Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial
RECOVERY,
Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre,..,
Collaborative Group, NEJM, doi:10.1056/NEJMoa2022926 (press release 6/5) (Preprint), RECOVERY, NCT04381936
RECOVERY trial finds no significant benefit for very late stage (9 days after symptom onset) very sick patients. Results may be due to the unusually high dosage used (9.2g total over 10 days)
[, ].
The overall dosage used is only 23% less than the high dosage that Borba et al. show greatly increases risk (OR 2.8)
[Borba].
Authors do not report results based on weight, BMI, or related conditions such as diabetes, which may provide additional evidence of toxic dosages. Authors do not adjust dosage based on patient weight, so toxicity may be higher in patients of lower weight.
KM curves show a spike in HCQ mortality days 5-8, corresponding to ~85% of the total excess seen at day 28 (a similar spike is seen in the SOLIDARITY trial).
Authors note: "we did not observe excess mortality in the first 2 days of treatment ... when early effects of dose-dependent toxicity might be expected", but they are ignoring the very long half-life of HCQ and the dosing regimen - much higher levels of HCQ will be reached later. Increased mortality in Borba et al. occurred after 2 days.
Patients were extremely sick (median 9 days post symptoms, 60% requiring oxygen and an additional 17% requiring ventilation/ECMO), with an unusually high mortality rate was seen in both arms. 1,561 HCQ patients, 3,155 SOC.
A secondary analysis has found several inconsistencies in the data:
[francesoir.fr]. Hypoxia may inhibit HCQ entering cells
[], making it less effective for late stage use. For more on the dosing problems see
[kristianfranciscomillanielsen.medium.com], also noting that concentrations vary substantially in different tissues and lung concentration may be >30x plasma concentration.
This study is excluded in the after exclusion results of meta
analysis:
excessive dosage in late stage patients, results do not apply to typical dosages.
risk of death, 9.0% higher, RR 1.09, p = 0.15, treatment 421 of 1,561 (27.0%), control 790 of 3,155 (25.0%).
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risk of mechanical ventilation, 15.0% higher, RR 1.15, p = 0.19, treatment 128 of 1,300 (9.8%), control 225 of 2,623 (8.6%).
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Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
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RECOVERY et al., 5 Jun 2020, Randomized Controlled Trial, United Kingdom, preprint, baseline oxygen required 76.8%, 29 authors, average treatment delay 9.0 days, trial
NCT04381936 (history) (RECOVERY).
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
Effect of Hydroxychloroquine
in Hospitalized Patients with Covid-19
The RECOVERY Collaborative Group*
A BS T R AC T
BACKGROUND
The members of the writing committee
(Peter Horby, F.R.C.P., Marion Mafham,
M.D., Louise Linsell, D.Phil., Jennifer L.
Bell, M.Sc., Natalie Staplin, Ph.D., Jonathan R. Emberson, Ph.D., Martin Wiselka,
Ph.D., Andrew Ustianowski, Ph.D., Einas
Elmahi, M.Phil., Benjamin Prudon, F.R.C.P.,
Tony Whitehouse, F.R.C.A., Timothy Felton, Ph.D., John Williams, M.R.C.P., Jakki
Faccenda, M.D., Jonathan Underwood,
Ph.D., J. Kenneth Baillie, M.D., Ph.D.,
Lucy C. Chappell, Ph.D., Saul N. Faust,
F.R.C.P.C.H., Thomas Jaki, Ph.D., Katie
Jeffery, Ph.D., Wei Shen Lim, F.R.C.P.,
Alan Montgomery, Ph.D., Kathryn Rowan,
Ph.D., Joel Tarning, Ph.D., James A. Watson, D.Phil., Nicholas J. White, F.R.S., Edmund Juszczak, M.Sc., Richard Haynes,
D.M., and Martin J. Landray, Ph.D.) assume responsibility for the overall content and integrity of this article.
The affiliations of the members of the
writing committee are listed in the Appendix. Address reprint requests to Dr.
Horby or Dr. Landray at the RECOVERY
Central Coordinating Office, Richard Doll
Bldg., Old Road Campus, Roosevelt Dr.,
Oxford OX3 7LF, United Kingdom, or at
recoverytrial@ndph.ox.ac.uk.
*A complete list of collaborators in the
RECOVERY trial is provided in the Supplementary Appendix, available at NEJM.org.
Drs. Horby, Mafham, and Linsell and Prof.
Juszczak, Dr. Haynes, and Dr. Landray
contributed equally to this article.
This article was published on October 8,
2020, at NEJM.org.
This is the New England Journal of Medicine
version of record, which includes all Journal
editing and enhancements. The Author Final Manuscript, which is the author’s version after external peer review and before
publication in the Journal, is available under a CC BY license at PMC7556338.
Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from
uncontrolled studies and small, randomized trials.
METHODS
In this randomized, controlled, open-label platform trial comparing a range of
possible treatments with usual care in patients hospitalized with Covid-19, we
randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive
usual care. The primary outcome was 28-day mortality.
RESULTS
The enrollment of patients in the hydroxychloroquine group was closed on June 5,
2020, after an interim analysis determined that there was a lack of efficacy. Death
within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group
and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P = 0.15). Consistent results were seen in all prespecified
subgroups of patients. The results suggest that patients in the hydroxychloroquine
group were less likely to be discharged from the hospital alive within 28 days than
those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to
0.98). Among the patients who were not undergoing mechanical ventilation at
baseline, those in the hydroxychloroquine group had a higher frequency of invasive
mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to
1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points)
but no difference in the incidence of new major..
Late treatment
is less effective
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