N-Acetylcysteine in Biliary Atresia After Kasai Portoenterostomy

NCT03499249 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: H-40962135796
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

Biliary atresia (BA) is a devastating liver disease of infancy, characterized by bile duct obstruction leading to liver fibrosis, cirrhosis, and eventual need for transplantation in most cases. BA is treated with Kasai portoenterostomy (KP). KPs can achieve bile drainage and improve outcomes. However, even with standard evidence of "good bile flow," bile flow rarely normalizes completely and liver disease continues to progress. In this study, the investigators test whether intravenous N-acetylcysteine (NAC) can improve bile flow after KP. The rationale is that NAC leads to synthesis of glutathione, which is a powerful stimulator of bile flow. The primary objective is to determine whether NAC normalizes total serum bile acid (TSBA) concentrations within 24 weeks of KP. Achieving normal TSBAs is uncommon with current standard-of-care, and is predicted to be associated with better long-term outcomes. The secondary objectives are to describe how other parameters commonly followed in BA change with NAC therapy, as well as report adverse events occurring with therapy and in the first two years of life. This study follows the "minimax" Phase 2 clinical trial design.

Conditions

Biliary Atresia

Keywords

Biliary Atresia; N-Acetylcysteine; Glutathione; Kasai portoenterostomy; Bile flow; Serum bile acids; Serum bilirubin

Outcome Measures

Primary Outcomes (1)

• Number of Patients With Biliary Atresia (BA) Achieving Total Serum Bile Acids Less Than or Equal to 10 *U*Mol/L Within 24 Weeks of Kasai Portoenterostomy (KP)

  Expected is \~5% of participants based on historical controls (see protocol for summary of historical controls); a higher number is a better outcome

  Within 24 weeks after KP

Secondary Outcomes (3)

• Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Gamma-glutamyltransferase (GGT) Fold, and Conjugated Bilirubin (Bc) Change Above Baseline at 3 Days and 7 Days After KP (During Treatment)

  3 days after KP compared to baseline (before KP); 7 days after KP compared to baseline (before KP)

• Number of Patients Experiencing Sentinel Events in the First 2 Years of Life

  First two years of life

• Number of Patients With Adverse Events Possibly Related to NAC, Including Rash, Urticaria, Pruritus, Tachycardia, Hypotension, Vomiting, Edema, Anaphylaxis, and Intravenous Line Issues

  Within four weeks after KP

Study Arms (1)

N-Acetylcysteine Treatment

EXPERIMENTAL

Will receive continuous intravenous NAC therapy (6.25 mg/kg/hour of 10 mg/ml solution, or 0.625 ml/kg/hour, to give 150 mg/kg/day), starting within 24 hours of completion of KP and lasting for a total of 7 days

Drug: N-Acetyl cysteine

Interventions

N-Acetyl cysteine DRUG

Intravenous NAC therapy (6.25 mg/kg/hour of 10 mg/ml solution, or 0.625 ml/kg/hour, to give 150 mg/kg/day), starting within 24 hours of completion of KP and lasting for a total of 7 days

N-Acetylcysteine Treatment

Eligibility Criteria

• Age: 0 Days - 90 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Age less than or equal to 90 days at time of KP (standard age range in which KPs are performed)
• BA diagnosis made by intraoperative cholangiography and KP performed at Texas Children's Hospital, Texas Medical Center Campus
• Legal guardian(s) sign consent after understanding risks and investigational nature of study

You may not qualify if:

• Decompensated liver disease (INR \>1.3) despite parenteral Vitamin K administration)
• KP not performed for any reason (i.e., normal intraoperative cholangiography, or liver found to be too diseased intraoperatively to proceed with KP)
• Active respiratory infection
• Renal impairment, as defined by having an eGFR \< 60 mL/min/1.73m2 or creatinine clearance \< 60 mL/min (https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-calculators/children-conventional-units)
• Presence of severe concurrent illnesses, such as pulmonary (i.e., bronchopulmonary dysplasia), neurological, cardiovascular, metabolic, endocrine, and renal disorders, which may be congenital or acquired, that would interfere with the conduct and results of the study

Sponsors & Collaborators

• Baylor College of Medicine: lead

Study Sites (1)

Texas Children's Hospital and Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Related Publications (23)

• Ahola T, Lapatto R, Raivio KO, Selander B, Stigson L, Jonsson B, Jonsbo F, Esberg G, Stovring S, Kjartansson S, Stiris T, Lossius K, Virkola K, Fellman V. N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: a randomized controlled trial. J Pediatr. 2003 Dec;143(6):713-9. doi: 10.1067/S0022-3476(03)00419-0.

  PMID: 14657813 BACKGROUND

• Ballatori N, Truong AT. Relation between biliary glutathione excretion and bile acid-independent bile flow. Am J Physiol. 1989 Jan;256(1 Pt 1):G22-30. doi: 10.1152/ajpgi.1989.256.1.G22.

  PMID: 2912148 BACKGROUND

• Ballatori N, Truong AT. Glutathione as a primary osmotic driving force in hepatic bile formation. Am J Physiol. 1992 Nov;263(5 Pt 1):G617-24. doi: 10.1152/ajpgi.1992.263.5.G617.

  PMID: 1443136 BACKGROUND

• Ballatori N, Jacob R, Boyer JL. Intrabiliary glutathione hydrolysis. A source of glutamate in bile. J Biol Chem. 1986 Jun 15;261(17):7860-5.

  PMID: 2872220 BACKGROUND

• Ballatori N, Truong AT, Ma AK, Boyer JL. Determinants of glutathione efflux and biliary GSH/GSSG ratio in perfused rat liver. Am J Physiol. 1989 Mar;256(3 Pt 1):G482-90. doi: 10.1152/ajpgi.1989.256.3.G482.

  PMID: 2564253 BACKGROUND

• 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.

  PMID: 24794368 BACKGROUND

• Flynn DM, Mohan N, McKiernan P, Beath S, Buckels J, Mayer D, Kelly DA. Progress in treatment and outcome for children with neonatal haemochromatosis. Arch Dis Child Fetal Neonatal Ed. 2003 Mar;88(2):F124-7. doi: 10.1136/fn.88.2.f124.

  PMID: 12598501 BACKGROUND

• Galicia-Moreno M, Rodriguez-Rivera A, Reyes-Gordillo K, Segovia J, Shibayama M, Tsutsumi V, Vergara P, Moreno MG, Muriel P. N-acetylcysteine prevents carbon tetrachloride-induced liver cirrhosis: role of liver transforming growth factor-beta and oxidative stress. Eur J Gastroenterol Hepatol. 2009 Aug;21(8):908-14. doi: 10.1097/MEG.0b013e32831f1f3a.

  PMID: 19398917 BACKGROUND

• Galicia-Moreno M, Favari L, Muriel P. Antifibrotic and antioxidant effects of N-acetylcysteine in an experimental cholestatic model. Eur J Gastroenterol Hepatol. 2012 Feb;24(2):179-85. doi: 10.1097/MEG.0b013e32834f3123.

  PMID: 22241216 BACKGROUND

• Jenkins DD, Wiest DB, Mulvihill DM, Hlavacek AM, Majstoravich SJ, Brown TR, Taylor JJ, Buckley JR, Turner RP, Rollins LG, Bentzley JP, Hope KE, Barbour AB, Lowe DW, Martin RH, Chang EY. Fetal and Neonatal Effects of N-Acetylcysteine When Used for Neuroprotection in Maternal Chorioamnionitis. J Pediatr. 2016 Jan;168:67-76.e6. doi: 10.1016/j.jpeds.2015.09.076. Epub 2015 Nov 3.

  PMID: 26545726 BACKGROUND

• Jimenez-Rivera C, Jolin-Dahel KS, Fortinsky KJ, Gozdyra P, Benchimol EI. International incidence and outcomes of biliary atresia. J Pediatr Gastroenterol Nutr. 2013 Apr;56(4):344-54. doi: 10.1097/MPG.0b013e318282a913.

  PMID: 23263590 BACKGROUND

• Kortsalioudaki C, Taylor RM, Cheeseman P, Bansal S, Mieli-Vergani G, Dhawan A. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure. Liver Transpl. 2008 Jan;14(1):25-30. doi: 10.1002/lt.21246.

  PMID: 18161828 BACKGROUND

• Lynch RM, Robertson R. Anaphylactoid reactions to intravenous N-acetylcysteine: a prospective case controlled study. Accid Emerg Nurs. 2004 Jan;12(1):10-5. doi: 10.1016/j.aaen.2003.07.001.

  PMID: 14700565 BACKGROUND

• Mager DR, Marcon M, Wales P, Pencharz PB. Use of N-acetyl cysteine for the treatment of parenteral nutrition-induced liver disease in children receiving home parenteral nutrition. J Pediatr Gastroenterol Nutr. 2008 Feb;46(2):220-3. doi: 10.1097/MPG.0b013e3180653ce6. No abstract available.

  PMID: 18223385 BACKGROUND

• 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.

  PMID: 26725209 BACKGROUND

• Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.

  PMID: 2702835 BACKGROUND

• Soghier LM, Brion LP. Cysteine, cystine or N-acetylcysteine supplementation in parenterally fed neonates. Cochrane Database Syst Rev. 2006 Oct 18;2006(4):CD004869. doi: 10.1002/14651858.CD004869.pub2.

  PMID: 17054219 BACKGROUND

• Sokol RJ, Shepherd RW, Superina R, Bezerra JA, Robuck P, Hoofnagle JH. Screening and outcomes in biliary atresia: summary of a National Institutes of Health workshop. Hepatology. 2007 Aug;46(2):566-81. doi: 10.1002/hep.21790.

  PMID: 17661405 BACKGROUND

• Squires RH, Dhawan A, Alonso E, Narkewicz MR, Shneider BL, Rodriguez-Baez N, Olio DD, Karpen S, Bucuvalas J, Lobritto S, Rand E, Rosenthal P, Horslen S, Ng V, Subbarao G, Kerkar N, Rudnick D, Lopez MJ, Schwarz K, Romero R, Elisofon S, Doo E, Robuck PR, Lawlor S, Belle SH; Pediatric Acute Liver Failure Study Group. Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebo-controlled clinical trial. Hepatology. 2013 Apr;57(4):1542-9. doi: 10.1002/hep.26001. Epub 2013 Feb 4.

  PMID: 22886633 BACKGROUND

• Tahan G, Tarcin O, Tahan V, Eren F, Gedik N, Sahan E, Biberoglu N, Guzel S, Bozbas A, Tozun N, Yucel O. The effects of N-acetylcysteine on bile duct ligation-induced liver fibrosis in rats. Dig Dis Sci. 2007 Dec;52(12):3348-54. doi: 10.1007/s10620-006-9717-9. Epub 2007 Apr 12.

  PMID: 17436097 BACKGROUND

• 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.

  PMID: 25419594 BACKGROUND

• Wiest DB, Chang E, Fanning D, Garner S, Cox T, Jenkins DD. Antenatal pharmacokinetics and placental transfer of N-acetylcysteine in chorioamnionitis for fetal neuroprotection. J Pediatr. 2014 Oct;165(4):672-7.e2. doi: 10.1016/j.jpeds.2014.06.044. Epub 2014 Jul 23.

  PMID: 25064164 BACKGROUND

• Harpavat S, Borovsky KA, Scheurer ME, Cavallo L, Erhiawarie FE, Vasudevan S, Vogel AM, Cerminara D, Tessier EM, Patel KR, Devaraj S, Shneider BL. A phase 2 trial of short-term intravenous N-acetylcysteine in biliary atresia after Kasai portoenterostomy. Hepatol Commun. 2025 Jun 9;9(7):e0729. doi: 10.1097/HC9.0000000000000729. eCollection 2025 Jul 1.

  PMID: 40489761 DERIVED

MeSH Terms

Conditions

Biliary Atresia

Interventions

Acetylcysteine

Condition Hierarchy (Ancestors)

Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Digestive System Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Sanjiv Harpavat
• Organization: Baylor College of Medicine and Texas Children's Hospital

harpavat@bcm.edu

832-824-2099

Study Officials

• Sanjiv Harpavat, MD. PhD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Department of Pediatrics

Model Details: This is a Phase 2 clinical trial using the two-stage "minimax" design described by Simon (Simon, 1989). As a Phase 2 trial, the trial's objective is to determine whether NAC has sufficient biological activity as adjunctive therapy for BA to warrant further study. By choosing the two-stage "minimax" design, we gain two advantages: (i) early termination if the drug is not efficacious, and (ii) using historical controls and therefore an overall smaller sample size to test the hypothesis, i.e., no randomization or control arm. This study design only identifies large effects (response \>20%). For BA this is appropriate, because the field is in need of a robust therapy that can substantially limit liver damage and delay/prevent need for liver transplantation.

Study Record Dates

• First Submitted: April 4, 2018
• First Posted: April 17, 2018
• Study Start: May 18, 2018
• Primary Completion: October 31, 2022
• Study Completion: March 23, 2024
• Last Updated: March 26, 2024
• Results First Posted: January 10, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)