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

Study Description

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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

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Study Design

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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

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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

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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

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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

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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
St 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

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Additional Information:

Children Liver Disease Research and Education Network (ChiLDREN) 

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.

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.

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 History of Changes
Other Study ID Numbers:	CHILDREN (START) (IND)
First Posted:	February 22, 2006
Results First Posted:	May 5, 2017
Last Update Posted:	May 5, 2017
Last Verified:	March 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	Archived dataset will be entered into NIDDK Repository

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; Prednisolone acetate; Methylprednisolone acetate; Prednisolone; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone hemisuccinate; Prednisolone phosphate	Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Neuroprotective Agents; Protective Agents