Clinical Advances in Liver, Pancreas, and Biliary TractIntravenous N-Acetylcysteine Improves Transplant-Free Survival in Early Stage Non-Acetaminophen Acute Liver Failure
Section snippets
Objective
The primary outcome measure for this trial was the overall number of patients surviving at 3 weeks after study admission; our research hypothesis was that patients receiving NAC would have a significantly higher overall survival rate than those receiving the placebo. The secondary outcome measures were the number of patients surviving without transplantation and the number of patients undergoing transplantation at 3 weeks after study admission. Our research hypothesis for transplant-free
Study Population
Among 820 eligible patients at sites with institutional review board approval, 558 (68%) met exclusion criteria (Supplementary Figure 1). Of the remaining 262 patients, 89 were excluded either because consent was refused (46 patients), was unobtainable (34 patients), or, after randomization, because of protocol violations (9 patients). The 9 protocol violations included inadvertent enrollment of 2 prisoners who were removed from consideration once their status was recognized, 1 patient for whom
Discussion
There is no established treatment for non-acetaminophen acute liver failure other than liver transplantation. Our study suggests that transplant-free survival was improved by NAC. However, this improvement in survival was observed primarily in those with early stage hepatic encephalopathy: among those with coma grades I–II at admission, 52% receiving NAC survived without transplantation vs 30% survival for those who received placebo. This finding was supported by the survival analyses (Figure 1
Acknowledgments
The Data and Safety Monitoring Board for the trial included Michael W. Fried, Chair, University of North Carolina, Chapel Hill, NC; Edward Geehan, Georgetown University, Washington, DC; Lewis Tepperman, New York University, New York, NY; Caroline Riely, University of Tennessee, Memphis, TN; Patrick Northup, University of Virginia, Charlottesville, VA; Prashant Pandya, VA Medical Center, Kansas City, MO; and Aynar Unalp-Arida, Johns Hopkins University, Baltimore, MD.
The authors dedicate this
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Conflict of interest The authors disclose no conflicts. The statistical analysis of the entire data sets pertaining to efficacy (specifically primary and major secondary efficacy end points) and safety (specifically, serious adverse events as defined in federal guidelines) have been confirmed independently by a biostatistician who is not employed by the corporate entity. The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and analysis. This was a randomized clinical trial (ClinicalTrials.gov number NCT00004467).
Funding The study was supported by the following grants: R-03 DK52827, R-01 DK58369, and U-01 DK58369 from the National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and FD-R-001661 from the Orphan Products Division, United States Food and Drug Administration. Additional funding was provided by the Stephen Tips Fund of the Northwestern Medical Foundation and the Jeanne Roberts and Rollin and Mary Ella King Funds of the Southwestern Medical Foundation. This study was performed under IND #56925, filed with the Food and Drug Administration. The N-acetylcysteine used in the trial was supplied initially by Apothecon/Geneva Pharmaceuticals (Princeton, NJ), a division of Bristol Myers Squibb, and after April 2003 was supplied by Cumberland Pharmaceuticals (Nashville, TN). No additional support, data analysis, or input of any kind was provided by these companies.
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