N-Acetylcysteine in Biliary Atresia After Kasai Portoenterostomy

Study Overview
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Brief Summary
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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.

Detailed Description
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Biliary atresia (BA) is a disease characterized by fibro-obliteration of extrahepatic bile ducts leading to impaired bile flow (Sokol et al., 2007). BA is treated with the Kasai portoenterostomy (KP), an operation which connects the liver directly to the intestine in attempt to relieve bile back-up and promote bile flow. KPs have variable success. KPs occasionally normalize bile flow and stop disease progression (Jimenez-Rivera et al., 2013). More commonly, however, bile flow never completely normalizes after KP. This can be detected by elevated total bilirubin (TB) or conjugated bilirubin (Bc) serum concentrations, or, when TB and Bc are normal, elevated total serum bile acids (TSBA) concentrations (Bezerra et al., 2014; Shneider et al., 2015; Venkat et al., 2014). Impaired flow leads to fibrosis, cirrhosis, and eventual need for liver transplantation. Given these uneven results, therapies are urgently needed to enhance the KP's success. The investigators hypothesize that N-acetylcysteine (NAC) will improve outcomes after KP, because NAC is a precursor for the powerful choleretic molecule glutathione (Ballatori and Truong, 1989, 1992, Ballatori et al., 1986, 1989). The hypothesis assumes that better bile flow will lead to better outcomes. This is supported by previous reports demonstrating that good bile flow correlates with slower disease progression in BA. For example, a recent study showed infants with good bile flow after KP were significantly less likely to develop failure-to-thrive, ascites, hypoalbuminemia, or coagulopathy in the first two years of life (Shneider et al., 2015). Furthermore, these infants had significantly higher transplant-free survival in the same time period. In this study, TB <2.0 mg/dL within three months of KP was used as the marker for good bile flow. NAC has a number of properties that make it an especially attractive potential therapeutic agent. First, glutathione creates an osmotic gradient in the bile duct lumen which drives one-third of total bile flow in humans (the other drivers are bile acids and secretin/bicarbonate) (Ballatori and Truong, 1989, 1992, Ballatori et al., 1986, 1989). Second, NAC is a Food and Drug Administration-approved therapy for another serious liver condition in neonates and children (acetaminophen overdose). It has also been used for other liver and non-liver indications in neonates, with few reported adverse events (Ahola et al., 2003; Flynn et al., 2003; Jenkins et al., 2016; Kortsalioudaki et al., 2008; Mager et al., 2008; Soghier and Brion, 2006; Squires et al., 2013; Wiest et al., 2014). Third, glutathione is an anti-oxidant, which could scavenge the free radicals contributing to cirrhosis. Preclinical studies are also promising, with glutathione's strong choleretic properties best established in rat flow studies and NAC's hepatoprotective effects documented in rescuing different mouse models of cholestasis (Ballatori et al., 1986; Galicia-Moreno et al., 2009, 2012; Tahan et al., 2007). To test the hypotheses, the investigators will administer intravenous NAC continuously for seven days and determine the number of subjects with normal TSBAs (0-10 umol/L) within 24 weeks of KP. In addition, markers of BA progression, such as abnormal laboratory results, failure-to-thrive, and occurrence of complications related to chronic liver disease, will be described over the first two years of life. Finally, all adverse events occurring during NAC infusion and in the 21 days after its completion will be recorded. The study employs the two-stage minimax Phase 2 clinical trial design, a design commonly used in oncological trials to determine whether a particularly therapy has sufficient activity to warrant a larger Phase 3 trial (Simon, 1989). The two-stage minimax design offers two distinct advantages compared to other designs: (i) early termination if the drug is not efficacious; and (ii) small sample sizes, because historical controls rather than a separate control arm are used.

Official Title
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A Phase 2 Trial of N-Acetylcysteine in Biliary Atresia After Kasai Portoenterostomy

Conditions
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Biliary Atresia

Intervention / Treatment
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* Drug: N-Acetyl cysteine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 0 Days
Maximum Age: 90 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: N-Acetylcysteine Treatment<br>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<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total serum bile acids | Total serum bile acids (TSBAs) within 24 weeks after Kasai portoenterostomy (KP) for biliary atresia (BA) | Within 24 weeks after KP | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Laboratory Markers | Laboratory markers for liver disease progression in the first two years of life, including conjugated bilirubin (Bc), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), albumin, sodium, total bilirubin (TB), platelets, international normalized ratio (INR), 25-hydroxy Vitamin D, Vitamin A, and Vitamin E | First two years of life | 
| Weight | Weight measurements in the first two years of life | First two years of life | 
| Sentinel Events | Occurrence of sentinel events related to worsening liver disease (cholangitis, development of ascites, variceal bleed, liver transplant listing, liver transplant, death) in the first two years of life | First two years of life | 
| Adverse Events | Adverse events possibly related to NAC, including rash, urticaria, pruritus, tachycardia, hypotension, vomiting, edema, anaphylaxis, and intravenous line issues | Within four weeks after KP | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biliary Atresia, N-Acetylcysteine, Glutathione, Kasai portoenterostomy, Bile flow, Serum bile acids, Serum bilirubin