Prospective, Randomized, Multicenter, Controlled Trial of a
Prospective, Randomized, Multicenter, Controlled Trial of a
Objective: The HepatAssist liver support system is an extracorporeal porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective, randomized, controlled, multicenter trial in patients with severe acute liver failure.
Summary Background Data: In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL. Similarly, Phase I trials of the BAL in acute liver failure patients yielded promising results.
Methods: A total of 171 patients (86 control and 85 BAL) were enrolled. Patients with fulminant/subfulminant hepatic failure and primary nonfunction following liver transplantation were included. Data were analyzed with and without accounting for the following confounding factors: liver transplantation, time to transplant, disease etiology, disease severity, and treatment site.
Results: For the entire patient population, survival at 30 days was 71% for BAL versus 62% for control (P = 0.26). After exclusion of primary nonfunction patients, survival was 73% for BAL versus 59% for control (n = 147; P = 0.12). When survival was analyzed accounting for confounding factors, in the entire patient population, there was no difference between the 2 groups (risk ratio = 0.67; P = 0.13). However, survival in fulminant/subfulminant hepatic failure patients was significantly higher in the BAL compared with the control group (risk ratio = 0.56; P = 0.048).
Conclusions: This is the first prospective, randomized, controlled trial of an extracorporeal liver support system, demonstrating safety and improved survival in patients with fulminant/subfulminant hepatic failure.
Currently, the standard treatment of acute liver failure (ALF) involves supportive care that focuses on bridging patients to either transplantation or spontaneous recovery. Orthotopic liver transplantation is the only current therapy shown to improve patient survival. Several extracorporeal liver support systems have been used to treat patients with ALF attempting to either bridge them to recovery or to transplantation. These include cell-based and non-cell-based systems. Non-cell-based techniques (eg, high-volume plasma exchange and albumin dialysis), initially developed for other conditions, have been used to treat severe acute liver failure for more than a decade. No controlled, multicenter, large, randomized, prospective trials have been carried out using non-cell-based systems; therefore, their effect on survival remains unknown.
Extracorporeal liver perfusion using whole human and pig livers has been shown to effectively support patients with ALF for several days, but it is impractical for wider use because of limited availability of human livers and lack of quality control and consistency for animal livers. As a result, several extracorporeal cell-based devices were developed. Early Phase I studies have been performed using whole blood or plasma perfusion through cartridges (mostly hollow-fiber bioreactors) containing either human hepatoblastoma (HepG2-C3A) cells or freshly isolated porcine hepatocytes. The devices appeared to be well tolerated by the patients, but these studies did not demonstrate a survival advantage over standard of care in appropriately controlled settings.
A bioartificial liver (BAL), developed by the group at Cedars-Sinai Medical Center using cryopreserved porcine hepatocytes, is the most extensively studied of the extracorporeal cell-based liver support systems. Several preliminary uncontrolled clinical studies examining the effect of this therapy in patients with ALF have shown that BAL treatment improved neurologic function, reduced intracranial pressure (ICP), and increased cerebral perfusion pressure. Here, we report the results of the first Phase II/III prospective, randomized, multicenter, controlled trial examining the effect of BAL treatment on survival in patients with ALF. This is the largest prospective, randomized, controlled, multicenter trial of any artificial liver support system to date.
Objective: The HepatAssist liver support system is an extracorporeal porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective, randomized, controlled, multicenter trial in patients with severe acute liver failure.
Summary Background Data: In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL. Similarly, Phase I trials of the BAL in acute liver failure patients yielded promising results.
Methods: A total of 171 patients (86 control and 85 BAL) were enrolled. Patients with fulminant/subfulminant hepatic failure and primary nonfunction following liver transplantation were included. Data were analyzed with and without accounting for the following confounding factors: liver transplantation, time to transplant, disease etiology, disease severity, and treatment site.
Results: For the entire patient population, survival at 30 days was 71% for BAL versus 62% for control (P = 0.26). After exclusion of primary nonfunction patients, survival was 73% for BAL versus 59% for control (n = 147; P = 0.12). When survival was analyzed accounting for confounding factors, in the entire patient population, there was no difference between the 2 groups (risk ratio = 0.67; P = 0.13). However, survival in fulminant/subfulminant hepatic failure patients was significantly higher in the BAL compared with the control group (risk ratio = 0.56; P = 0.048).
Conclusions: This is the first prospective, randomized, controlled trial of an extracorporeal liver support system, demonstrating safety and improved survival in patients with fulminant/subfulminant hepatic failure.
Currently, the standard treatment of acute liver failure (ALF) involves supportive care that focuses on bridging patients to either transplantation or spontaneous recovery. Orthotopic liver transplantation is the only current therapy shown to improve patient survival. Several extracorporeal liver support systems have been used to treat patients with ALF attempting to either bridge them to recovery or to transplantation. These include cell-based and non-cell-based systems. Non-cell-based techniques (eg, high-volume plasma exchange and albumin dialysis), initially developed for other conditions, have been used to treat severe acute liver failure for more than a decade. No controlled, multicenter, large, randomized, prospective trials have been carried out using non-cell-based systems; therefore, their effect on survival remains unknown.
Extracorporeal liver perfusion using whole human and pig livers has been shown to effectively support patients with ALF for several days, but it is impractical for wider use because of limited availability of human livers and lack of quality control and consistency for animal livers. As a result, several extracorporeal cell-based devices were developed. Early Phase I studies have been performed using whole blood or plasma perfusion through cartridges (mostly hollow-fiber bioreactors) containing either human hepatoblastoma (HepG2-C3A) cells or freshly isolated porcine hepatocytes. The devices appeared to be well tolerated by the patients, but these studies did not demonstrate a survival advantage over standard of care in appropriately controlled settings.
A bioartificial liver (BAL), developed by the group at Cedars-Sinai Medical Center using cryopreserved porcine hepatocytes, is the most extensively studied of the extracorporeal cell-based liver support systems. Several preliminary uncontrolled clinical studies examining the effect of this therapy in patients with ALF have shown that BAL treatment improved neurologic function, reduced intracranial pressure (ICP), and increased cerebral perfusion pressure. Here, we report the results of the first Phase II/III prospective, randomized, multicenter, controlled trial examining the effect of BAL treatment on survival in patients with ALF. This is the largest prospective, randomized, controlled, multicenter trial of any artificial liver support system to date.
