Rice-derived recombinant human serum albumin as an alternative to human plasma for patients with decompensated liver cirrhosis: a randomised, double-blind, positive-controlled and non-inferiority trial

Abstract

Background: Despite inadequate supply and potential contamination risk, human plasma has remained the only source for human serum albumin (pHSA) intravenous administration since the 1940s.

Objective: We sought to establish the safety and efficacy of OsrHSA, a recombinant HSA from bioengineered Oryza sativa (rice).

Design: In this multicentre, randomised, double-blind and positive-controlled study, patients with decompensated liver cirrhosis and serum albumin ≤30 g/L were recruited from 22 centres in China. The patients were randomly assigned to OsrHSA or pHSA (4:1) to once-daily intravenous injection (10 g or 20 g) until their serum albumin level reached 35 g/L, for a maximum of 2 weeks, with 2 weeks of follow-up. The primary outcome was the proportion of patients to reach a serum albumin level of 35 g/L (non-inferiority margin <-0.20). Outcomes were evaluated in patients who received the study drug and had at least one post-baseline serum albumin value (full analysis set, FAS). Safety was evaluated in all patients who received the study drug.

Results: Between 22 March 2021 and 2 June 2022, 220 patients received OsrHSA (n=175) or pHSA (n=45). 216 patients were included in the FAS (OsrHSA, n=171; pHSA, n=45). Primary outcome of OsrHSA (130/171, 76%) was non-inferior to pHSA (34/45, 75.6%) (difference=0.5%; lower limit of 97.5% CI=-0.119). There was no significant difference between all secondary outcomes of OsrHSA and pHSA. There were no drug-related serious adverse events.

Conclusions: Rice-derived HSA is non-inferior to plasma-derived HSA in efficacy and safety. This finding should be confirmed in phase 3 trial.

Trial registration number: NCT04835480.

Keywords: HEALTH ECONOMICS; LIVER CIRRHOSIS.

Figure 1. Trial profile. *Four ineligible patients were randomly assigned in error and not treated. ^†Decision to withdraw is not due to lack of efficacy, but due to error in determining eligibility. Full analysis set is defined as patients who received treatment and had at least one post-treatment measurement for albumin. Four patients (three in OsrHSA 10 g and one in OsrHSA 20 g) withdrew before serum was collected and were therefore not included in the full analysis set. OsrHSA, Oryza sativa recombinant human serum albumin; pHSA, plasma-derived human serum albumin.

Figure 2. Primary outcome. (A) Non-inferiority analysis of primary outcome in the full analysis set (all doses: OsrHSA, 130/171; pHSA, 34/45; 10 g: OsrHSA, 58/85; pHSA, 13/22; 20 g: OsrHSA, 72/86; pHSA, 21/23). The adjusted difference and lower 97.5% confidence level (CL) were calculated using Newcombe CI. The non-inferiority margin was 20%. (B) Kaplan-Meier analysis of time to reach primary outcome (full analysis set). (C) Serum albumin, creatinine, bilirubin concentration and MELD 3.0 score from predose to end of follow-up (pharmacokinetic population, defined by patients in the full analysis set who had at least one serum value after EOT). Datapoints are mean and error bars are SD. EOT, end of treatment; MELD, Model for End-stage Liver Diseases; OsrHSA, Oryza sativa recombinant human serum albumin; pHSA, plasma-derived human serum albumin.