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EPIC-HR RCT – Nirmatrelvir Highly Effective for Outpatients with COVID-19

April 26, 2022

Written by Laura Murphy

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For outpatients with mild-to-moderate Covid-19 at risk of progression to severe disease, treatment with nirmatrelvir and ritonavir within 5 days of symptom onset reduced 28-day hospitalization or death.

Why is this important?
As the COVID-19 pandemic continues, we continue to search for effective treatment options.. This trial studied the efficacy and safety of nirmatrelvir-ritonavir (Paxlovid) as a treatment for nonhospitalized patients with mild-to-moderate COVID-19 at risk for progression to severe disease.

The treatment we’ve all been waiting for?
Nirmatrelvir is an oral medication that targets a specific protease enzyme in the SARS-CoV-2 replication cycle, and is coadministered with CYP3A4 inhibitor (ritonavir) to enhance its pharmacokinetics. The EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High Risk Patients) was an industry-sponsored, phase 2-3 double-blind, randomized controlled trial that evaluated the efficacy and safety of nirmatrelvir and ritonavir for treatment of mild-to-moderate Covid-19 in patients with at least one risk factor for progression to severe disease. These included age ≥ 60, BMI > 25 kg/m2, smoking, immunosuppressive disease or iatrogenic immunosuppression, chronic lung, cardiovascular, kidney, or sickle cell disease, hypertension, diabetes, cancer, neurodevelopmental disorders or other medically complex conditions.

The trial excluded patients with prior confirmed SARS-CoV-2 infection or hospitalization for Covid-19, anticipated need for hospitalization within 48 hours after randomization, prior receipt of convalescent Covid-19 plasma or SARS-CoV-2 vaccine, pregnancy or breastfeeding, history of renal impairment, known HIV (viral load >400 copies/mL) or suspected active systemic infection, comorbidity requiring hospitalization/surgery ≤7 days prior to study entry or disease considered life-threatening ≤30 days prior to study entry.

Patient characteristics were similar between the treatment and placebo groups. The primary analysis was conducted in a modified intention-to-treat population including patients who began treatment within 3 days of symptom onset and did not receive monoclonal antibodies (only 1,379 of the 2,246 enrolled patients). The primary outcome, a composite of Covid-19 related hospitalization or death by day 28, was lower in the nirmatrelvir group compared to placebo (0.72% vs 6.53%, -5.81 percentage points, 95%CI -7.78 to -3.84, P<0.001) with relative risk reduction of 88.9%. There was a 1.3% reduction in mortality in the treatment group. The supplementary index includes the results of multiple prespecified subgroup analyses, and results were consistent with the primary analysis.

Secondary analyses showed that treatment group had reduction in viral load at day 5 of treatment and a similar incidence of adverse events when compared to placebo group. The most common treatment-related adverse events were dysgeusia and diarrhea.

While these results are promising, this study had strict inclusion criteria, so further data will be needed to determine if the treatment benefit is generalizable to patients outside of the study group or superior to other treatment options.  NIH guidelines currently recommend its use (more here); stay tuned for further studies on its use.

Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med 2022 Apr 14; 386(15): 1397-1408. Doi: 10.1056/NEJMoa2118542. Epub 2022 Feb 16.