A phase 2 trial of N-Acetylcysteine in Biliary atresia after Kasai portoenterostomy

Abstract

Background: Biliary atresia (BA) is a life-threatening liver disease of infancy, characterized by extrahepatic biliary obstruction, bile retention, and progressive liver injury. The Kasai portoenterostomy (KP) is BA's only nontransplant treatment. Its success is variable and depends on restoration of hepatic bile flow. Many adjunctive therapeutics have been studied to improve outcomes after the KP, but none demonstrate effectiveness. This study tests if N-acetylcysteine (NAC), a precursor to the choleretic glutathione, improves bile flow after KP.

Methods: This report describes the design of an open-label, single center, Phase 2 study to determine the effect of NAC following KP on markers of bile flow and outcomes in BA. The intervention is intravenous NAC (150 mg/kg/day) administered continuously for seven days starting 0-24 h after KP. The primary outcome is normalization of total serum bile acid (TSBA) concentrations within 24 weeks of KP. The secondary objectives are to describe NAC therapy's effect on other clinical parameters followed in BA for 24 months and to report adverse events occurring with therapy. This study follows the "minimax" clinical trial design.

Discussion: This is the first clinical trial to test NAC's effectiveness in improving bile flow after KP in BA. It introduces three important concepts for future BA therapeutic trials: (1) the "minimax" study design, a pertinent design for rare diseases because it detects potential effects quickly with small subject size; (2) the more sensitive bile flow marker, TSBAs, which may correlate with positive long-term outcomes better than traditional bile flow markers such as serum bilirubin; and (3) liver enzyme changes immediately after KP, which can be a guideline for potential drug-induced liver injury in other BA peri-operative adjunctive therapeutic trials.

Keywords: ALT, Alanine transaminase; AST, Aspartate aminotransferase; BA, Biliary atresia; Bc, Conjugated bilirubin; Biliary atresia; DILI, Drug-induced liver injury; DSMB, Data and Safety Monitoring Board; DoL, Day of life; Drug-induced liver injury; FDA, Food and Drug administration; GGT, Gamma-glutamlytransferase; IOC, Intraoperative cholangiogram; KP, Kasai portoenterostomy; Kasai portoenterostomy; Minimax design; N-acetylcysteine; NAC, N-acetylcysteine; START, Steroids in Biliary Atresia Randomized Trial; Serum bile acids; TB, Total bilirubin; TCH, Texas Children's Hospital; TSBA, Total serum bile acids.

Fig. 1

Trial Design. This is a two-stage Phase 2 trial based on the “minimax” design. In Stage 1, 12 patients will be enrolled. If no patient in Stage 1 achieves a TSBA ≤10 μmol/L, the trial will stop. If at least one patient achieves a normal TSBA, an additional four patients will be enrolled. The trial is designed to detect a change in response rate from 5% without NAC treatment (based on historical controls) to 25% with NAC treatment, with a type I error rate of 5% and power of 80%.

Fig. 2

Liver Enzyme Changes in the First Seven Days after KP. Thirteen infants undergoing KP had laboratory values followed in the first seven post-operative days. (A and B) AST and ALT rose substantially above baseline on post-operative day 1 and then trended downwards. (C) GGT rose above baseline 5–7 days post-operatively. (D) Bc remained close to baseline in the immediate post-operative period. Dashed lines denote proposed upper limits for DILI.