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EPIC-SR RCT- Nirmatrelvir for Low-Risk COVID-19 Patients?

June 13, 2024

Written by Laura Murphy

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Time to alleviation of signs and symptoms of COVID-19 did not differ significantly between patients receiving treatment with nirmatrelvir-ritonavir and those receiving placebo.

Too good to be true?
This was a manufacturer-sponsored trial (EPIC-SR) that enrolled 1,300 patients who were either: 1) vaccinated and had at least one risk factor for severe disease OR 2) unvaccinated (or not vaccinated in the last year) without risk factors. 

Patients were randomized to treatment with nirmatrelvir-ritonavir or placebo every 12 hours for 5 days. Of enrolled patients, 57% were vaccinated, and 50% had at least one risk factor for severe disease. Median age was 42 years. The most common risk factors were obesity (17.8%), smoking (13.3%), hypertension (12.3%); there were few patients with heart or lung disease (<2%) or age of 65 or greater (5%).

The primary end point was time to sustained alleviation of symptoms, and this was similar in the treatment and placebo groups (median 12 vs 13 days, P=0.60). Data was tracked by participants logging presence and severity of Covid-19 signs and symptoms from day 1 to 28. Secondary end point was Covid-19 related hospitalization and death through day 28.

Overall, rates of hospitalization and death were low* (0.8% in treatment group vs 1.6% in placebo group), and the difference was not statistically significant (difference of -0.8%, 95%CI, -3.3 to 0.7). That said, this study was not adequately powered to assess this question. This study also suggested that symptom and viral rebound were not statistically associated with nirmatrevir-ritonavir use (contrary to some other studies), and that symptoms from this are not severe. There was not a significant difference in the number of adverse events between the two groups (25.8% treatment vs 24.1% placebo). The most common treatment-related adverse events were dysgeusia (5.8%) and diarrhea (2.1%).

This study generates more questions for me than answers, as variation in risk factors across the study population were somewhat heterogeneous. The highest rate of hospitalizations occur in elderly patients who are immunocompromised or have heart or lung disease, and this group was not represented well in this study. I would also be interested in longer term follow up to understand if treatment impacts frequency of post-Covid conditions.

How will this change my practice?
Bottom line: we still need more studies. Antiviral treatment with nirmaltrevir-ritonavir benefits unvaccinated patients who are high-risk for severe disease* and even vaccinated vulnerable patients, but this benefit does not clearly extend to patients who are at lower risk. I will probably offer treatment to these highest risk patients, even when they are vaccinated, and defer in lower risk patients. For some bonus reading, see commentary on EPIC-SR in NEJM.

Editor’s note: It’s not a good look for Pfizer that it took so long for EPIC-SR to be published. As Paul Sax points out on the Journal Watch blog in a timeline, “August 2023, the negative results of EPIC-SR were posted on clinicaltrials.gov. Yes, these results have been in the public domain since last summer.” ~Clay Smith

Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19. N Engl J Med. 2024 Apr 4;390(13):1186-1195. doi: 10.1056/NEJMoa2309003. PMID: 38598573.

*Recall that in the EPIC-HR study of high-risk unvaccinated individuals, rate of hospitalization in placebo group was ~6.3%.

What are your thoughts?