New England Journal of Medicine FEBRUARY 16, 2022

Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19 (EPIC-HR)

Jennifer Hammond, Heidi Leister-Tebbe, Annie Gardner, Paula Abreu, Weihang Bao, Wayne Wisemandle, Marylynn Baniecki, Victoria M. Hendrick, Bharat Damle, Abraham Simón-Campos, Rienk Pypstra, James M. Rusnak

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Bottom Line

In unvaccinated, non-hospitalized adults at high risk of severe COVID-19, initiation of nirmatrelvir-ritonavir within five days of symptom onset significantly reduced the risk of COVID-19-related hospitalization or death by 88%.

Key Findings

1. Nirmatrelvir-ritonavir (Paxlovid) demonstrated an 89% relative risk reduction in COVID-19-related hospitalization or death through Day 28 when administered within 3 days of symptom onset (0.7% in the treatment arm vs. 6.5% in the placebo arm; P<0.0001).

2. When administered within 5 days of symptom onset, treatment resulted in an 88% relative risk reduction in hospitalization or death compared to placebo (0.8% in the treatment arm vs. 6.3% in the placebo arm; P<0.0001).

3. There were no deaths reported in the nirmatrelvir-ritonavir treatment arm, compared to 12 deaths in the placebo arm by Day 28.

4. Treatment-emergent adverse events were similar between the treatment (22.6%) and placebo (23.9%) groups, with serious adverse events reported less frequently in the treatment group (1.6% vs 6.6%).

Study Design

Design

RCT

Double-Blind

Sample

2,246

Patients

Duration

28 days

Median

Setting

Multicenter, Global

Population Symptomatic, unvaccinated, non-hospitalized adults at high risk for progression to severe COVID-19.

Intervention Nirmatrelvir (300 mg) plus ritonavir (100 mg) administered orally every 12 hours for 5 days.

Comparator Matching placebo administered orally every 12 hours for 5 days.

Outcome Proportion of participants with COVID-19–related hospitalization or death from any cause through Day 28.

Study Limitations

• The trial was conducted in a population that was unvaccinated and primarily infected with the Delta variant, limiting generalizability to vaccinated individuals or populations infected with subsequent, potentially less virulent variants.

• The study excluded patients who were expected to receive monoclonal antibody treatment or had previously received it, potentially limiting its application in broader clinical settings where such therapies might be indicated.

• The trial did not evaluate the efficacy of the treatment in preventing long-term sequelae of COVID-19 (post-acute sequelae of SARS-CoV-2).

• The study was stopped early by the Data Monitoring Committee due to overwhelming efficacy, which can sometimes lead to an overestimation of the treatment effect.

Clinical Significance

The EPIC-HR trial provided the foundational clinical evidence for the emergency use authorization and eventual approval of nirmatrelvir-ritonavir as a first-line oral antiviral therapy for high-risk, non-hospitalized patients to prevent disease progression, hospitalization, and death.

Historical Context

The EPIC-HR trial was conducted during the height of the COVID-19 pandemic in 2021, primarily while the Delta variant was dominant, addressing an urgent need for easily administered oral treatments to reduce pressure on healthcare systems.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Explain the mechanistic synergy between nirmatrelvir and ritonavir as presented in the EPIC-HR trial, and why nirmatrelvir cannot be administered effectively as a monotherapy?

Key Response

Nirmatrelvir is a reversible inhibitor of the SARS-CoV-2 main protease (Mpro), which is essential for processing viral polyproteins. However, it is rapidly metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Ritonavir, while an HIV protease inhibitor, is used here solely as a pharmacokinetic 'booster' to inhibit CYP3A4, thereby maintaining therapeutic plasma concentrations of nirmatrelvir necessary to inhibit viral replication over the 5-day treatment course.

Resident

The EPIC-HR trial required treatment initiation within 5 days of symptom onset. In a clinical setting, what are the most critical contraindications and drug-drug interactions (DDIs) that a resident must screen for before prescribing Paxlovid to a high-risk patient?

Key Response

Due to ritonavir's potent inhibition of CYP3A4, Paxlovid is contraindicated with drugs that have high dependency on this pathway for clearance and where elevated levels lead to serious reactions (e.g., amiodarone, certain statins, rivaroxaban, and midazolam). Residents must also assess renal function, as the dose must be adjusted for moderate renal impairment (eGFR 30-60 mL/min) and is not recommended for severe impairment (eGFR <30 mL/min).

Fellow

How do the findings of EPIC-HR, which focused on an immunologically naive population during the Delta variant surge, translate to the management of immunocompromised patients who are fully vaccinated but fail to mount an adequate serologic response?

Key Response

While EPIC-HR targeted unvaccinated individuals, the fellow must integrate evidence suggesting that patients with impaired B-cell or T-cell function remain at high risk for progression regardless of vaccination status. In these cases, the 88% relative risk reduction observed in the trial provides a strong rationale for use, though clinicians must be vigilant for prolonged viral shedding which may necessitate longer or repeated courses, a concept currently outside the trial's 5-day protocol.

Attending

Given the absolute risk reduction (ARR) of approximately 6% observed in EPIC-HR, how should we adapt our 'test-and-treat' strategy for lower-risk vaccinated patients where the baseline risk of hospitalization is significantly lower than that of the trial cohort?

Key Response

In the EPIC-HR high-risk, unvaccinated cohort, the NNT was approximately 17 to prevent one hospitalization or death. In a vaccinated, low-risk population, the ARR would be much smaller, potentially increasing the NNT to hundreds. Attendings must lead the discussion on cost-effectiveness and the prioritization of resources, shifting focus toward those with the highest 'clinical' risk (e.g., the elderly or those with multiple comorbidities) rather than applying the trial's broad inclusion criteria to the general population.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the primary composite endpoint of 'COVID-19-related hospitalization or death from any cause' used in EPIC-HR. How might the inclusion of all-cause mortality versus COVID-specific mortality influence the power of the study and the interpretation of the hazard ratio?

Key Response

By including all-cause mortality, the researchers ensure that deaths potentially caused by drug toxicity or indirect complications of COVID-19 are captured, which increases the trial's safety signal detection. However, if non-COVID deaths were frequent, it could dilute the perceived efficacy of the antiviral. In EPIC-HR, the overwhelming majority of events were hospitalizations, and the lack of deaths in the treatment group versus 12 in the placebo group strongly suggests that the composite endpoint was driven by the drug's specific effect on viral progression.

Journal Editor

As a peer reviewer, the EPIC-HR trial was stopped early for efficacy after an interim analysis. What are the potential statistical risks of stopping a trial early, and did the magnitude of effect in this case justify the loss of long-term safety and efficacy data in the full planned cohort?

Key Response

Stopping early for efficacy (truncation) can lead to an overestimation of the treatment effect size and a smaller-than-ideal safety database. However, with a p-value of <0.001 and an 88% risk reduction, the ethical imperative to provide the drug to the placebo group usually outweighs the need for additional precision. Editors would look for whether the O'Brien-Fleming or similar conservative stopping boundaries were strictly followed to maintain the alpha level.

Guideline Committee

The NIH and IDSA guidelines prioritize nirmatrelvir-ritonavir over molnupiravir and remdesivir for non-hospitalized patients. Based on EPIC-HR, what specific criteria should define the 'high-risk' tiering if supply shortages occur, and how do these findings compare to the MOVE-OUT trial results for molnupiravir?

Key Response

EPIC-HR showed 88% efficacy compared to the roughly 30% efficacy seen in the MOVE-OUT trial for molnupiravir, justifying its higher-tier status in the NIH/IDSA guidelines. The committee must decide if the 'high-risk' definition should remain tied to the trial's criteria (unvaccinated/comorbidities) or evolve to include age >65 regardless of vaccination status, as age remains the strongest predictor of severe outcomes in the post-EPIC-HR era.

Clinical Landscape

Noteworthy Related Trials

2020

RECOVERY Trial

n = 11,500 · NEJM

Tested

Dexamethasone 6 mg once daily

Population

Hospitalized patients with COVID-19

Comparator

Standard care

Endpoint

28-day mortality

Key result: Dexamethasone reduced deaths by one-third in ventilated patients and by one-fifth in other patients receiving oxygen.

2021

PINETREE Trial

n = 562 · NEJM

Tested

Remdesivir (3-day intravenous course)

Population

Nonhospitalized patients with COVID-19 at high risk of disease progression

Comparator

Placebo

Endpoint

COVID-19-related hospitalization or all-cause death by day 28

Key result: A 3-day course of remdesivir significantly reduced the risk of hospitalization or death by 87% compared to placebo.

2022

ACTIV-2/A5401 Trial

n = 2,096 · NEJM

Tested

Sotrovimab 500 mg intravenously

Population

Nonhospitalized adults with mild-to-moderate COVID-19

Comparator

Placebo

Endpoint

Hospitalization or death by day 29

Key result: Sotrovimab reduced the risk of progression to severe COVID-19 by 85% among high-risk patients.

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