A Randomized, Double-Blinded, Placebo-Controlled Trial of Corticosteroid Therapy Following Portoenterostomy
A Randomized, Double-Blinded, Placebo-Controlled Trial of Corticosteroid Therapy Following Portoenterostomy
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).
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):
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