A phase 2 trial of short-term intravenous N-acetylcysteine in biliary atresia after Kasai portoenterostomy

Abstract

Background: For infants with biliary atresia, the only treatment that can establish bile flow and delay need for liver transplant is the Kasai portoenterostomy (KP). Unfortunately, the KP has variable success. In this study, we hypothesized that intravenous N-acetylcysteine (IV NAC) treatment following KP would improve bile flow.

Methods: This was a phase 2 study following the two-stage "minimax" trial design. Participants received IV NAC (150 mg/kg/day) for 7 days after KP, and the primary endpoint was achieving total serum bile acids (TSBA) ≤10 μmol/L within 24 weeks of KP. Secondary endpoints were clinical markers and the occurrence of sentinel events.

Results: There were 12 participants in stage 1 who received treatment, with none achieving TSBAs ≤10 μmol/L within 24 weeks of KP. As a result, no participants were enrolled in stage 2. There were 32 adverse events in 11 participants, including 5 serious adverse events which were considered part of the participants' natural clinical course and not directly attributable to NAC treatment. Analyses of secondary outcomes demonstrated no difference in clinical markers or occurrence of sentinel events between study participants and matched historical controls.

Conclusions: This study demonstrates how the two-stage "minimax" trial design can be used to efficiently evaluate potential therapies for BA. Although the primary endpoint was not met, NAC therapy was generally well-tolerated. NAC therapy may prove efficacious in future trials with (i) a less stringent primary endpoint and/or (ii) a longer course of treatment (NCT03499249).

Keywords: Kasai portoenterostomy; N-acetylcysteine; bile acids; biliary atresia; minimax design.

Graphical abstract

FIGURE 1

(A) Diagram of two-stage “minimax” trial design of 7 days of IV NAC in BA, with the primary outcome of achieving TSBAs ≤10 µmol/L within 24 weeks after KP. (B) Summary of patient flow through the trial. Because no patient in stage 1 achieved TSBAs ≤10 µmol/L, the trial was stopped, and participants were not enrolled in stage 2. Abbreviations: BA, biliary atresia; IV NAC, intravenous N-acetylcysteine; KP, Kasai portoenterostomy; TSBAs, total serum bile acids.

FIGURE 2

Trajectory of TSBAs over time in 12 study participants who completed 7 days of IV NAC. Participants with red symbols required a liver transplant before 2 years of life. Open diamonds represent the lowest TSBA level within 6 months after KP. The dashed line marks the primary endpoint cutoff of 10 µmol/L. Abbreviations: IV NAC, intravenous N-acetylcysteine; KP, Kasai portoenterostomy; TSBAs, total serum bile acids.

FIGURE 3

Comparison of bilirubin clearance in study participants and historical controls, with proportion of patients achieving bilirubin level in parentheses above each bar: Bc levels ≤0.2 mg/dL at 3 months post-KP, p=0.74; TB levels ≤2.0 mg/dL at 3 months post-KP, p=0.74; Bc levels ≤0.2 mg/dL at 6 months post-KP, p=0.74; TB levels ≤1.5 mg/dL at 6 months post-KP, p=0.18. Abbreviations: Bc, conjugated bilirubin; KP, Kasai portoenterostomy; TB, total bilirubin.

FIGURE 4

Kaplan–Meier survival curves comparing liver transplant-free survival in study participants and historical controls, log-rank p=0.98.