Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19
EPIC-HR RCT, 1,039 higher risk patients treated with paxlovid (PF-07321332 + ritonavir) and 1,046 control patients, showing significantly lower mortality and hospitalization with treatment. NCT04960202 (history)
risk of death, 96.0% lower, RR 0.04, p < 0.001, treatment 0 of 1,039 (0.0%), control 12 of 1,046 (1.1%), NNT 87, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), within 5 days.
risk of death, 94.8% lower, RR 0.05, p = 0.002, treatment 0 of 697 (0.0%), control 9 of 682 (1.3%), NNT 76, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), within 3 days.
risk of hospitalization, 87.6% lower, RR 0.12, p < 0.001, treatment 8 of 1,039 (0.8%), control 65 of 1,046 (6.2%), NNT 18, within 5 days.
risk of hospitalization, 88.9% lower, RR 0.11, p < 0.001, treatment 5 of 697 (0.7%), control 44 of 682 (6.5%), NNT 17, within 3 days.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Hammond et al., 16 Feb 2022, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, 12 authors, average treatment delay 2.93 days, trial NCT04960202 (history)
Abstract: T h e n e w e ng l a n d j o u r na l o f m e dic i n e
Oral Nirmatrelvir for High-Risk,
Nonhospitalized Adults with Covid-19
Jennifer Hammond, Ph.D., Heidi Leister‑Tebbe, B.S.N.,
Annie Gardner, M.P.H., M.S.P.T., Paula Abreu, Ph.D., Weihang Bao, Ph.D.,
Wayne Wisemandle, M.A., MaryLynn Baniecki, Ph.D., Victoria M. Hendrick, B.Sc.,
Bharat Damle, Ph.D., Abraham Simón‑Campos, M.D., Rienk Pypstra, M.D.,
and James M. Rusnak, M.D., Ph.D., for the EPIC-HR Investigators*
A BS T R AC T
Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus
2 main protease (Mpro) inhibitor with potent pan–human-coronavirus activity in vitro.
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.
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.
From Global Product Development, Pfizer, Collegeville, PA (J.H., H.L.-T.); Global
Product Development (A.G.) and Early
Clinical Development (M.L.B.), Pfizer,
Cambridge, MA; Global Product Development, Pfizer, New York (P.A., W.B.,
B.D., R.P.); Global Product Development,
Pfizer, Lake Forest, IL (W.W.); Medical
and Safety, Pfizer, Sandwich, United
Kingdom (V.M.H.); Köhler and Milstein
Research, Mérida, Yucatan, Mexico
(A.S.-C.); and Global Product Development, Pfizer, Tampa, FL (J.M.R.). Dr.
Hammond can be contacted at jennifer
.email@example.com, or at Pfizer,..
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