Efficacy and safety of obeldesivir in low-risk, non-hospitalised patients with COVID-19 (OAKTREE): a phase 3, randomised, double-blind, placebo-controlled study

Abstract

Background: Obeldesivir is an oral nucleoside analogue prodrug antiviral that inhibits SARS-CoV-2 replication. We aimed to assess the efficacy, safety, and tolerability of obeldesivir for the treatment of COVID-19 in non-hospitalised individuals at low risk of progression to severe disease.

Methods: OAKTREE was a phase 3, randomised, double-blind, placebo-controlled trial in 107 centres (including research centres, primary care centres, and hospitals) in Japan and the USA. Low-risk, non-hospitalised adults and adolescents with mild-to-moderate COVID-19 were enrolled within 3 days of symptom onset. Eligible participants were randomly assigned 1:1 using permuted block randomisation (block size of four), stratified by historical completion of a primary COVID-19 vaccination series, to receive either oral obeldesivir 350 mg or matched placebo twice daily for 5 days. The primary efficacy endpoint was time to COVID-19 symptom alleviation by day 29, which was assessed in all randomly assigned participants who received one or more doses of study drug, had positive SARS-CoV-2 RT-PCR (per central laboratory testing) at baseline, and had COVID-19 symptom data (full analysis positive set). The primary safety endpoint was the incidence of adverse events and laboratory abnormalities and was assessed in all randomly assigned participants who received one or more doses of study drug. As a secondary endpoint we assessed change from baseline in nasal swab viral RNA copy number at day 5 in all randomly assigned participants who received one or more doses of study drug and had a quantifiable baseline value. This trial is registered with ClinicalTrials.gov, NCT05715528, and is complete.

Findings: Between Feb 13, 2023 and Oct 31, 2023, 1955 participants (1155 female and 800 male; 1698 White, 207 Black, 42 Asian, and eight Other) were randomly assigned and received at least one dose of either obeldesivir (n=979) or placebo (n=976). Overall, 1368 (70·0%) participants had completed a primary COVID-19 vaccination series and 1938 (99·6%) were seropositive for SARS-CoV-2 antibodies. There were 884 participants in each group in the full analysis positive set. Among those in the full analysis positive set who completed the symptom questionnaire (ie, who had COVID-19 symptom data; 879 obeldesivir, 882 placebo), median time to COVID-19 symptom alleviation was 5·9 days (95% CI 5·4-6·1) in the obeldesivir group and 6·0 days (5·8-6·3) in the placebo group (hazard ratio 1·099 [95% CI 0·997-1·211], p=0·068). The least-squares mean change from baseline in viral RNA copy number at day 5 was -2·13 log₁₀ copies per mL (SE 0·04) and -1·95 log₁₀ copies per mL (0·04) for the obeldesivir group (n=637) and placebo group (n=622), respectively, with a least-squares mean difference of -0·18 (95% CI -0·30 to -0·06) log₁₀ copies per mL (p=0·0037). The safety profile was comparable between groups. 53 (5·4%) of 979 participants in the obeldesivir group and 56 (5·7%) of 976 participants in the placebo group had one or more treatment-emergent adverse events. 753 (77·5%) participants in the obeldesivir group and 757 (78·5%) participants in the placebo group had one or more graded laboratory abnormalities, most of which were grade 1 or 2.

Interpretation: Obeldesivir was generally safe and well tolerated, with greater reduction of SARS-CoV-2 viral RNA copy number versus placebo at day 5. However, obeldesivir did not significantly reduce time to symptom alleviation, possibly reflecting the challenges of assessing efficacy in this population in an era of high rates of vaccine-induced and natural immunity.

Funding: Gilead Sciences.