Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial

Abstract

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. (ClinicalTrials.gov: 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.

Primary funding source: Private donors.

Visual Abstract.. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19

There is no known effective oral therapy for early COVID-19. This randomized, double-blind, placebo-controlled trial evaluated effects of oral hydroxychloroquine on symptoms and disease severity in adult outpatients with early COVID-19.

Figure 1.. Study flow diagram.

Eligible participants were allocated in a 1:1 ratio to receive masked placebo or hydroxychloroquine, 800 mg (4 tablets) once, then 600 mg (3 tablets) in 6–8 h, then 600 mg (3 tablets) daily for 4 more days. Persons who were exposed to a contact with a positive result on a polymerase chain reaction (PCR) test and who remained asymptomatic (n = 821) were enrolled in our companion trial on postexposure prophylaxis (11); however, 100 persons became symptomatic before receiving study medicine on day 1 and were included in this early treatment trial, as per the protocol-specified plan. Of these, 81 met the U.S. coronavirus disease 2019 (COVID-19) case definition on day 1 on the basis of their symptom complex, whereas 19 were possible COVID-19 on day 1 (10). Most of the 2237 symptomatic persons who were ineligible had >4 d of symptoms (55%) or did not have access to PCR testing (41%). PrEP = preexposure prophylaxis.

Figure 2.. Venn diagram of qualification for study enrollment.

Venn diagram showing the distribution of how 378 participants qualified for enrollment. Two of 3 major symptoms were from among cough, shortness of breath, and fever. An additional 26 participants qualified by having pending (or unavailable) PCR tests at entry, having symptoms compatible with coronavirus disease 2019 (COVID-19), and meeting the case definition after adjudication by an infectious disease physician (10). Five persons later reported PCR-positive contact, with test results returning after enrollment. In addition, 19 initially asymptomatic persons who had been randomly assigned in the postexposure prophylaxis trial (11) developed new symptoms on day 1 but not 2 of 3 major symptoms. Figure 5 shows hierarchical outcomes by confirmed PCR positive, contact PCR positive, or probable case only. PCR = polymerase chain reaction.

Figure 3.. Percentage of participants with ongoing COVID-19 symptoms.

The percentage of participants reporting symptoms over time did not statistically differ by use of hydroxychloroquine or placebo. By day 14, the proportion of hydroxychloroquine participants with symptoms was 6 percentage points less than that of placebo participants (24% vs. 30%; P = 0.21). The stacked bar graph distinguishes the relative proportions of those with presentation of cough, fever, or shortness of breath vs. other COVID-19–related symptoms. Exact percentages can be found in Supplement Figure 2. COVID-19 = coronavirus disease 2019.

Figure 4.. Overall symptom severity score over 14 d.

At each visit, participants reported their overall severity of coronavirus disease 2019 (COVID-19) symptoms on a continuous visual analogue scale of 0–10 points. The primary end point (overall change in symptom severity score) was calculated with linear mixed-effects models, adjusted for baseline severity score. Hydroxychloroquine was associated with a 12% relative difference over placebo, based on an absolute difference of −0.27 (95% CI, −0.61 to 0.07; P = 0.117) on the visual analogue scale. Supplement Table 4) shows mean values and 95% CIs. At day 5, symptom severity had worsened from baseline in 16% of participants receiving hydroxychloroquine and 20% of those receiving placebo.

Figure 5.. Change in symptom severity score over 14 d, by a priori subgroups.

Mean change from baseline and estimated difference from a longitudinal mixed model adjusted for baseline severity score. P values for trend of continuous variables are in parentheses. Subgroups were defined a priori in the protocol. The final diagnosis includes all diagnostic testing results during the study period. Probable diagnosis is based on the U.S. clinical case definition (10). The final diagnosis categories are hierarchical as listed (and thus mutually exclusive). Participants with symptom duration of 1–2 d before enrollment in the hydroxychloroquine group had a larger reduction in symptom score than those receiving placebo, but this was not observed in those who enrolled with symptom durations <1 d, where one might expect an even greater effect if hydroxychloroquine therapy helped mitigate disease severity if started very early in the disease course. Additional post hoc subgroups of medication adherence, zinc, and vitamin C are presented in Supplement Table 2.