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.

Biliary atresia (BA), a neonatal liver disease characterized by impaired bile flow, is the most common indication for pediatric liver transplantation. The only identified treatment option other than liver transplant is a Kasai portoenterostomy (KP). This surgical procedure directly connects the intestines to the liver in an attempt to restore bile flow. By restoring bile flow and decreasing bile retention, the KP's goal is to slow disease progression. Restored bile flow within the first 3-6 months post-operatively is associated with better clinical outcomes. Unfortunately the success of the procedure is quite variable with one-third of KPs never achieving sufficient bile flow to slow disease progression and the remaining one-third never achieving any bile flow. These patients go on to require liver transplantation with 60% of liver transplants in infants <1 year of age and 30% of all pediatric liver transplants being performed for BA. The lack of adjuvant medical therapies for KP is a major gap in the current field of pediatric hepatology.

NAC is an attractive potential therapy for BA, because NAC is the precursor for glutathione. Glutathione in turn addresses much of the problematic pathophysiology in biliary atresia including poor bile flow, oxidative damage, and inflammation. Preclinical studies have demonstrated that glutathione in the form of NAC therapy has been shown to improve liver histology in various rodent models of cholestasis and biliary atresia. In a recent study by Luo et al, rotavirus-induced mouse models of biliary atresia were injected with saline for placebo or 150 mg/kg/day NAC. The mice that received NAC demonstrated better weight gain, decreased hepatic injury, and improved survival when compared to mice that received saline. Liver biopsies demonstrate decreased inflammation, epithelial injury, and portal inflammation in the RRV-induced BA mice that received NAC (RRV+NAC; right two panels) when compared to RRV-induced BA mice that received placebo saline injections (RRV+PBS; middle two panels). These results support the notion that glutathione may reduce inflammation and fibrosis, perhaps by preventing oxidative damage caused by retained bile.

Luo et al also reported clinical data that demonstrated cholestatic infants with upregulation of genes related to regulating glutathione metabolism had improved survival rates at two years of age, lending further support to the hypothesis that glutathione can improve outcomes in cholestatic infants. There is a list of gene groups from livers of patients with biliary atresia at time of diagnosis that were discovered to be upregulated in patients that demonstrated improved survival with their native liver at two years of age. Notably genes for glutathione metabolism, glutathione biosynthesis, and glutathione conjugation were all upregulated in the patients with improved survival with their native liver. This suggests that increased glutathione is associated with improved survival in patients with BA.

An important advantage of NAC therapy is that it is been shown to be safe in both pre-term and term infants with other conditions such as increased risk for chorioamnionitis. Prolonged intravenous (IV) NAC therapy has also been demonstrated to be safe in infants with other liver conditions such as cholestasis secondary to total parental nutrition. Additionally, IV NAC was given to infants and children with non-acetaminophen induced liver failure in similar doses as proposed in this study and there was no significant difference in rates of adverse events between the treatment and control groups.

While NAC is a promising therapeutic agent post-KP that has been demonstrated to be safe in multiple previous studies, the only study to date investigating NAC in BA used an IV formulation (study performed at Texas Children's Hospital, data analysis in process). An IV formulation is the logical choice when infants are on bowel rest immediately post-KP and remain hospitalized with IV access. However, discharging a patient home with indwelling venous access poses a substantial infection risk with up to 30% of peripherally inserted central catheters having at least one complication. Transitioning to oral NAC prior to discharge home would allow for longer duration of therapy without the potential consequences of indwelling venous access, however oral NAC has a sulfuric, unpleasant taste.

To address the unpleasant taste of oral NAC, the investigators plan to utilize novel powdered NAC - which has a less sulfuric flavor and odor when compared to typical NAC solution - mixed into a small amount of applesauce just prior to oral administration. This method of medication administration is frequently utilized to give pancreatic enzymes to infants with cystic fibrosis as young as one week of age. Additionally, as the goal of this study is to determine if oral NAC can be safely administered to relatively well infants with BA that will be starting purees around 4-6 months of age, the risk of choking and aspiration should be no greater than baseline.

These infants will be captured for the 2-4 day study when admitted to the hospital for other indications such as fever, concern for cholangitis, or expedited liver transplantation evaluation. These hospitalizations are frequent, and infants typically are stable and do not require intensive care unit care. As infants with BA are typically initially very clinically stable with a slow decline in synthetic liver function and overall health during the first year of life, most infants eligible for study inclusion will be relatively healthy and eating by mouth at time of being approached for study inclusion. This will also eliminate any increased risk of choking or aspiration.

The ultimate goal of this trial is to demonstrate that infants with biliary atresia are able to tolerate oral NAC prior to proposing and conducting a prolonged efficacy trial of NAC in relatively well infants with BA in an ambulatory setting.

The investigators hypothesize that infants will tolerate this novel administration of oral NAC. To test this hypothesis, the investigators will perform a two-part study. In the first part, applesauce will be administered and its tolerability assessed. In the second part, only those infants who tolerated applesauce will receive up to four total doses of oral applesauce plus NAC medication over the course of two days. The primary outcome will be measured only in infants taking applesauce plus NAC and based on total number of doses without emesis (defined as forceful oral expulsion of any milk/formula, medication, or gastric content containing liquid). The secondary outcomes are infants' facial expressions when taking applesauce or applesauce plus NAC compared to their facial expression when taking other medications routinely given to cholestatic infants, such as ursodeoxycholic acid and fat-soluble vitamins. Other secondary outcomes are adverse events occurring during applesauce and applesauce plus NAC administration. This study employs the Bayesian Optimal Interval (BOIN) design, which was initially developed for phase 1 oncology trials and allows for a higher probability of identifying the maximum tolerated dose with a small sample size.

Inclusion Criteria:

• 122-273 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

Exclusion Criteria:

• 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

IPD will not be available to other researchers.

N/A. No Masking