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Randomized Controlled Trial
. 2020 May 7;382(19):1787-1799.
doi: 10.1056/NEJMoa2001282. Epub 2020 Mar 18.

A Trial of Lopinavir-Ritonavir in Adults Hospitalized With Severe Covid-19

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Free PMC article
Randomized Controlled Trial

A Trial of Lopinavir-Ritonavir in Adults Hospitalized With Severe Covid-19

Bin Cao et al. N Engl J Med. .
Free PMC article

Abstract

Background: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.

Methods: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.

Results: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.

Conclusions: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).

Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Figures

Figure 1
Figure 1. Randomization and Treatment Assignment.
Figure 2
Figure 2. Time to Clinical Improvement in the Intention-to-Treat Population.
Figure 3
Figure 3. Mean Change from Baseline in SARS-CoV-2 Viral RNA Load by qPCR on Throat Swabs.
bars indicate 95% confidence intervals. Results less than the lower limit of quantification of polymerase-chain-reaction (PCR) assay and greater than the limit of qualitative detection are imputed with 1 log10 copies per milliliter; results for patients with viral-negative RNA are imputed with 0 log10 copies per milliliter. Among the 199 patients, 130 (59 patients in the lopinavir–ritonavir group and 71 in the standard-care group) had virologic data that were used for viral load calculation, whereas the rest of the patients had undetectable viral RNA on throat swabs over the time.

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