#Ensitrelvir for #Covid19 Postexposure #Prophylaxis in #Household Contacts

 

Abstract

Background

Ensitrelvir, an oral inhibitor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease, is approved in Japan for the treatment of mild-to-moderate coronavirus disease 2019 (Covid-19). Previously, no antiviral agents were approved for postexposure prophylaxis in household contacts of patients with Covid-19.

Methods

In this double-blind, randomized, placebo-controlled trial, we randomly assigned persons who were SARS-CoV-2–negative on local diagnostic testing but were household contacts of a patient with Covid-19 (the index patient) to receive either ensitrelvir (375 mg on day 1 and 125 mg daily on days 2 through 5) or placebo within 72 hours after symptom onset in the index patient. The primary end point was Covid-19 (defined by a central laboratory–confirmed positive reverse-transcriptase–polymerase-chain-reaction assay and the presence of ≥1 of 14 prespecified Covid-19 symptoms lasting ≥48 hours) by day 10 in a household contact in the modified intention-to-treat population (all the participants who underwent randomization, had a central laboratory–confirmed negative RT-PCR test for SARS-CoV-2 at baseline, and received at least one dose of the trial drug or placebo).

Results

The modified intention-to-treat population included 1030 participants in the ensitrelvir group and 1011 in the placebo group. The mean age of the participants was 42.4 years; 71.1% had undergone randomization within 48 hours after symptom onset in the index patient, and 37.0% had at least one risk factor for severe Covid-19. The incidence of Covid-19 was lower in the ensitrelvir group than in the placebo group (2.9% vs. 9.0%; risk ratio, 0.33; 95% confidence interval [CI], 0.22 to 0.49; P<0.001). The incidence of adverse events during the trial was similar in the two groups (15.1% in the ensitrelvir group and 15.5% in the placebo group), as was the incidence of serious adverse events (0.2% in each group). No Covid-19–related hospitalizations or deaths were reported.

Conclusions

Ensitrelvir administered to household contacts of a patient with Covid-19 within 72 hours after symptom onset in the index patient was effective in preventing Covid-19 in the contacts. (Funded by Shionogi; SCORPIO-PEP Japan Registry for Clinical Trials number, jRCT2031230124; ClinicalTrials.gov number, NCT05897541.)

Source: 

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2509306?query=TOC

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#Ensitrelvir for the #treatment of hospitalized adults with #COVID19: an international phase 3 randomized placebo-controlled trial

 

Abstract

Background

Antivirals remain an important treatment strategy for persons who experience severe and life-threatening COVID-19. Ensitrelvir is an oral 3CL protease inhibitor with potent antiviral activity.

Methods

We conducted an international randomized, placebo-controlled trial of ensitrelvir with standard of care (SOC) among adults hospitalized for COVID-19. The primary outcome was clinical recovery assessed by the Days to Recovery Scale through Day 60 (DRS-60), analyzed using a Van Elteren test.

Results

From 2023 to 2025, 589 participants received blinded study treatment (293 ensitrelvir and 296 placebo). Median age was 69 years, 49% were female, 68% were White, and SOC commonly included corticosteroids (61% and 54%) and remdesivir (62% and 60%) in ensitrelvir and placebo groups, respectively. Median DRS-60 category was 6 (IQR: 3-15) in the ensitrelvir and 5.5 (IQR: 3-12) in the placebo group (p=0.19), and the OR was 0.82 (95% CI: 0.62-1.09) for a better DRS-60 category with ensitrelvir. Ensitrelvir participants had lower detectable viral antigen in plasma at Day 5 (13.4% vs 25.1%; p<0.001). There was no difference in secondary clinical outcomes or pre-specified safety outcomes, though the mortality rate was 6.1% vs 4.4% and the frequency of hemorrhagic events was 3.4% vs 0.3% among ensitrelvir and placebo groups, respectively.

Conclusions

Ensitrelvir treatment did not improve clinical recovery in addition to SOC for adults hospitalized for COVID-19. The lower illness severity in the Omicron era compared to earlier periods in the COVID-19 pandemic, and high use of remdesivir and corticosteroids, may have contributed to the lack of clinical benefit.

Source: 

Link: https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciag272/8660678?redirectedFrom=fulltext

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#Antiviral efficacy of oral #ensitrelvir versus oral ritonavir-boosted #nirmatrelvir in #COVID19 (PLATCOV): an open-label, phase 2, randomised, controlled, adaptive trial

 

Summary

Background

Ensitrelvir is an oral antiviral treatment for COVID-19 with the same molecular target (the main protease) as ritonavir-boosted nirmatrelvir—the current oral first-line treatment. We aimed to compare the clinical antiviral effects of the two drugs.

Methods

In an open-label, phase 2, randomised, controlled, adaptive pharmacometric platform trial, low-risk adult outpatients aged 18–60 years with early symptomatic COVID-19 (<4 days of symptoms) were recruited from hospital acute respiratory infection clinics in Thailand and Laos. Patients were randomly assigned in blocks (block sizes depended on the number of interventions available) to one of eight treatment groups, including oral ensitrelvir and oral ritonavir-boosted nirmatrelvir at standard doses, both given for 5 days, and no study drug. The primary endpoint was the oropharyngeal SARS-CoV-2 viral clearance rate assessed between day 0 and day 5 in the modified intention-to-treat population (defined as patients with at least 2 days of follow-up). Patients had four oropharyngeal swabs taken on day 0 and two swabs taken daily from days 1 to 7, then on days 10 and 14. Viral clearance rates were derived under a Bayesian hierarchical linear model fitted to log10 viral densities in standardised paired oropharyngeal swab eluates taken daily over the 5 days (14 samples). An individual patient data meta-analysis of all small molecule drugs evaluated in this platform trial using published results was also performed, adjusting for temporal trends in viral clearance. This trial is registered at ClinicalTrials.gov, NCT05041907.

Findings

Between March 17, 2023, and April 21, 2024, 604 of 903 patients enrolled were concurrently assigned to the three treatment groups (ensitrelvir n=202; ritonavir-boosted nirmatrelvir n=207; no study drug n=195). Median estimated SARS-CoV-2 clearance half-lives were 5·9 h (IQR 4·0–8·6) with ensitrelvir, 5·2 h (3·8–6·6) with nirmatrelvir, and 11·6 h (8·1–14·5) with no study drug. Viral clearance following ensitrelvir was 82% faster (95% credible interval 61–104) than no study drug and 16% slower (5–25) than ritonavir-boosted nirmatrelvir. In the meta-analysis of all unblinded small molecule drugs evaluated in the platform trial, nirmatrelvir and ensitrelvir had the largest antiviral effects (1157 patients). Viral rebound occurred in 15 (7%) of 207 patients in the nirmatrelvir group and 10 (5%) of 202 in the ensitrelvir group (p=0·45).

Interpretation

Both ensitrelvir and nirmatrelvir accelerate oropharyngeal SARS-CoV-2 viral clearance. Ensitrelvir is an effective alternative to currently available antivirals in treating COVID-19. Although COVID-19 is now generally a mild disease, it still causes substantial morbidity, particularly in vulnerable groups, and new variants or other coronaviruses could still emerge with pandemic potential. Safe effective and affordable antivirals are needed, and these are best assessed initially in pharmacometric platform trials assessing viral clearance.

Funding

Wellcome Trust through the COVID-19 Therapeutics Accelerator.

Source: The Lancet Infectious Diseases, https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(25)00482-7/fulltext?rss=yes

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