18 febrero, 2022

Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19

Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M^pro) inhibitor with potent pan–human-coronavirus activity in vitro.

METHODS

We conducted a phase 2–3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19–related hospitalization or death from any cause through day 28, viral load, and safety were evaluated.

RESULTS

A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19–related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], −9.04 to −3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of −5.81 percentage points (95% CI, −7.78 to −3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmaltrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of −0.868 log₁₀ copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo.

CONCLUSIONS

Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202. opens in new tab.)

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and illness with the associated coronavirus disease 2019 (Covid-19) continue to threaten global health.¹ Persons with particular characteristics such as older age, current smoking, or underlying clinical conditions such as cardiovascular disease, diabetes, obesity, and cancer are at high risk for severe Covid-19 and associated adverse outcomes.^2-5 In a meta-analysis, patients with prespecified coexisting conditions were approximately twice as likely to have progression to severe Covid-19 and five times as likely to die from Covid-19 as patients without those conditions.⁴ Mortality among older adults may be greater than that among persons with prespecified coexisting conditions.^2,3,6

A need exists for safe and effective oral Covid-19 treatments that can prevent the progression of infection to more severe disease, hospitalization, and death; shorten the time to clinical recovery; and reduce the transmission rate. Such treatments would help reduce current strains on health care systems, including overwhelmed hospital facilities and lack of beds in intensive care units. For nonhospitalized patients with mild-to-moderate Covid-19, treatment options include monoclonal antibodies, which are currently available under emergency use authorization by the Food and Drug Administration for patients at high risk for progression to severe Covid-19.^7-10 Although monoclonal antibodies significantly reduce the risk of progression to severe Covid-19,^11-13 limitations to their use include the need for administration and monitoring in a health care setting and the potential for reduced efficacy against emerging SARS-CoV-2 variants.¹⁰

Nirmatrelvir (PF-07321332) is an orally administered antiviral agent targeting the SARS-CoV-2 3-chymotrypsin–like cysteine protease enzyme (M^pro).¹⁴ M^pro is an attractive antiviral target because it is essential in the viral replication cycle (i.e., in processing viral polyproteins into functional units)¹⁵ and has a low likelihood of off-target activity, owing to the absence of recognized human analogues.¹⁶ Nirmatrelvir exhibited potent inhibition of M^pro activity and virus replication across a wide spectrum of coronaviruses in vitro; oral administration was associated with SARS-CoV-2 lung titers that were significantly lower than titers associated with placebo in a mouse model.¹⁴ Nirmatrelvir is metabolized mainly by CYP3A4.¹⁴ Coadministration of nirmatrelvir with a low dose (100 mg) of ritonavir, a CYP3A4 inhibitor, enhances nirmatrelvir pharmacokinetics.^14,17 A first-in-human study in healthy participants (ClinicalTrials.gov number, NCT04756531. opens in new tab) showed a clinically acceptable safety profile up to the highest dose and exposure evaluated (500 mg of nirmatrelvir plus 100 mg of ritonavir twice daily for 10 days). Simulations showed that twice-daily administration of 300 mg of nirmatrelvir plus 100 mg of ritonavir achieves and maintains plasma trough concentrations approximately five to six times the in vitro 90% effective concentration of nirmatrelvir (i.e., the concentration at which 90% inhibition of SARS-CoV-2 viral replication is observed) (data on file).

The EPIC-HR trial (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) evaluated the safety and efficacy of nirmatrelvir plus ritonavir in nonhospitalized adults with mild-to-moderate Covid-19 at high risk for progression to severe disease.

Methods

OBJECTIVES, PATIENTS, AND OVERSIGHT

This phase 2–3, double-blind, randomized, placebo-controlled trial evaluated the efficacy, viral load, and safety associated with the use of nirmatrelvir plus ritonavir among nonhospitalized, symptomatic adults with Covid-19 who were at high risk for progression to severe disease. Eligible patients were required to be at least 18 years old; to have confirmed SARS-CoV-2 infection and symptom onset no more than 5 days before randomization, with at least one sign or symptom of Covid-19 on the day of randomization (see Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org); and to have at least one characteristic or coexisting condition associated with high risk of progression to severe Covid-19.^2-4,6 The trial was approved by an ethics committee at each site, and all participants provided written informed consent.

Key exclusion criteria were previous confirmed SARS-CoV-2 infection or hospitalization for Covid-19, anticipated need for hospitalization within 48 hours after randomization, and prior receipt of convalescent Covid-19 plasma or SARS-CoV-2 vaccine. The Supplementary Appendix provides additional inclusion and exclusion criteria and information on prohibited prior or concomitant therapies, trial blinding, ethical conduct, and responsibilities of the sponsor. All the data were available to all the authors, who vouch for the accuracy and completeness of the data as well as the adherence of the trial to the protocol, which is available at NEJM.org and includes the statistical analysis plan.

PROCEDURES

Eligible patients were randomly assigned in a 1:1 ratio, by means of an interactive response technology system, to receive either nirmatrelvir plus ritonavir or matched placebo every 12 hours for 5 days (10 doses total). Randomization was stratified by geographic region and by receipt or expected receipt (based on investigator opinion) of Covid-19 monoclonal antibodies. Nirmatrelvir and matching placebo were manufactured by Pfizer, ritonavir tablets were manufactured and tested by Hetero Labs, and blinding of the tablets was performed by Pfizer through over-encapsulation. The assessment schedule is outlined in Figure S1.

EFFICACY

The primary objective of the trial was to assess the efficacy of nirmatrelvir plus ritonavir as compared with placebo by comparing the percentage of patients with Covid-19–related hospitalization or death from any cause through day 28 in the two groups. This comparison was performed in the modified intention-to-treat population, which included patients whose treatment began within 3 days after the onset of Covid-19 signs and symptoms and excluded patients who at randomization had received or were expected to receive monoclonal antibody treatment (see Table S2 for definitions of all analysis populations). A key secondary end point was the primary comparison analyzed similarly among patients whose treatment began within 5 days after the onset of Covid-19 signs and symptoms. A supplementary analysis was conducted to include patients who had received or were expected to receive monoclonal antibody treatment. Prespecified subgroup analyses of primary and secondary end points were conducted, and nominal 95% confidence intervals were provided to evaluate whether the treatment effect varied according to age, sex, race, body-mass index (BMI, the weight in kilograms divided by the square of the height in meters), baseline serology status and viral load, and number of baseline coexisting conditions and risk factors (see the Supplementary Appendix for details on the serology methods).

VIRAL LOAD

Detection and quantification of SARS-CoV-2 viral load in nasopharyngeal swabs by reverse-transcriptase–polymerase-chain-reaction assay was a secondary end point. Nasopharyngeal or nasal swabs were collected on day 1 (baseline) and days 3, 5, 10, and 14.

SAFETY

Safety end points included adverse events that emerged during or after the treatment period (starting on or before day 34), serious adverse events, and adverse events leading to discontinuation of the trial drug or placebo, as coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 24.0. Incidence data were provided for each treatment group within the safety analysis population, which included all patients who received at least one dose of drug or placebo. Investigators actively collected safety information through day 34.

STATISTICAL ANALYSIS

The trial planned to enroll approximately 3000 patients. Of these, 1717 were to be included in the primary analysis to ensure 90% power, accounting for an interim analysis, to detect a 50% difference in Covid-19–related hospitalization or death from any cause with nirmatrelvir plus ritonavir, as compared with placebo (anticipated event rate with placebo, 7.0%)¹¹ in patients who had undergone randomization within 3 days after symptom onset and who received no monoclonal antibodies.

The primary analysis compared proportions of patients in the two groups who were hospitalized for Covid-19 or died from any cause through day 28, using the Kaplan–Meier method to account for all patients, including those prematurely withdrawn from the trial or lost to follow-up. A z-test was used for the comparison, with standard errors estimated from Greenwood’s formula. The end points were tested sequentially (i.e., first the primary end point, then the first key secondary end point, and finally other secondary end points) to ensure the overall alpha level of 0.05.

Changes from baseline to day 5 in log₁₀-transformed viral load were compared between treatment groups with an analysis of covariance (ANCOVA) model adjusted for baseline viral load and serology status. Patients without detectable virus at baseline were excluded from the analysis. Viral loads below the limit of detection (2 log₁₀ copies per milliliter) were imputed as 1.70 log₁₀ copies per milliliter.

On the basis of a group sequential design utilizing a Lan–DeMets alpha-spending function with an O’Brien–Fleming stopping boundary,^18,19 a prespecified interim analysis of the primary end point for efficacy, futility, and sample size re-estimation was performed by an external data monitoring committee once approximately 45% of patients in the primary analysis population had completed assessments through day 28. The prespecified significance level for early termination was 0.002 for efficacy and 0.9184 for futility. See the Supplementary Appendix for additional details regarding the statistical analyses, including handling of missing data.

https://www.nejm.org/doi/full/10.1056/NEJMoa2118542?fbclid=IwAR0MoibK59fsFIUlM6jiDNdpNRsHoq91eyJU9SZQyNcBr9PhwF-_WY9Sfjg

Créditos: Comité científico Covid