Nirmatrelvir fails to shorten COVID-19 symptoms in latest trial

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In a recent study published in The New England Journal of Medicine, researchers evaluate the efficacy of nirmatrelvir in combination with ritonavir against the coronavirus disease 2019 (COVID-19).

Study: Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19. Image Credit: Alexsey t17 /

A brief history of COVID-19 patient care

Since its emergence at the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has infected almost 700 million individuals and claimed over seven million lives worldwide. COVID-19 is associated with a wide range of pathologies in different populations, with the very young and elderly at the most significant risk of mortality and morbidity.

Rapid global medical research and vaccination programs have significantly reduced the burden of COVID-19 by attenuating SARS-CoV-2 transmission. Currently, COVID-19 patients are treated symptomatically through general antiviral interventions; however, an extensive search for a COVID-19-specific cure is still in the clinical trials phase.

Nirmatrelvir is an orally administered antiviral agent that inhibits the SARS-CoV-2 main protease (Mpro), which is critical for viral replication. Nirmatrelvir is administered with the pharmacokinetic enhancer ritonavir to inhibit metabolism by CYP3A4."

One of the most promising antiviral therapies currently in clinical trials is the combination of nirmatrelvir and ritonavir. In unvaccinated adults, phase II and III clinical trials have produced promising results by reducing COVID-19 mortality risk by over 80%. Nevertheless, the anti-COVID-19 benefits of this intervention in vaccinated individuals remain unverified.

About the study

In the current study, researchers evaluate the efficacy and side effects of nirmatrelvir-ritonavir in non-hospitalized patients of various ages, ethnicities, and infection severity.

Data were obtained from the Evaluation of Protease Inhibition for Covid-19 in Standard-Risk Patients (EPIC-SR) trial, which is a randomized, double-blind, and placebo-controlled trial involving adult participants 18 years of age and older with laboratory reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed COVID-19. Individuals were enrolled in the study between August 2021 and July 2022 if their symptoms initially appeared in the five days prior to study enrollment.

Study participants were randomly assigned to receive either the nirmatrelvir-ritonavir intervention, which comprised 300 mg of nirmatrelvir and 100 mg of ritonavir, or placebo. The dosage was fixed once every 12 hours for five days, thus leading to a final total of 10 doses.

For statistical analyses, randomization was stratified across vaccination status, geographic region, and COVID-19 symptom onset. Data collection included participants' sociodemographic, anthropometric, and medical records.

Digital diaries were also used to record daily intervention use, COVID-19 symptom severity on a four-point scale, and associated side effects. Efficacy measurements were conducted through day 34.

Sustained alleviation was considered to have occurred on the first of four consecutive days during which all symptoms that had been scored as moderate or severe and as mild or absent at baseline were scored as mild or absent and as absent, respectively."

Study findings and relevance

Of the 1,296 participants initially enrolled in the study, 1,288 individuals, 654 of whom received nirmatrelvir-ritonavir and 634 placebo, provided completed data and were included in the statistical analyses. The study cohort primarily comprised women and individuals of the White ethnicity at 54% and 78.5%, respectively.

About 57% of the study cohort were vaccinated, with smoking as the most commonly severe COVID-19 risk factor reported among 13.3% of the study participants. Study intervention compliance was high across both cohorts at 94.8% and 96.5% for nirmatrelvir-ritonavir and placebo, respectively.

Efficacy evaluations revealed no statistically different outcomes between nirmatrelvir-ritonavir and placebo treatment cohorts. While the safety evaluation found no statistically significant differences between the side effects reported across trial groups, dysgeusia, diarrhea, and nausea were often reported by those who received nirmatrelvir-ritonavir during the study.


The study findings suggest that nirmatrelvir-ritonavir may not be as effective as suspected in alleviating adverse viral SARS-CoV-2 outcomes, especially in symptomatic, non-hospitalized, vaccinated, or unvaccinated adults. Given the known and study-reported side effects, nirmatrelvir-ritonavir cannot yet be established as a safe and beneficial treatment for severe COVID-19 outpatients, irrespective of prior vaccination status.

Nirmatrelvir–ritonavir was not associated with a significantly shorter time to sustained alleviation of COVID-19 symptoms than placebo, and the usefulness of nirmatrelvir–ritonavir in patients who are not at high risk for severe COVID-19 has not been established."

Journal reference:
  • Hammond, J., Fountaine, R. J., Yunis, C., et al. (2024). Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19. The New England Journal of Medicine 390(13); 1186-1195. doi:10.1056/nejmoa2309003
Hugo Francisco de Souza

Written by

Hugo Francisco de Souza

Hugo Francisco de Souza is a scientific writer based in Bangalore, Karnataka, India. His academic passions lie in biogeography, evolutionary biology, and herpetology. He is currently pursuing his Ph.D. from the Centre for Ecological Sciences, Indian Institute of Science, where he studies the origins, dispersal, and speciation of wetland-associated snakes. Hugo has received, amongst others, the DST-INSPIRE fellowship for his doctoral research and the Gold Medal from Pondicherry University for academic excellence during his Masters. His research has been published in high-impact peer-reviewed journals, including PLOS Neglected Tropical Diseases and Systematic Biology. When not working or writing, Hugo can be found consuming copious amounts of anime and manga, composing and making music with his bass guitar, shredding trails on his MTB, playing video games (he prefers the term ‘gaming’), or tinkering with all things tech.


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