Efficacy and safety of onradivir in adults with acute uncomplicated influenza A infection in China: a multicentre, double-blind, randomised, placebo-controlled and oseltamivir-controlled, phase 3 trial

Abstract

Background

Onradivir (ZSP1273) is a potent inhibitor of the PB2 subunit of influenza A virus (IAV) polymerase. Our previous, phase 2 clinical trial showed that a 600 mg regimen of onradivir initiated within 48 h of symptom onset can expedite the recovery of adult patients from acute, uncomplicated influenza. Here, we aimed to evaluate the safety and therapeutic efficacy of onradivir in a larger group with acute, uncomplicated influenza.

Methods

This randomised, double-blind, multicentre, placebo-controlled and oseltamivir-controlled, phase 3 trial was conducted at 68 clinical sites in China. Eligible participants were adults (aged 18–64 years) with an influenza-like illness who screened positive by rapid IAV antigen testing at the first clinical visit, and had a fever (axillary temperature ≥38·0°C) with at least one moderate systemic and one moderate respiratory symptom within 48 h of symptom onset. Patients were randomly assigned into three treatment groups, stratified by influenza symptom scores (≤11 or ≥12), in a 2:1:1 ratio by an interactive web response system, with each treatment lasting 5 days: 600 mg oral onradivir tablets once daily, 75 mg oral oseltamivir phosphate capsules twice daily, or oral placebo. The primary outcome was the efficacy of onradivir versus placebo in the time to alleviation of symptoms (TTAS), from treatment initiation to the remission of influenza symptoms, in the intention-to-treat infection (ITTI) population (ie, all participants who were randomly assigned and tested positive for IAV). The safety endpoints were the frequency and severity of adverse events in all participants who received treatment at least once. This trial is registered with ClinicalTrials.gov (NCT04683406) and is completed. This clinical trial was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (EC-2020-080[YW]-02).

Findings

Between May 12, 2022, and May 16, 2023, 943 patients were screened, of whom 750 met the inclusion criteria and were randomly assigned to a group. 48 had negative IAV tests, resulting in an ITTI population of 702 participants (413 [59%] men and 289 [41%] women; mean age 28·1 years [SD 9·7]): 349 in the onradivir group, 177 in the oseltamivir group, and 176 in the placebo group. The baseline viral load (mean 5·15 log₁₀ copies per mL [SD 1·02]) and the total score of seven influenza symptoms at enrolment were similarly distributed among the groups. The median TTAS in the onradivir group was significantly shorter than that of placebo (38·83 h [95% CI 35·32–41·18] vs 63·35 h [55·48–68·48], difference –24·52 h, p<0·0001, HR 1·53 [95% CI 1·27–1·85]) and similar to that of the oseltamivir group (42·17 h [38·27–52·83], p=0·092, HR 1·12 [0·93–1·35]. Adverse events occurred in 250 (67%) of 373 in the onradivir group, 104 (55%) of 189 in the placebo group, and 89 (47%) of 188 in the oseltamivir group. Although the incidence of diarrhoea was higher in the onradivir group (184 [49%]) than in the placebo (44 [23%]) or oseltamivir (28 [15%]) groups, most incidences were grade 1 or 2, lasted a median of 2 days (IQR 1–3), and resolved without medication.

Interpretation

Onradivir has similar curative efficacy to oseltamivir for acute, uncomplicated influenza infections in adult patients, with an acceptable safety profile. At a time when reduced susceptibility to antiviral drugs is a growing concern, this study indicates that onradivir could be an alternative antiviral option or a candidate for use in combination with other antiviral agents for uncomplicated IAV infection.

Funding

National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine; National Natural Science Foundation of China; Guangdong Science and Technology Foundation; Major Project of Guangzhou National Laboratory; Guangdong Raynovent Biotechnology.