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

NCT ID: NCT00294684

Last Updated: 2019-10-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 141 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-11-30
• Study Completion Date: 2013-01-31

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):

Conditions

Biliary Atresia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Corticosteroids

Group Type: EXPERIMENTAL

Corticosteroids

Intervention Type: DRUG

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

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

methylprednisolone; prednisolone

Eligibility 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

• Maximum Eligible Age: 6 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ronald Sokol, MD

Role: STUDY_CHAIR

Children's Hospital Colorado

Ed Doo, MD

Role: STUDY_DIRECTOR

National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

John Magee, MD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan Medical Center, Ann Arbor

Averell Sherker, MD

Role: STUDY_DIRECTOR

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Locations

Children's Hospital Los Angeles

Los Angeles, California, United States

University of California at San Francisco

San Francisco, California, United States

The Children's Hospital

Aurora, Colorado, United States

Children's Hospital of Atlanta - Emory University

Atlanta, Georgia, United States

Children's Memorial Hospital

Chicago, Illinois, United States

Riley Children's Hospital

Indianapolis, Indiana, United States

Johns Hopkins School of Medicine

Baltimore, Maryland, United States

Washington University School of Medicine

St Louis, Missouri, United States

Mount Sinai Medical Center

New York, New York, 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

Texas Children's Hospital/Baylor College of Medicine

Houston, Texas, United States

Children's Hospital and Regional Medical Center

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 24794368 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30244988 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29519540 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26725209 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25419594 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 22891232 (View on PubMed)

Related Links

http://www.childrennetwork.org

Children Liver Disease Research and Education Network (ChiLDREN)

Other Identifiers

U01DK062456

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CHILDREN (START) (IND)

Identifier Type: -

Identifier Source: org_study_id