番茄社区

With oral simnotrelvir/ritonavir treatment in a vaccinated population, COVID-19 symptoms went away about 1.5 days earlier and SARS-CoV-2 viral loads fell, a Chinese placebo-controlled phase II/III trial found.

In patients with mild-to-moderate COVID-19, the median time to sustained symptom resolution was significantly shortened from 216 hours to approximately 180 hours when simnotrelvir/ritonavir was taken within 72 hours of symptom onset and continued twice daily for 5 days (P=0.006), Bin Cao, MD, from the China-Japan Friendship Hospital in Beijing, and colleagues reported.

Also by day 5, simnotrelvir/ritonavir significantly decreased the SARS-CoV-2 viral load from baseline when compared to placebo (mean difference -1.51 log₁₀ copies/mL, 95% CI -1.79 to -1.24). Viral load reductions at day 7 and day 9 were also greater in the simnotrelvir/ritonavir group, the authors detailed in the .

In the trial's subgroup with risk factors for severe COVID-19, simnotrelvir shortened median time to symptom resolution by 60.4 hours. Investigators found no safety concerns, though adverse events occurred in a greater proportion of patients in the simnotrelvir group.

Currently available antivirals for COVID outpatients, namely nirmatrelvir-ritonavir (Paxlovid) and remdesivir (Veklury), are recommended for high-risk groups based on studies demonstrating their ability to reduce the risk for COVID-related hospitalization or death. But the drugs are associated with high out-of-pocket costs ever since the U.S. ended universal access to free COVID treatments last year.

"Because of the high costs of the drugs and inequity in their distribution, more drug options are needed to accelerate the resolution of symptoms among patients with mild-to-moderate COVID-19," Cao and co-authors wrote.

Simnotrelvir, an oral 3-CL-like protease inhibitor, has received emergency conditional authorization in China for mild-to-moderate COVID-19, though any plans for regulatory approval in the U.S. are unclear.

"I think we have to be interested -- and even a bit excited -- about these results, but we should like to see them applied in the population of greatest interest," said William Schaffner, MD, of Vanderbilt University in Nashville, Tennessee, in an interview with 番茄社区.

Schaffner, who was not involved in the study, pointed out that trial participants were relatively young, healthy, and vaccinated. "Some of them did have some cardiovascular disease, but this was not the population we're most concerned with who are older, who have one or more serious chronic underlying medical conditions."

And the trial was not designed to provide information on simnotrelvir's effects on outcomes of greatest clinical relevance, Schaffner noted -- COVID-related hospitalization, ICU admissions, or mortality.

That said, he stressed that it is important to develop new COVID-19 treatments that have the potential to overcome some of the limitations of nirmatrelvir-ritonavir. "Having an alternative is always a good thing," he commented.

The trial enrolled over 1,200 patients from 35 sites in China from August to December 2022. Participants were adults with symptoms of mild or moderate COVID-19, most commonly sore or dry throat, cough, stuffy or runny nose, headache, and fever. Half were randomized to receive 750 mg simnotrelvir/100 mg ritonavir and half to a matching placebo, twice daily for 5 days.

For this analysis, Cao's group relied on the 1,007 people in the modified intention-to-treatment cohort who received their assigned treatment within 72 hours of symptom onset. Nearly half received the trial drug or placebo within 48 hours.

Patients were quarantined, observed, and assessed for treatment adherence in designated hospitals. Patients provided self-assessment of COVID-19 related signs and symptoms on a subjective scale. Investigators quantified SARS-CoV-2 RNA from nasal or oropharyngeal samples obtained at regular intervals through day 29.

Study authors reported that the trial population had a median age of 35 years, with 59% being men. A majority (53.5%) had a risk factor for severe COVID-19, including overweight or obesity (35.7%), current or former smoking (22.7%), and cardiovascular disease (4.5%). Approximately 96% were vaccinated for COVID-19 and 77% had received a booster vaccination.

Other secondary endpoints showed that treatment with simnotrelvir/ritonavir shortened the median time to sustained alleviation of symptoms by about 48 hours and accelerated the resolution of respiratory symptoms by about 41 hours.

Adverse events occurred in 17.5% of patients in the simnotrelvir group and 10.2% in the placebo group. The three most common drug-related adverse events were an increase in triglyceride levels (4.3%), a decrease in neutrophil count (1.9%), and diarrhea (1.7%). No patients died during the trial period.

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