Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19
et al., NEJM, July 23, 2020, doi:10.1056/NEJMoa2019014
, Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19, NEJM, July 23, 2020, doi:10.1056/NEJMoa2019014
Late stage RCT of 667 hospitalized patients with up to 14 days of symptoms at enrollment and receiving up to 4 liters per minute supplemental oxygen, not finding a significant effect after 15 days.Authors note: "the trial cannot definitively rule out either a substantial benefit of the trial drugs or a substantial harm", sample sizes are too small.The paper uses the terms mild and moderate, however all patients had serious enough disease to be hospitalized, and 14% were actually randomized in the ICU.The trial had significant protocol deviations and unusually low medication adherence. Randomization resulted in 64.3% male patients (HCQ) vs. 54.2% (control) which may significantly affect results due to the much higher risk for male patients.Authors note: "our aim was to exclude patients already receiving longer and potentially therapeutic doses of the study treatments" in explanation for why the study protocol was changed to exclude patients with previous use of the medications >24hrs. Analyzing these patients rather than excluding them may have revealed effectiveness with early use as shown in other studies.The trial initially required enrollment within 48 hours of admission and was changed to remove this requirement, this change is likely to reduce effectiveness because enrollment was moved later, compared to the time the disease became serious enough for hospitalization. Total HCQ dosage 5.6g.A correction for 17 errors has been published: [nejm.org]Although the 16% lower mortality is not statistically significant, it is consistent with the significant 22% lower mortality [18‑27%] from meta analysis of the 232 mortality results to date.
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risk of death, 16.0% lower, RR 0.84, p = 0.77, treatment 8 of 331 (2.4%), control 5 of 173 (2.9%), NNT 211, HCQ+HCQ/AZ.
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risk of hospitalization, 28.0% higher, RR 1.28, p = 0.30, treatment 331, control 173, HCQ+HCQ/AZ.
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| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
Cavalcanti et al., 23 Jul 2020, Randomized Controlled Trial, Brazil, peer-reviewed, baseline oxygen required 41.8%, 14 authors, average treatment delay 7.0 days.
Abstract: The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Original Article
Hydroxychloroquine with or without
Azithromycin in Mild-to-Moderate Covid-19
A.B. Cavalcanti, F.G. Zampieri, R.G. Rosa, L.C.P. Azevedo, V.C. Veiga, A. Avezum,
L.P. Damiani, A. Marcadenti, L. Kawano‑Dourado, T. Lisboa, D.L.M. Junqueira,
P.G.M. de Barros e Silva, L. Tramujas, E.O. Abreu‑Silva, L.N. Laranjeira,
A.T. Soares, L.S. Echenique, A.J. Pereira, F.G.R. Freitas, O.C.E. Gebara,
V.C.S. Dantas, R.H.M. Furtado, E.P. Milan, N.A. Golin, F.F. Cardoso, I.S. Maia,
C.R. Hoffmann Filho, A.P.M. Kormann, R.B. Amazonas, M.F. Bocchi de Oliveira,
A. Serpa‑Neto, M. Falavigna, R.D. Lopes, F.R. Machado, and O. Berwanger,
for the Coalition Covid-19 Brazil I Investigators*
A BS T R AC T
BACKGROUND
Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of
these therapies is limited.
METHODS
We conducted a multicenter, randomized, open-label, three-group, controlled trial
involving hospitalized patients with suspected or confirmed Covid-19 who were
receiving either no supplemental oxygen or a maximum of 4 liters per minute of
supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive
standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice
daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily
plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome
was clinical status at 15 days as assessed with the use of a seven-level ordinal scale
(with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed.
The authors’ full names, academic degrees, and affiliations are listed in the
Appendix. Address reprint requests to Dr.
Cavalcanti at HCor Research Institute, Rua
Abílio Soares 250, 12th Fl., São Paulo,
04005-909, Brazil, or at abiasi@hcor.com.br.
*A list of the Coalition Covid-19 Brazil I
Investigators is provided in the Supplementary Appendix, available at NEJM.org.
Drs. Cavalcanti and Zampieri contributed
equally to this article.
This article was published on July 23,
2020, and updated on September 10, 2020,
at NEJM.org.
N Engl J Med 2020;383:2041-52.
DOI: 10.1056/NEJMoa2019014
Copyright © 2020 Massachusetts Medical Society.
RESULTS
A total of 667 patients underwent randomization; 504 patients had confirmed
Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the
seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine
alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or
hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73;
P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme
levels were more frequent in patients receiving hydroxychloroquine, alone or with
azithromycin, than in those who were not receiving either agent.
CONCLUSIONS
Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days
as compared with standard care. (Funded by the Coalition Covid-19 Brazil and
EMS Pharma; ClinicalTrials.gov number, NCT04322123.)
n engl j med..
Late treatment
is less effective
is less effective
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