N-Acetylcysteine in Biliary Atresia After Kasai Portoenterostomy
Condition: Biliary Atresia
MeSH terms: Biliary Atresia
Intervention: N-Acetyl cysteine
Intervention description: 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
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention 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)
Enrollment: 13.0
Sex: All
Minimum age: 0 Days
Maximum age: 90 Days
Healthy volunteers: No
Keywords: Biliary Atresia; N-Acetylcysteine; Glutathione; Kasai portoenterostomy; Bile flow; Serum bile acids; Serum bilirubin

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age less than or equal to 90 days at time of KP (standard age range in which KPs are
             performed)

          2. BA diagnosis made by intraoperative cholangiography and KP performed at Texas
             Children's Hospital, Texas Medical Center Campus

          3. Legal guardian(s) sign consent after understanding risks and investigational nature of
             study

        Exclusion Criteria:

          1. Decompensated liver disease (INR >1.3) despite parenteral Vitamin K administration)

          2. KP not performed for any reason (i.e., normal intraoperative cholangiography, or liver
             found to be too diseased intraoperatively to proceed with KP)

          3. Active respiratory infection

          4. 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)

          5. 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