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

A Randomized, Double-Blinded, Placebo-Controlled Trial of Corticosteroid Therapy Following Portoenterostomy in Infants With Biliary Atresia

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).

Study Overview

• Status: Completed
• Conditions: Biliary Atresia
• Intervention / Treatment: Drug: Corticosteroids; Drug: Placebo

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):

• Study Type: Interventional
• Enrollment (Actual): 141
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • San Francisco, California, United States, 94143
      • University of California at San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Hospital of Atlanta - Emory University
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins School of Medicine
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital at Pittsburgh
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital/Baylor College of Medicine
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: 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
Experimental: Corticosteroids	Drug: 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; Other Names: prednisolone; methylprednisolone

What is the study measuring?

Primary Outcome Measures

Outcome 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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 12 Months		12 Months post HPE
Total Bilirubin Concentration at 24 Months of Age		At 24 Months of Age
Weight Z-Score	weight for age Z-score (in subjects without ascites) over the course of the study	HPE until 24 months of age
Height Z-Score	Height by Age Z-score over the course of the study	HPE to age 24 Months
Presence of Ascites at 12 Months		12 Months
Presence of Ascites at 24 Months		24 Months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin E	Vitamin E sufficiency is measured as the ratio of serum vitamin E/total lipids	24 Months
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin K	Vitamin K sufficiency is measured by INR (international normalized ratio)	24 Months
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin D	Vitamin D sufficiency is measured by the serum level of 25-hydroxy vitamin D	24 Months
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	24 months
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin D	Vitamin D sufficiency is measured by the serum level of 25-hydroxy vitamin D	12 Months
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin K	Vitamin K sufficiency is measured by INR (international normalized ratio)	12 Months
Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin E	Vitamin E sufficiency is measured as the ratio of serum vitamin E/total lipids	12 Months
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	12 months

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Study Chair: Ronald Sokol, MD, Children's Hospital Colorado; Study Director: Ed Doo, MD, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK); Principal Investigator: John Magee, MD, University of Michigan Medical Center, Ann Arbor

Publications and helpful links

General Publications

• Ng VL, Sorensen LG, Alonso EM, Fredericks EM, Ye W, Moore J, Karpen SJ, Shneider BL, Molleston JP, Bezerra JA, Murray KF, Loomes KM, Rosenthal P, Squires RH, Wang K, Arnon R, Schwarz KB, Turmelle YP, Haber BH, Sherker AH, Magee JC, Sokol RJ; Childhood Liver Disease Research Network (ChiLDReN). Neurodevelopmental Outcome of Young Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study. J Pediatr. 2018 May;196:139-147.e3. doi: 10.1016/j.jpeds.2017.12.048. Epub 2018 Mar 5.
• Shneider BL, Magee JC, Karpen SJ, Rand EB, Narkewicz MR, Bass LM, Schwarz K, Whitington PF, Bezerra JA, Kerkar N, Haber B, Rosenthal P, Turmelle YP, Molleston JP, Murray KF, Ng VL, Wang KS, Romero R, Squires RH, Arnon R, Sherker AH, Moore J, Ye W, Sokol RJ; Childhood Liver Disease Research Network (ChiLDReN). Total Serum Bilirubin within 3 Months of Hepatoportoenterostomy Predicts Short-Term Outcomes in Biliary Atresia. J Pediatr. 2016 Mar;170:211-7.e1-2. doi: 10.1016/j.jpeds.2015.11.058. Epub 2015 Dec 24.
• Bezerra JA, Spino C, Magee JC, Shneider BL, Rosenthal P, Wang KS, Erlichman J, Haber B, Hertel PM, Karpen SJ, Kerkar N, Loomes KM, Molleston JP, Murray KF, Romero R, Schwarz KB, Shepherd R, Suchy FJ, Turmelle YP, Whitington PF, Moore J, Sherker AH, Robuck PR, Sokol RJ; Childhood Liver Disease Research and Education Network (ChiLDREN). Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial. JAMA. 2014 May 7;311(17):1750-9. doi: 10.1001/jama.2014.2623.
• Alonso EM, Ye W, Hawthorne K, Venkat V, Loomes KM, Mack CL, Hertel PM, Karpen SJ, Kerkar N, Molleston JP, Murray KF, Romero R, Rosenthal P, Schwarz KB, Shneider BL, Suchy FJ, Turmelle YP, Wang KS, Sherker AH, Sokol RJ, Bezerra JA, Magee JC; ChiLDReN Network. Impact of Steroid Therapy on Early Growth in Infants with Biliary Atresia: The Multicenter Steroids in Biliary Atresia Randomized Trial. J Pediatr. 2018 Nov;202:179-185.e4. doi: 10.1016/j.jpeds.2018.07.002. Epub 2018 Sep 21.
• Venkat VL, Shneider BL, Magee JC, Turmelle Y, Arnon R, Bezerra JA, Hertel PM, Karpen SJ, Kerkar N, Loomes KM, Molleston J, Murray KF, Ng VL, Raghunathan T, Rosenthal P, Schwartz K, Sherker AH, Sokol RJ, Teckman J, Wang K, Whitington PF, Heubi JE; Childhood Liver Disease Research and Education Network. Total serum bilirubin predicts fat-soluble vitamin deficiency better than serum bile acids in infants with biliary atresia. J Pediatr Gastroenterol Nutr. 2014 Dec;59(6):702-7. doi: 10.1097/MPG.0000000000000547.
• Shneider BL, Magee JC, Bezerra JA, Haber B, Karpen SJ, Raghunathan T, Rosenthal P, Schwarz K, Suchy FJ, Kerkar N, Turmelle Y, Whitington PF, Robuck PR, Sokol RJ; Childhood Liver Disease Research Education Network (ChiLDREN). Efficacy of fat-soluble vitamin supplementation in infants with biliary atresia. Pediatrics. 2012 Sep;130(3):e607-14. doi: 10.1542/peds.2011-1423. Epub 2012 Aug 13.

Helpful Links

• Children Liver Disease Research and Education Network (ChiLDREN)

Study record dates

Study Major Dates

• Study Start: November 1, 2005
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): January 1, 2013

Study Registration Dates

• First Submitted: February 21, 2006
• First Submitted That Met QC Criteria: February 21, 2006
• First Posted (Estimate): February 22, 2006

Study Record Updates

• Last Update Posted (Actual): October 22, 2019
• Last Update Submitted That Met QC Criteria: October 11, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: corticosteroids; biliary atresia; hepatoportoenterostomy
• Additional Relevant MeSH Terms: Digestive System Diseases; Congenital Abnormalities; Biliary Tract Diseases; Bile Duct Diseases; Digestive System Abnormalities; Biliary Atresia; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone
• Other Study ID Numbers: CHILDREN (START) (IND); U01DK062456 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Archived dataset will be entered into NIDDK Repository
• IPD Sharing Time Frame: Within six months of the publication date for the primary outcome publication or within two years of the date that the database is locked for analysis, whichever occurs first.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE