THERAPEUTIC EFFICACY OF L-ORNITHINE-L-ASPARTATE INFUSIONS IN PATIENTSWITH CIRRHOSIS AND HEPATIC-ENCEPHALOPATHY - RESULTS OF A PLACEBO-CONTROLLED, DOUBLE-BLIND-STUDY

One hundred twenty-six patients with cirrhosis, hyperammonemia (>50 mu mol/L), and chronic (persistent) hepatic encephalopathy (HE), which d eveloped spontaneously without the existence of known precipitating fa ctors, were enrolled in a randomized, double-blind, placebo controlled clinical trial of intravenously administered L-ornithine-L-aspartate (OA). Patients with subclinical (grade 0, West-Haven criteria) hepatic encephalopathy (SHE), characterized by a prolonged number connection test A (NCT-A) time, and manifest HE (grades I and II, West-Haven crit eria) were included in the investigation. The trial was planned as a c onfirmatory clinical trial. OA administered in a dose of 20 g/d, as we ll as placebo, were dissolved in 250 mL of 5% fructose and infused int ravenously for a period of 4 hours during 7 consecutive days with a su perimposed protein load at the end of the daily treatment period. Prim ary variables were postprandial venous ammonia and NOT-A performance t ime measured following OA or placebo infusions to evaluate the net eff ect of the treatment on the prevention of the protein-induced hyperamm onemia, and on parameters such as NCT-A influenced by hyperammonemia. Mental state gradation, portal systemic encephalopathy index (PSEI), a nd fasting ammonia levels were estimated as additional efficacy parame ters. The data presented are based on the total study sample (intent-t o-treat analysis), which included 63 patients in the placebo group and 63 patients in the OA group. Of the 126 patients, 114 met all the cri teria for inclusion and completed the trial and treatment as outlined in the protocol (treated-per-protocol analysis). During baseline, the placebo and treatment groups were homogeneous with regard to mental st ates, NOT-A performance time, fasting venous blood ammonia levels, and Child-Pugh criteria. Although a slight improvement occurred in the pl acebo group, NCT-A performance times (P < .001) and post-prandial veno us ammonia concentrations in the OA-treated group showed improvements in comparison with placebo. In addition, venous fasting blood ammonia concentration (P < .01), mental state gradation (P < .001), and PSEI ( P < .01), which includes the mental state gradation, NCT-A time, and p ostprandial venous ammonia in this trial, improved to a much higher de gree in the OA group than in the placebo group. In subgroups retrospec tively classified according to their initial mental state gradation, O A showed differential but uniformly significant efficacies in patients with manifest HE with respect to ammonia-lowering, improvement in NCT times, and mental state gradation. In patients with initial SHE, OA r evealed differences between the medications in the psychometric test u sed. Adverse events consisting of mild gastrointestinal disturbances w ere observed in 3 of the OA-treated patients (5%). OA infusion appears to be a safe, effective treatment of chronic (persistent) manifest HE in cirrhotic patients. Additional investigations are required to asse ss the efficacy of OA in patients with SHE, as well as in patients wit h more severe grades of HE.