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Nirmatrelvir/ritonavir (Paxlovid) failed to shorten COVID-19 symptom duration among people at standard risk for severe COVID-19 and among vaccinated people with at least one risk factor for severe disease, according to final results of the phase II/III trial.

In vaccinated and unvaccinated patients with COVID-19 at standard risk for severe disease and in fully vaccinated people with at least one risk factor who took nirmatrelvir/ritonavir, the median time to alleviation of COVID-19 symptoms was 12 days, compared with 13 days in patients who took a placebo (P=0.60), reported Jennifer Hammond, PhD, development head of antivirals at Pfizer in Collegeville, Pennsylvania, and colleagues in the .

"The usefulness of nirmatrelvir-ritonavir in patients who are not at high risk for severe COVID-19 has not been established," the authors wrote.

There was a trend toward fewer hospitalizations and death among participants who took nirmatrelvir/ritonavir, where five (0.8%) of these participants were hospitalized for COVID-19 or died from any cause, compared with 10 (1.6%) of those in the placebo group through day 28 (95% CI −2.0 to 0.4). However, the difference did not reach statistical significance.

In a subgroup analysis of at-risk participants only, three (0.9%) of the participants receiving nirmatrelvir/ritonavir were hospitalized or died versus seven (2.2%) in the placebo group (95% CI -3.3 to 0.7).

In 2022, the drug's manufacturer Pfizer announced an updated interim analysis of the EPIC-SR that reached similar conclusions to these final results. Because of low rates of hospitalization in the study population, Pfizer ended enrollment in EPIC-SR at that time.

In contrast to EPIC-SR, the EPIC-HR trial that enrolled high-risk unvaccinated participants found that nirmatrelvir/ritonavir reduced hospitalization or death by 88%.

"What can we conclude from these two trials about nirmatrelvir-ritonavir for the treatment of COVID-19?" wrote Rajesh Gandhi, MD, and Martin Hirsch, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, in an .

"Clearly, the benefit observed among unvaccinated high-risk persons does not extend to those at lower risk for severe COVID-19," they noted. The EPIC-SR results add support to that nirmatrelvir/ritonavir is only indicated for in persons at high risk for disease progression, they said.

However, Gandhi and Hirsch also pointed out that although the EPIC-SR trial failed to show that nirmatrelvir/ritonavir shortened COVID-19 symptoms in vaccinated participants with at least one risk factor, the study enrolled only a small percentage of patients who were most likely to be hospitalized with COVID-19.

"Other than obesity, smoking, and hypertension, risk factors for severe COVID-19 were uncommon; for example, less than 2% of the participants had heart or lung disease," they wrote. Of note, only 5% of EPIC-SR enrollees were 65 years or older.

"As with many medical interventions, there is likely to be a gradient of benefit for nirmatrelvir–ritonavir, with the patients at highest risk for progression most likely to derive the greatest benefit," Gandhi and Hirsch commented.

About 26% of participants who received nirmatrelvir/ritonavir experienced an adverse event, similar to the 24.1% in the placebo group. The most commonly reported treatment-related adverse events among those who took nirmatrelvir/ritonavir were dysgeusia (5.8%) and diarrhea (2.1%). In participants receiving nirmatrelvir/ritonavir, 3.7% reported grade 3 or 4 adverse events versus 3.9% in the placebo group. No grade 5 adverse events occurred in the treatment group.

Of note, symptom rebound at day 14 occurred in 11.4% of participants treated with nirmatrelvir/ritonavir versus 16.1% in the placebo group. Viral load rebound at day 14 was similar between the 2 groups (4.3% in the nirmatrelvir/ritonavir group vs 4.1% in the placebo group).

The EPIC-SR trial included 1,296 participants who had confirmed COVID-19 and symptom onset within the previous 5 days. Participants were randomized 1:1 to receive either nirmatrelvir/ritonavir (n=654) or placebo (n=634). Participants recorded COVID-19 symptoms on a daily basis from day 1 through day 28.

The primary end point of the study was time to sustained alleviation of all targeted COVID-19 signs and symptoms. COVID-19-related hospitalization and death from any cause were also assessed through day 28. A total of 1,250 participants completed efficacy and safety follow-up assessments.

Of participants, 54% were women and the median age was 42 years. The majority of participants were white (78.5%) and 41.4% were Hispanic or Latino. Approximately 57% had been vaccinated for COVID-19, and about 50% had at least one risk factor for severe COVID-19. The most common comorbidity was hypertension (12.3%) and the most common risk factor was cigarette smoking (13.3%).

Most participants (72.5%) underwent randomization within 3 days after symptom onset. Adherence to nirmatrelvir/ritonavir -- defined as having taken at least 80% of the pills -- was nearly 95%.

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