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

Biliary Atresia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00294684
• Other study ID #: CHILDREN (START) (IND)
• Secondary ID: U01DK062456
• Status: Completed
• Phase: N/A
• Start date: November 2005
• Est. completion date: January 2013

Study information

• Verified date: October 2019
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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):

Recruitment information / eligibility

• Status: Completed
• Enrollment: 141
• Est. completion date: January 2013
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 6 Months

Eligibility

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

Related Conditions & MeSH terms

• Biliary Atresia

Intervention

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
• 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

Locations

Country	Name	City	State
United States	Children's Hospital of Atlanta - Emory University	Atlanta	Georgia
United States	The Children's Hospital	Aurora	Colorado
United States	Johns Hopkins School of Medicine	Baltimore	Maryland
United States	Children's Memorial Hospital	Chicago	Illinois
United States	Children's Hospital Medical Center	Cincinnati	Ohio
United States	Texas Children's Hospital/Baylor College of Medicine	Houston	Texas
United States	Riley Children's Hospital	Indianapolis	Indiana
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Mount Sinai Medical Center	New York	New York
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital at Pittsburgh	Pittsburgh	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of California at San Francisco	San Francisco	California
United States	Children's Hospital and Regional Medical Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin K	Vitamin K sufficiency is measured by INR (international normalized ratio)	24 Months
Other	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
Other	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
Other	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
Other	Serum Biomarkers of Sufficiency of Fat-soluble Vitamins - Vitamin K	Vitamin K sufficiency is measured by INR (international normalized ratio)	12 Months
Other	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
Other	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
Primary	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	Survival With Native Liver at 24 Months of Age		Measurements will be made at 24 months of age
Secondary	Serum Total Bilirubin Concentration		Measurements will be made at 3 months after portoenterostomy
Secondary	Total Bilirubin Concentration at 12 Months		12 Months post HPE
Secondary	Total Bilirubin Concentration at 24 Months of Age		At 24 Months of Age
Secondary	Weight Z-Score	weight for age Z-score (in subjects without ascites) over the course of the study	HPE until 24 months of age
Secondary	Height Z-Score	Height by Age Z-score over the course of the study	HPE to age 24 Months
Secondary	Presence of Ascites at 12 Months		12 Months
Secondary	Presence of Ascites at 24 Months		24 Months

External Links

•   Children Liver Disease Research and Education Network (ChiLDREN)