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

• ClinicalTrials.gov Identifier: NCT00294684
• Recruitment Status: Completed
• First Posted: February 22, 2006
• Results First Posted: May 5, 2017
• Last Update Posted: October 22, 2019
• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Biliary Atresia	Drug: Corticosteroids; Drug: Placebo	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 141 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blinded, Placebo-Controlled Trial of Corticosteroid Therapy Following Portoenterostomy in Infants With Biliary Atresia
• Study Start Date: November 2005
• Actual Primary Completion Date: January 2013
• Actual Study Completion Date: January 2013

Arms and Interventions

Arm	Intervention/treatment
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: methylprednisolone; prednisolone
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

Outcome Measures

Primary Outcome Measures :

1. 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 ]

Secondary Outcome Measures :

1. Survival With Native Liver at 24 Months of Age [ Time Frame: Measurements will be made at 24 months of age ]
2. Serum Total Bilirubin Concentration [ Time Frame: Measurements will be made at 3 months after portoenterostomy ]
3. Total Bilirubin Concentration at 12 Months [ Time Frame: 12 Months post HPE ]
4. Total Bilirubin Concentration at 24 Months of Age [ Time Frame: At 24 Months of Age ]
5. Weight Z-Score [ Time Frame: HPE until 24 months of age ]
   weight for age Z-score (in subjects without ascites) over the course of the study
6. Height Z-Score [ Time Frame: HPE to age 24 Months ]
   Height by Age Z-score over the course of the study
7. Presence of Ascites at 12 Months [ Time Frame: 12 Months ]
8. Presence of Ascites at 24 Months [ Time Frame: 24 Months ]

Other Outcome Measures:

1. Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin E [ Time Frame: 24 Months ]
   Vitamin E sufficiency is measured as the ratio of serum vitamin E/total lipids
2. Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin K [ Time Frame: 24 Months ]
   Vitamin K sufficiency is measured by INR (international normalized ratio)
3. Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin D [ Time Frame: 24 Months ]
   Vitamin D sufficiency is measured by the serum level of 25-hydroxy vitamin D
4. Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin A [ Time Frame: 24 months ]
   Vitamin A sufficiency is defined as the molar ratio of serum retinol/retinol binding protein
5. Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin D [ Time Frame: 12 Months ]
   Vitamin D sufficiency is measured by the serum level of 25-hydroxy vitamin D
6. Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin K [ Time Frame: 12 Months ]
   Vitamin K sufficiency is measured by INR (international normalized ratio)
7. Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin E [ Time Frame: 12 Months ]
   Vitamin E sufficiency is measured as the ratio of serum vitamin E/total lipids
8. Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin A [ Time Frame: 12 months ]
   Vitamin A sufficiency is measured by the molar ratio of serum retinol/retinol binding protein

Eligibility Criteria

• Ages Eligible for Study: up to 6 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Children's Hospital Los Angeles

Los Angeles, California, United States, 90027

University of California at San Francisco

San Francisco, California, United States, 94143

United States, Colorado

The Children's Hospital

Aurora, Colorado, United States, 80045

United States, Georgia

Children's Hospital of Atlanta - Emory University

Atlanta, Georgia, United States, 30322

United States, Illinois

Children's Memorial Hospital

Chicago, Illinois, United States, 60614

United States, Indiana

Riley Children's Hospital

Indianapolis, Indiana, United States, 46202

United States, Maryland

Johns Hopkins School of Medicine

Baltimore, Maryland, United States, 21287

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, New York

Mount Sinai Medical Center

New York, New York, United States, 10029

United States, Ohio

Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Children's Hospital at Pittsburgh

Pittsburgh, Pennsylvania, United States, 15213

United States, Texas

Texas Children's Hospital/Baylor College of Medicine

Houston, Texas, United States, 77030

United States, Washington

Children's Hospital and Regional Medical Center

Seattle, Washington, United States, 98105

Sponsors and Collaborators

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
• Study Director: Averell Sherker, MD; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

More Information

Additional Information:

Children Liver Disease Research and Education Network (ChiLDREN) 

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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. Epub 2012 Aug 13.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT00294684
• Other Study ID Numbers: CHILDREN (START) (IND); U01DK062456 ( U.S. NIH Grant/Contract )
• First Posted: February 22, 2006
• Results First Posted: May 5, 2017
• Last Update Posted: October 22, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Archived dataset will be entered into NIDDK Repository
• Supporting Materials: Study Protocol; Analytic Code
• 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.
• URL: https://repository.niddk.nih.gov/studies/start/?query=start

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

biliary atresia; hepatoportoenterostomy; corticosteroids

Additional relevant MeSH terms:

Biliary Atresia; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Digestive System Abnormalities; Congenital Abnormalities; Methylprednisolone; Prednisolone; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents