Tolerability of Enteral NAC in Infants

NCT06260566 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: H-52570
• Study Type: interventional
• Target: 12
• Locations: 0 countries
• Sites: N/A

Brief Summary

Biliary atresia (BA) is a neonatal liver disease characterized by impaired bile flow and is the most common indication for pediatric liver transplantation. BA can be treated with the Kasai portoenterostomy (KP), a procedure that attempts to restore bile flow and slow disease progression. However, success of the KP procedure is quite variable, and lack of adjuvant medical therapies following KP is a major gap in pediatric hepatology. This study begins to explore oral N-acetylcysteine (NAC) as a potential medical therapy in BA by determining whether an oral formulation can be given to infants. The primary objective is to determine tolerability of the oral NAC formulation. The primary outcome is tolerating at least 3 out of 4 total doses without emesis. The Bayesian Optimal Interval Design (BOIN) trial design will be used to determine the maximum tolerated dose of oral NAC. Our secondary objective is to assess palatability of the oral NAC formulation by comparing facial expressions when taking oral NAC versus other medications commonly given to cholestatic infants.

Conditions

Biliary Atresia

Keywords

Biliary Atresia; N-Acetylcysteine; glutathione; bile flow; serum bilirubin; serum bile acids; cholestasis

Outcome Measures

Primary Outcomes (1)

• No emesis within 30 minutes of administration of at least 3 of 4 total doses of oral NAC

  No emesis with administration of at least 3 of 4 total doses of oral NAC

  within 30 minutes

Secondary Outcomes (2)

• Oral NAC palatability compared to clinically indicated medications using the facial expression scale

  at the time of adminsitration

• Oral NAC-specific adverse event evaluation

  28 days

Study Arms (1)

Infants with Biliary Atresia

EXPERIMENTAL

* Administering applesauce alone * Administering applesauce plus NAC (for infants who tolerate applesauce alone)

Drug: N-Acetylcysteine

Interventions

N-Acetylcysteine DRUG

This is a phase 1 study of tolerance of a novel delivery method of oral NAC medication in infants with biliary atresia. The study consists of two parts: * Administering applesauce alone (lead-in): In study days 1-2, infants will receive one infant spoon (approximately ½ teaspoon) of plain applesauce by mouth twice a day. If the infant tolerates 3-4 of 4 total doses without emesis, the infant will progress to the final two days of the study. * Administering applesauce plus NAC (for infants who tolerate applesauce in study days 1-2): In study days 3-4, infants will receive an individualized dose of powdered oral NAC mixed into one infant spoon of applesauce by mouth twice a day for a maximum of four doses of NAC medication. 4 doses will be trialed: 150 mg/kg/day, 240 mg/kg/day, 330 mg/kg/day, and 420 mg/kg/day using BOIN study design for dose escalation.

Also known as: NAC

Infants with Biliary Atresia

Eligibility Criteria

• Age: 122 Days - 273 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• days of life at time of enrollment
• Confirmed diagnosis of biliary atresia based on intraoperative cholangiogram
• Able to tolerate oral nutrition and medications and not on continuous tube feeds
• Anticipated inpatient admission of at least 4 days
• Legal guardian(s) consent to study enrollment after understanding the risks and investigational nature of the study

You may not qualify if:

• Gestational age of \<32 weeks at birth
• Inability or contraindication to taking oral nutrition
• Neonatal intensive care unit admission
• Short bowel, or other malabsorptive, syndrome
• Decompensated liver disease (INR \> 1.3 despite vitamin K administration)
• Active respiratory infection
• Severe concurrent illnesses that would interfere with the conduct and/or results of the study
• Concurrent participation in another drug trial

Sponsors & Collaborators

• Sanjiv Harpavat: lead
• Baylor College of Medicine: collaborator

Related Publications (26)

• Squires RH, Ng V, Romero R, Ekong U, Hardikar W, Emre S, Mazariegos GV. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology. 2014 Jul;60(1):362-98. doi: 10.1002/hep.27191. No abstract available.

  PMID: 24782219 BACKGROUND

• Bezerra JA, Wells RG, Mack CL, Karpen SJ, Hoofnagle JH, Doo E, Sokol RJ. Biliary Atresia: Clinical and Research Challenges for the Twenty-First Century. Hepatology. 2018 Sep;68(3):1163-1173. doi: 10.1002/hep.29905.

  PMID: 29604222 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

• Karrer FM, Price MR, Bensard DD, Sokol RJ, Narkewicz MR, Smith DJ, Lilly JR. Long-term results with the Kasai operation for biliary atresia. Arch Surg. 1996 May;131(5):493-6. doi: 10.1001/archsurg.1996.01430170039006.

  PMID: 8624194 BACKGROUND

• Sundaram SS, Mack CL, Feldman AG, Sokol RJ. Biliary atresia: Indications and timing of liver transplantation and optimization of pretransplant care. Liver Transpl. 2017 Jan;23(1):96-109. doi: 10.1002/lt.24640.

  PMID: 27650268 BACKGROUND

• Tessier MEM, Shneider BL, Brandt ML, Cerminara DN, Harpavat S. A phase 2 trial of N-Acetylcysteine in Biliary atresia after Kasai portoenterostomy. Contemp Clin Trials Commun. 2019 May 2;15:100370. doi: 10.1016/j.conctc.2019.100370. eCollection 2019 Sep.

  PMID: 31193715 BACKGROUND

• Luo Z, Shivakumar P, Mourya R, Gutta S, Bezerra JA. Gene Expression Signatures Associated With Survival Times of Pediatric Patients With Biliary Atresia Identify Potential Therapeutic Agents. Gastroenterology. 2019 Oct;157(4):1138-1152.e14. doi: 10.1053/j.gastro.2019.06.017. Epub 2019 Jun 19.

  PMID: 31228442 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

• 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

• 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

• 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

• 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

• 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

• 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

• Barrier A, Williams DJ, Connelly M, Creech CB. Frequency of peripherally inserted central catheter complications in children. Pediatr Infect Dis J. 2012 May;31(5):519-21. doi: 10.1097/INF.0b013e31824571b0.

  PMID: 22189533 BACKGROUND

• Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 2007 Aug;7(4):355-9. doi: 10.1016/j.coph.2007.04.005. Epub 2007 Jun 29.

  PMID: 17602868 BACKGROUND

• AbbVie Inc. "Creon (Pancrelipase) Delayed-Release Capsule: Official Website - Tips for Giving Enzymes to Your Baby." 2017, https://www.creon.com/infants/infantdosing. Accessed 2022.

  BACKGROUND

• Yuan Y, Hess KR, Hilsenbeck SG, Gilbert MR. Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials. Clin Cancer Res. 2016 Sep 1;22(17):4291-301. doi: 10.1158/1078-0432.CCR-16-0592. Epub 2016 Jul 12.

  PMID: 27407096 BACKGROUND

• Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988 Dec 15;319(24):1557-62. doi: 10.1056/NEJM198812153192401.

  PMID: 3059186 BACKGROUND

• Rumack BH, Peterson RC, Koch GG, Amara IA. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981 Feb 23;141(3 Spec No):380-5. doi: 10.1001/archinte.141.3.380.

  PMID: 7469629 BACKGROUND

• Viscomi C, Burlina AB, Dweikat I, Savoiardo M, Lamperti C, Hildebrandt T, Tiranti V, Zeviani M. Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy. Nat Med. 2010 Aug;16(8):869-71. doi: 10.1038/nm.2188. Epub 2010 Jul 25.

  PMID: 20657580 BACKGROUND

• Tirouvanziam R, Conrad CK, Bottiglieri T, Herzenberg LA, Moss RB, Herzenberg LA. High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4628-33. doi: 10.1073/pnas.0511304103. Epub 2006 Mar 13.

  PMID: 16537378 BACKGROUND

• Hardan AY, Fung LK, Libove RA, Obukhanych TV, Nair S, Herzenberg LA, Frazier TW, Tirouvanziam R. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry. 2012 Jun 1;71(11):956-61. doi: 10.1016/j.biopsych.2012.01.014. Epub 2012 Feb 18.

  PMID: 22342106 BACKGROUND

• Seattle Children's Hospital. "Medicine - Refusal to Take." 2022. https://www.seattlechildrens.org/conditions/a-z/medicine-refusal-to-take/. Accessed 2022.

  BACKGROUND

• Acetylcysteine solution, USP10% and 20%teartop vials. labeling.pfizer.com. (n.d.). https://labeling.pfizer.com/ShowLabeling.aspx?id=4101

  BACKGROUND

• Mullins ME, Schmidt RU Jr, Jang TB. What is the rate of adverse events with intravenous versus oral N-acetylcysteine in pediatric patients? Ann Emerg Med. 2004 Nov;44(5):547-8; author reply 548-9. doi: 10.1016/j.annemergmed.2004.03.051. No abstract available.

  PMID: 15523751 BACKGROUND

MeSH Terms

Conditions

Biliary Atresia; Cholestasis

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

Study Officials

• Sanjiv Harpavat, M.D., PH.D.

  Baylor College of Medicine - Texas Children's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sanjiv Harpavat, M.D., PH.D.

CONTACT

832-824-3896; harpavat@bcm.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Masking Details: N/A. No Masking
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Model Details: The study consists of two parts: * Administering applesauce alone (lead-in): In study days 1-2, infants will receive one infant spoon (approximately ½ teaspoon) of plain applesauce by mouth twice a day. If the infant tolerates 3-4 of 4 total doses without emesis, the infant will progress to the final two days of the study. * Administering applesauce plus NAC (for infants who tolerate applesauce in study days 1-2): In study days 3-4, infants will receive an individualized dose of powdered oral NAC mixed into one infant spoon of applesauce by mouth twice a day for a maximum of four doses of NAC medication.

Study Record Dates

• First Submitted: February 7, 2024
• First Posted: February 15, 2024
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2030
• Study Completion (Estimated): October 1, 2031
• Last Updated: March 4, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share