Clinical trial NCT00294684: A Randomized, Double-Blinded, Placebo-Controlled Trial of Corticosteroid Therapy Following Portoenterostomy
Official title: A Randomized, Double-Blinded, Placebo-Controlled Trial of Corticosteroid Therapy Following Portoenterostomy in Infants With Biliary Atresia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Biliary Atresia
Keywords: biliary atresia
hepatoportoenterostomy
corticosteroids
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
First posted: 2006-02-22
Enrollment: 141
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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):

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

Primary outcomes:
measure: The Percentage of Patients With Serum Total Bilirubin <1.5 mg/dL and With Native Liver at 6 Months After Portoenterostomy
timeFrame: Measurements will be made at 6 months after portoenterostomy
Secondary outcomes:
measure: Survival With Native Liver at 24 Months of Age
timeFrame: Measurements will be made at 24 months of age
measure: Serum Total Bilirubin Concentration
timeFrame: Measurements will be made at 3 months after portoenterostomy
measure: Total Bilirubin Concentration at 12 Months
timeFrame: 12 Months post HPE
measure: Total Bilirubin Concentration at 24 Months of Age
timeFrame: At 24 Months of Age
measure: Weight Z-Score
timeFrame: HPE until 24 months of age
measure: Height Z-Score
timeFrame: HPE to age 24 Months
measure: Presence of Ascites at 12 Months
timeFrame: 12 Months
measure: Presence of Ascites at 24 Months
timeFrame: 24 Months
Other outcomes:
measure: Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin E
timeFrame: 24 Months
measure: Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin K
timeFrame: 24 Months
measure: Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin D
timeFrame: 24 Months
measure: Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin A
timeFrame: 24 months
measure: Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin D
timeFrame: 12 Months
measure: Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin K
timeFrame: 12 Months
measure: Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin E
timeFrame: 12 Months
measure: Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin A
timeFrame: 12 months
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Aurora
country: United States
facility: The Children's Hospital
state: Colorado
city: Atlanta
country: United States
facility: Children's Hospital of Atlanta - Emory University
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Riley Children's Hospital
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins School of Medicine
state: Maryland
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Cincinnati
country: United States
facility: Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital at Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: Texas Children's Hospital/Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center
state: Washington
Study officials:
affiliation: Children's Hospital Colorado
name: Ronald Sokol, MD
role: STUDY_CHAIR
affiliation: National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)
name: Ed Doo, MD
role: STUDY_DIRECTOR
affiliation: University of Michigan Medical Center, Ann Arbor
name: John Magee, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Averell Sherker, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.