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

Not Applicable

Completed

Conditions: Biliary Atresia

Interventions: Drug: Placebo
Drug: Corticosteroids

Registration Number: NCT00294684

Lead Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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):

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 141

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	-
Corticosteroids	Corticosteroids	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Survival With Native Liver at 24 Months of Age	Measurements will be made at 24 months of age
Total Bilirubin Concentration at 24 Months of Age	At 24 Months of Age
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 24 Months	24 Months
Serum Total Bilirubin Concentration	Measurements will be made at 3 months after portoenterostomy
Total Bilirubin Concentration at 12 Months	12 Months post HPE
Presence of Ascites at 12 Months	12 Months

Trial Locations

Locations (14): Texas Children's Hospital/Baylor College of Medicine
🇺🇸
Houston, Texas, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Children's Hospital and Regional Medical Center
🇺🇸
Seattle, Washington, United States
University of California at San Francisco
🇺🇸
San Francisco, California, United States
Children's Memorial Hospital
🇺🇸
Chicago, Illinois, United States
Mount Sinai Medical Center
🇺🇸
New York, New York, United States
Riley Children's Hospital
🇺🇸
Indianapolis, Indiana, United States
Johns Hopkins School of Medicine
🇺🇸
Baltimore, Maryland, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Children's Hospital at Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
Children's Hospital of Atlanta - Emory University
🇺🇸
Atlanta, Georgia, United States
The Children's Hospital
🇺🇸
Aurora, Colorado, United States