14
; however,
that study was of smaller size (73 participants vs 140 partici-
pants in our trial), involved fewer centers (2 centers vs 14
centers), used lower doses of steroids (starting at 2 mg/kg/d
vs 4 mg/kg/d), and for a shorter duration (4 weeks vs 13
weeks).
14
Despite theoretical benefits of decreasing tissue inflam-
mation and inducing choleresis,
20-22
the use of high doses of
steroids starting within 3 days after hepatoportoenterostomy
in our study was associated with only an adjusted absolute
treatment difference of 8.7% relative to placebo in the propor-
tion of participants with a serum bilirubin level of less than 1.5
mg/dL at 6 months posthepatoportoenterostomy, which fell
short of the a priori 25% absolute increase deemed clinically
important based on a previous study using a similar steroid
dose after hepatoportoenterostomy.
6
It is possible that the lack
of statistical significance resulted from an overestimation of
the effect size. However, if the true benefit of steroids is as large
as 25%, we cannot exclude a clinical benefit because the 95%
upper confidence bound for the absolute treatment differ-
ence was 27.7%. We also cannot exclude that steroids could re-
sult in clinical harm because the 95% lower confidence bound
for the absolute treatment difference was −10.4%. Secondary
outcomes did not support any clinical benefit because total bil-
irubin values over time showed similar bilirubin levels at ear-
lier (1 and 3 months posthepatoportoenterostomy) and later
(at 12 months of age) time points; and the overall 2-year sur-
vival with native liver was nearly identical in both groups
(58.7% for steroids vs 59% for placebo).
A previous report
14
suggested that steroid therapy was as-
sociated with a greater reduction in serum bilirubin 1 month
after surgery and a higher percentage of children with normal
bilirubin levels at 12 months of age among participants younger
than 70 daysat hepatoportoenterostomy. In a subsequent open-
label trial, these investigators reported that the use of high
doses of steroids in the first month postoperatively in partici-
pants younger than 70 days was associated with lower serum
bilirubin compared with a historical control group and a higher
percentage with clearance of jaundice (66% vs 52%), but no im-
provement in transplant-free survival.
13
This study was lim-
ited by small cohort size, an open-label design, and the na-
ture of subgroup analyses. We found no evidence of an effect
of high doses of steroids in our appropriately sized cohort,
whose average age was 69 days at study enrollment. Addition-
ally, a subgroup analysis focusing on the 76 participants
younger than 70 days at the time of hepatoportoenterostomy
showed no statistically significant effect of age at the time of
surgery on bile drainage between the steroids or placebo
groups.
Safety concerns regarding the use of steroids in infants de-
rive from their known association with a spectrum of severe
adverse events, including immunosuppression and associ-
ated risk of infection, poor wound healing, hyperglycemia, gas-
trointestinal bleeding, poor growth, and inadequate re-
sponse to routine immunizations. With vigilant monitoring and
reporting of adverse events and serious adverse events, both
the steroids and placebo groups were found to have a high in-
cidence of adverse events, indicating that they were most likely
the direct consequences of the severe liver disease typical of
biliary atresia. However, during the active treatment period,
steroid therapy was associated with a significantly earlier on-
set of serious adverse events, among which were complica-
tions at the sites of surgical anastomoses and intestinal per-
foration. These findings differ from previous reports of no
adverse events associated with steroid use in children with bili-
ary atresia after hepatoportoenterostomy,
7-9,12,14
and raise
safety concerns for use of these drugs following surgery.
A limitation of this study is the inclusion of participants
undergoing surgical and medical treatments in different cen-
ters, which introduces a potential influence of the experience
of the care team and variation in the surgical procedure on clini-
cal outcome. Previous reports have suggested that the expe-
rience of the center influences the outcome of hepatoporto-
enterostomy, with better biliary drainage and transplant-free
survival in centers performing higher numbers of this
procedure.
23-25
Other studies have not found a relationship be-
tween the annual caseload of a center and improved
outcome.
26,27
Whether differences relate to experience with
hepatoportoenterostomy or a general expertise in complex
hepatobiliary surgery and management of severe liver dis-
ease in children is not known. To minimize this center effect,
all participating sites followed the same postoperative proto-
col. In addition, we randomized treatments by site and ac-
High-Dose Corticosteroids for Biliary Atresia Original Investigation Research
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counted for the influence of site as a random effect when ana-
lyzing the primary and secondary end points.
Conclusions
Among infants with biliary atresia who have undergone hepa-
toportoenterostomy, high doses of steroids posthepatoporto-
enterostomy did not result in statistically significant treat-
ment differences in bile drainage at 6 months, although a small
clinical benefit could not be excluded. The use of steroids was
associated with an earlier onset of serious adverse events.
Based on the strength of the evidence, the addition of high-
dose steroids as an adjuvant treatment for infants with bili-
ary atresia after hepatoportoenterostomy cannot be recom-
mended.
ARTICLE INFORMATION
Author Affiliations: Cincinnati Children’s Hospital
Medical Center, Cincinnati, Ohio (Bezerra);
University of Michigan, Ann Arbor (Spino, Magee,
Moore); Children’s Hospital of Pittsburgh of UPMC,
Pittsburgh, Pennsylvania (Shneider); UCSF Benioff
Children’s Hospital, San Francisco, California
(Rosenthal); Children’s Hospital Los Angeles and
University of Southern California, Los Angeles
(Wang); Children’s Hospital of Philadelphia,
Philadelphia, Pennsylvania (Erlichman, Haber,
Loomes); Baylor College of Medicine and Texas
Children’s Hospital, Houston (Hertel, Shepherd);
Emory University School of Medicine and Children’s
Healthcare of Atlanta, Atlanta, Georgia (Karpen,
Romero); Mount Sinai School of Medicine, New
York, New York (Kerkar); Indiana University School
of Medicine and Riley Hospital for Children,
Indianapolis (Molleston); Seattle Children’s
Hospital, Seattle, Washington (Murray); Johns
Hopkins University School of Medicine, Baltimore,
Maryland (Schwarz); University of Colorado School
of Medicine and Children’s Hospital Colorado,
Aurora (Suchy, Sokol); Washington University
School of Medicine, St Louis, Missouri (Turmelle);
Lurie Children’s Hospital of Chicago, Chicago, Illinois
(Whitington); National Institutes of Health, National
Institute of Diabetes and Digestive and Kidney
Diseases, Bethesda, Maryland (Sherker, Robuck). Dr
Haber is now with Merck Research Laboratories,
Upper Gwynedd, Pennsylvania. Dr Kerkar is now
with Children’s Hospital Los Angeles and University
of Southern California, Los Angeles.
Author Contributions: Dr Spino had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Bezerra, Magee,
Shneider, Rosenthal, Haber, Karpen, Schwarz,
Shepherd, Suchy, Whitington, Robuck, Sokol.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Bezerra, Spino, Magee,
Shneider, Rosenthal, Wang, Erlichman, Moore,
Sherker, Sokol.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Spino, Magee, Moore.
Obtained funding: Bezerra, Magee, Shneider,
Rosenthal, Wang, Karpen, Kerkar, Loomes,
Molleston, Murray, Romero, Schwarz, Turmelle,
Whitington, Sokol.
Administrative, technical, or material support:
Spino, Magee, Sherker, Robuck.
Study supervision: Bezerra, Spino, Magee, Shneider,
Sherker, Robuck, Sokol.
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Bezerra reported receiving grants from Molecular
Genetics Laboratory of Cincinnati Children’s
Hospital Medical Center outside the submitted
work. Dr Shneider reported serving on data
monitoring committes for Bristol-Myers Squibb and
Vertex on hepatitis B and C, respectively; serving as
associate editor for the American Association for
the Study of Liver Diseases; and receiving royalites
from PMPH-USA for a pediatric gastrointestinal
textbook. Dr Rosenthal reported receiving grants
from Roche, Bristol-Myers Squibb, Vertex, and
Gilead; and receiving consulting fees from General
Electric and Hyperion. Dr Haber reported receiving
grants from the National Institutes of Health during
the conduct of the study while with Children’s
Hospital of Philadelphia, University of Pennsylvania.
In January 2012, Dr Haber changed employment
and now works at Merck in the area of viral
hepatitis; however, her current work does not
overlap or effect any aspect of the article. Dr
Loomes reported receiving book royalties from
Lippincott Williams & Wilkins and payment for an
article on biliary atresia from Up-to-Date.Dr
Molleston reported receiving grants from Schering,
Roche, and Vertex outside the submitted work. Dr
Schwarz reported serving as a consultant to
Roche/Genentech; providing expert testimony for
the State of Pennsylvania; and receiving
institutional grants from the National Institute of
Diabetes, Digestive and Kidney Diseases,
Bristol-Myers Squibb, Roche/Genentech, and
Vertex. Dr Sokol reported receiving grants from
National Institute of Diabetes, Digestive and Kidney
Diseases, National Institutes of Health; receiving
nonfinancial support from Mead Johnson Nutrition
during the conduct of the study; receiving
consulting fees from Yasoo Health Inc, Ikaria
Pharmaceuticals, Roche Products, and Cardax
Pharmaceuticals; and having a patent for use of
antioxidants for treatment of cholestasis licensed to
Yasoo Health Inc. No other disclosures were
reported.
Funding/Support: The following National Institute
of Diabetes, Digestive and Kidney Diseases (NIDDK)
grants supported the START study: DK62503 and
TR000424 (awarded to Johns Hopkins University
School of Medicine), DK62436 and TR000150
(Lurie Children’s Hospital of Chicago), DK62497 and
TR000077 (Cincinnati Children’s Hospital Medical
Center), DK62453 and TR000154 (University of
Colorado School of Medicine and Children’s
Hospital Colorado, Aurora), DK62445 (Mount Sinai
School of Medicine), DK62481 and TR000003
(Children’s Hospital of Philadelphia), DK62466 and
TR000005 (Children’s Hospital of Pittsburgh of
UPMC), DK62500 and TR000004 (UCSF Benioff
Children’s Hospital), DK62452 and TR000448
(Washington University School of Medicine and St
Louis Children’s Hospital), DK62470 (Baylor College
of Medicine and Texas Children’s Hospital,
Houston), DK84575 and TR000423 (Seattle
Children’s Hospital), DK84538 and TR000130
(Children’s Hospital Los Angeles and University of
Southern California), DK84585, DK62470, and
TR000454 (Emory University School of Medicine
and Children’s Healthcare of Atlanta), DK84536 and
TR000007 (Indiana University School of Medicine
and Riley Hospital for Children), and DK62456
(University of Michigan data coordinating center).
The following companies provided support for the
START study, each of which provided formula or
medications as part of a cooperative agreement
with the NIDDK: GlaxoSmithKline supplied
ranitidine; Axcan Pharma US Inc, fat-soluble
vitamins and tocopherol polyethylene glycol
succinate; Axcan Pharma US Inc, ursodiol until
2009; and Mead Johnson Nutrition, Pregestimil.
Role of the Sponsors: The companies listed at the
end of the Funding/Support section were provided
copies of the START protocol prior to the start of
the trial. They did not participate in the design and
conduct of the study; collection, management,
analysis or interpretation of the data; or
preparation, review, or approval of the manuscript;
or decision to submit the manuscript for
publication. These industries were given a copy of
the manuscript before submission for publication as
per policy of the ChiLDREN Network.
Group Information: The Childhood Liver Disease
Research and Education Network (ChiLDREN)
additional investigators are NIDDK: Edward Doo,
MD, Rebecca Torrance, RN, Rebekah van Raaphorst,
MPH, Jay H. Hoofnagle, MD. Johns Hopkins
University School of Medicine: Paul Colombani, MD,
Henry Lau, MD, Kim Kafka, RN, Anitha Devadason.
Lurie Children’s Hospital of Chicago: Riccardo
Superina, MD, Sue Kelly, RN. Cincinnati Children’s
Hospital Medical Center: Greg Tiao, MD, Frederick
Ryckman, MD, Maria Alonso, MD, Jaimie Nathan,
MD, John Bucuvalas, MD, Alexander Miethke, MD,
James Heubi, MD, William F. Balistreri, MD,
Kathleen Campbell, MD, Rohit Kohli, MD, Mike
Leonis, MD, Julie Denlinger, RN, Andrea Ferris.
University of Colorado School of Medicine and
Children’s Hospital Colorado, Aurora: Frederick
Karrer, MD, Cara Mack, MD, Michael R. Narkewicz,
MD, Shikha S. Sundaram, MD, Mark Lovell, MD,
Joan Hines, MPH, Sheryl Faut, RN, Michelle Hite,
MA. Mount Sinai School of Medicine, New York:
Kishore Iyer, MBBS, Ronen Arnon, MD. Children’s
Hospital of Philadelphia: Alan Flake, MD, Elizabeth
Rand, MD. Children’s Hospital of Pittsburgh of
UPMC: Beverly Bernard, RN, Cartland Burns, MD,
Kathryn Bukauskas, RN, Robert Squires, MD, Veena
Venkat, MD. UCSF Benioff Children’s Hospital:
Camille Langlois, MS, Shannon Fleck. Washington
University School of Medicine and St Louis Children’s
Hospital: Patrick Dillon, MD, Frances White, MD,
Alexander Weymann, MD, David Rudnick, MD,
Kathy Harris, Stacy Postma. Baylor College of
Medicine and Texas Children’s Hospital, Houston:
Kimberly Pieplow, MPH, Mary Brandt, MD, Milton
Finegold, MD, Beth Carter, MD, Doug Fishman, MD,
Research Original Investigation High-Dose Corticosteroids for Biliary Atresia
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Val McLin, MD, David Wesson, MD, Zoe Apted, BA,
Alejander DeLaTorre, BBS, Darrell Cass, MD. Seattle
Children’s Hospital: Simon Horslen MB, ChB,
FRCPCH, Evelyn Hsu, MD, Patrick Healey, MD,
Melissa Young, Laura Finn, MD. Children’s Hospital
Los Angeles and University of Southern California:
Cat Goodhue, NP, Daniel Thomas, MD, Sonia
Michael, MD. Emory University School of Medicine
and Children’s Healthcare of Atlanta: Carlos
Abramowsky, MD, Matthew Clifton, MD, Liezl De La
Cruz, BA, Nitika Gupta, MD, DCH, DNM, MRCPCH,
Richard Ricketts, MD, Sundari Sekar, MBBS, DGO,
Bahig Shehata, MD, Miriam Vos, MD, MSPH. Indiana
University School of Medicine and Riley Hospital for
Children: Girish Subbarao, MD, Karen West, MD,
Beth Byam, RN. University of Michigan Data
Coordinating Center: Trivellore Raghunathan, PhD,
James Lopez, MD, Emily Fredericks, PhD, Beverley
Marchant, BSN, Karen Jones, BS, Kristina Slusser,
Yang Casher, MA. Investigators with different
institutional affiliations at the beginning of START:
Benjamin L. Shneider and Frederick J. Suchy
(Mount Sinai School of Medicine, New York, New
York), Saul J. Karpen (Texas Children’s Hospital,
Houston), Ross Shepherd (Washington University
School of Medicine, St Louis, Missouri).
Study Safety Monitor: M. James Lopez, MD,
University of Michigan School of Medicine.
Members of the Data and Safety Monitoring
Board of START: Keith Oldham, MD (Medical
College of Wisconsin, Milwaukee), P. Joan Chesney,
MD (St Jude Children’s Research Hospital,
Memphis, Tennessee), Richard Ehrenkranz, MD
(Yale University School of Medicine, New Haven,
Connecticut), Peter Imrey, PhD (Cleveland Clinic
Foundation, Cleveland, Ohio), Esther J. Israel, MD
(Massachusetts General Hospital for Children,
Boston, Massachusetts).
Additional Contributions: We acknowledge the
current and former members of the National
Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) START and ChiLDREN listed
above who played important roles in the
development of START and enrollment of
participants in the trial. We thank all the ChiLDREN
investigators, the research coordinators, the
participants, and the families who agreed to
participate in this study. We also thank Denise
Lagory, RPh, who was the central research
pharmacist for the trial. No compensation was
received by the individuals for contributions to the
trial outside the NIDDK grant funding.
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High-Dose Corticosteroids for Biliary Atresia Original Investigation Research
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    [Show abstract] [Hide abstract] ABSTRACT: Biliary atresia (BA), a chronic progressive cholestatic disease of infants, is the leading cause for liver transplant in children, especially in patients under two years of age. BA can be successfully treated with the Kasai portoenterostomy; however most patients still require a liver transplant, with up to one half of BA children needing a transplant by age two. In the current pediatric end-stage liver disease system, children with BA face the risk of not receiving a liver in a safe and timely manner. In this review, we discuss a number of possible solutions to help these children. We focus on two general approaches: (1) preventing/delaying need for transplantation, by optimizing the success of the Kasai operation; and (2) expediting transplantation when needed, by performing techniques other than the standard deceased-donor, whole, ABO-matched organ transplant.
    Preview · Article · Aug 2014 · World Journal of Gastroenterology
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    [Show abstract] [Hide abstract] ABSTRACT: Introduction: Biliary atresia (BA) remains one of the most challenging conditions in pediatric hepatology and surgery. The main therapeutic approach is entirely surgical with an initial attempt to restore bile flow and preserve the native liver using a Kasai portoenterostomy (KPE). Liver transplantation is usually offered if this fails and it remains the biggest single indication during childhood.Areas covered: The role of adjuvant medical therapy is still unclear and conclusive evidence of benefit is lacking. The review covers the current evidential basis for corticosteroids, prophylactic antibiotics, and choleretic agents such as ursodeoxycholic acid.Expert opinion: There are obvious areas for improving outcome in BA such as diminishing the time to KPE and concentration of resources to achieve a throughput of > 5 cases/year. High-dose steroids can improve the proportion of infants who clear their jaundice to normal levels by about 10 – 15%. It is not clear whether such improvements can be translated into a reduction in the number of transplants required however.
    Full-text · Article · Oct 2014 · Expert Opinion on Orphan Drugs
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    [Show abstract] [Hide abstract] ABSTRACT: Fat-soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acid. We hypothesized that serum bile acid (SBA) would predict biochemical FSV deficiency better than serum total bilirubin (TB) level in infants with biliary atresia. Infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia after hepatoportoenterostomy were the subjects of this investigation. Infants received standardized FSV supplementation and monitoring of TB, SBA, and vitamin levels at 1, 3, and 6 months. A logistic regression model was used with the binary indicator variable insufficient/sufficient as the outcome variable. Linear and nonparametric correlations were made between specific vitamin measurement levels and either TB or SBA. The degree of correlation for any particular vitamin at a specific time point was higher with TB than with SBA (higher for TB in 31 circumstances vs 3 circumstances for SBA). Receiver operating characteristic curve shows that TB performed better than SBA (area under the curve 0.998 vs 0.821). Including both TB and SBA did not perform better than TB alone (area under the curve 0.998). We found that TB was a better predictor of FSV deficiency than SBA in infants with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic liver diseases, such as progressive familial intrahepatic cholestasis, α-1-antitrypsin deficiency, and Alagille syndrome in which the pathophysiology is dominated by intrahepatic cholestasis, warrants further study.
    Full-text · Article · Dec 2014 · Journal of Pediatric Gastroenterology and Nutrition
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