Ornithine phenylacetate (OP) therapy did not lead to a significant difference in time to clinical improvement compared with placebo in patients with cirrhosis and hepatic encephalopathy (HE); however, the ammonia scavenger appeared to be safe and should be studied for hyperammonemia in patients who are hospitalized and receiving treatment for the underlying precipitant of acute or overt HE. These findings were published in Clinical Gastroenterology and Hepatology.
The investigators recruited 231 patients across 132 sites between January 7, 2014 and December 29, 2016. To be eligible to participate in the phase 2b trial (ClinicalTrials.gov Identifier: NCT01966419 [STOP-HE]), patients must have been hospitalized with cirrhosis, hyperammonemia, and stage II or higher overt HE (OHE) on the Hepatic Encephalopathy Staging Tool (HEST). Patients were randomly assigned to receive standard-of-care treatment with 20, 30, or 40 mg/mL intravenous OP (n=116) or placebo (n=115) with for 5 days or fewer. Patients were assessed by the Hepatic Encephalopathy Staging Tool (HEST) and monitored for clinical response.
Baseline demographic characteristics did not differ significantly between groups. The median age was 60 and 61 years in the OP and placebo arms, respectively. Seventy-two percent of patients in the OP group were men compared with 78% in the placebo group. Ammonia levels were observed to differ by HEST stage: stage II, 82.3; stage III, 94.9; and stage 4, 129.0 mmol/L; P =.003).
The median time to confirmed clinical response was 47 (95% CI, 34-69) hours in the OP group and 64 hours (95% CI, 53-98) in the placebo group (P =.129). The between-group difference equated to a hazard ratio of 1.25 (95% CI, 0.907-1.719), indicating a 25% increase in the probability of confirmed response with OP vs placebo.
The time to complete response (improvement to HEST stage 0/1) was 87 in the treatment group and 102 hours in the placebo group (HR, 1.16; 95% CI, 0.818-1.651; P =.361). In the OP and placebo groups, 71% and 63% of patients had a confirmed primary clinical response 3 hours post-infusion or early hospital discharge/termination, respectively (P =.228). Most patients in the OP (59%) and placebo groups (51%) had a complete response within these parameters (P =.230).
Of note, the median length of hospitalization was similar between the 2 groups. In the treatment arm, this value was 170 hours (95% CI, 146-192); in the placebo arm, it was 169 hours (95% CI, 142-212; P =.584).
The overall incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to discontinuation was similar in both groups (OP, 16% vs placebo, 13%; P =.568). “The only treatment-emergent clinically notable vital sign abnormality was a significant increase in heart rate” of 15 or more beats/minute with a value of more than 120 beats/minute in the placebo group vs the OP group,” the study authors said (4% vs 0%; P =.029).
Death occurred in 9.5% and 13% of the treatment and placebo groups, respectively, culminating in 26 total deaths. The death rates by study drug dose by baseline hepatic function (Child-Turcotte-Pugh score) in the OP and placebo groups were 24% vs 26% (10 g/24 hrs), 5% vs 12% (15 g/24 hrs), and 4% vs 0% (20 g/24 hrs). A patient death from ventricular tachycardia may have been related to OP administration.
This study was limited by potential discrepancies between local- and central laboratory-confirmed ammonia levels. The investigators hypothesized that a more dramatic response might have been observed among patients with stage III or higher HE on the HEST scale, but excluding patients with lower HEST staging “would have impeded patient enrollment,” they said.
The study authors concluded that the time to clinical improvement and median length of hospitalization were not significantly different among patients with HE receiving OP compared with placebo. However, “while a statistically significant treatment effect was not demonstrated in the primary end point, median time to clinical improvement was 17 hours shorter in patients treated with OP vs placebo, which is considered clinically meaningful,” the study authors stated.
Disclosure: This study was sponsored by Mallinckrodt Pharmaceuticals. Multiple authors declared affiliations with industry. Please refer to the original article for a full list of authors’ disclosures.
Rahimi RS, Safadi R, Thabut D, et al. Efficacy and safety of ornithine phenylacetate for treating overt hepatic encephalopathy in a randomized trial. Clin Gastroenterol Hepatol. Published online October 15, 2020. doi: 10.1016/j.cgh.2020.10.019