COVID-19 Evidence Alerts
from McMaster PLUSTM

Current best evidence for clinical care (more info)

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Treatment Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial. Ann Intern Med. 2020 Oct 20;173(8):623-631. doi: 10.7326/M20-4207. Epub 2020 Jul 16.

BACKGROUND: No effective oral therapy exists for early coronavirus disease 2019 (COVID-19).

OBJECTIVE: To investigate whether hydroxychloroquine could reduce COVID-19 severity in adult outpatients.

DESIGN: Randomized, double-blind, placebo-controlled trial conducted from 22 March through 20 May 2020. ( NCT04308668).

SETTING: Internet-based trial across the United States and Canada (40 states and 3 provinces).

PARTICIPANTS: Symptomatic, nonhospitalized adults with laboratory-confirmed COVID-19 or probable COVID-19 and high-risk exposure within 4 days of symptom onset.

INTERVENTION: Oral hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days) or masked placebo.

MEASUREMENTS: Symptoms and severity at baseline and then at days 3, 5, 10, and 14 using a 10-point visual analogue scale. The primary end point was change in overall symptom severity over 14 days.

RESULTS: Of 491 patients randomly assigned to a group, 423 contributed primary end point data. Of these, 341 (81%) had laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or epidemiologically linked exposure to a person with laboratory-confirmed infection; 56% (236 of 423) were enrolled within 1 day of symptoms starting. Change in symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups (difference in symptom severity: relative, 12%; absolute, -0.27 point [95% CI, -0.61 to 0.07 point]; P = 0.117). At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receiving placebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine versus 22% (46 of 211) receiving placebo (P < 0.001). With placebo, 10 hospitalizations occurred (2 non-COVID-19-related), including 1 hospitalized death. With hydroxychloroquine, 4 hospitalizations occurred plus 1 nonhospitalized death (P = 0.29).

LIMITATION: Only 58% of participants received SARS-CoV-2 testing because of severe U.S. testing shortages.

CONCLUSION: Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19.


Discipline / Specialty Area Score
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)
Infectious Disease
Public Health
Comments from MORE raters

Family Medicine (FM)/General Practice (GP) rater

I am a primary care physician who evaluates patients for SARS-CoV-2. This was a very well conducted RCT of hydroxychloroquine for early COVID-19. The study found a higher rate of adverse effects with hydroxychloroquine compared with placebo (mainly gastrointestinal), and no clear benefits of hydroxychloroquine treatment.

General Internal Medicine-Primary Care(US) rater

This is very timely, but I imagine most physicians have already heard this in the lay press. It might be worthwhile to actually see the data.

Infectious Disease rater

This study adds to the already substantial evidence that hydroxychloroquine, despite a biologically plausible mechanism of action against SARS-CoV-2, has no real or practical role in clinical practice.

Public Health rater

Good study with results that have the potential to guide policy. One of the unmentioned limitations of the reported findings is the 14% loss to follow-up that is relatively high. The reported high rate of adverse events (43%) in a group that took hydroxychloroquine would have affected its optimal uptake (effectiveness).

Respirology/Pulmonology rater

Very important information to forward to State Chiefs (not sure they will understand).