Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19

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 laboratoryconfirmed 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. Measures: 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, Ϫ0.27 points [95% CI, Ϫ0.61 to 0.07 points]; 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). Limitations: 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.

Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

“…Two trials compared convalescent plasma added to standard care versus standard care alone [ 40 , 52 ]. The remaining trials and comparisons included hydroxychloroquine with and without azithromycin added to standard care versus standard care alone [ 55 ], hydroxychloroquine versus placebo [ 54 , 68 ], hydroxychloroquine and chloroquine added to standard care versus standard care alone [ 49 ], methylprednisolone added to standard care versus standard care alone [ 57 ], lopinavir–ritonavir versus umifenovir and versus standard care [ 41 ], favipravir versus umifenovir [ 34 ], high-flow nasal oxygenation versus standard mask oxygenation prior to fibreotic tracheal intubation [ 45 ], α-lipoic acid versus placebo [ 47 ], the combination of novaferon plus lopinavir–ritonavir versus novaferon and versus lopinavir–ritonavir [ 46 ], baloxavir marboxil versus favipiravir and versus standard care [ 42 ], 5 versus 10 days of remdesivir [ 38 ], interferon β-1a added to standard care versus standard care alone [ 37 ], colchicine added to standard care versus standard care alone [ 50 ], high-dosage with low-dosage chloroquine diphosphate [ 51 ], intravenous immunoglobulin added to standard care versus standard care alone [ 58 ], ribavirin plus interferon alpha versus lopinavir/ritonavir plus interferon alpha versis ribavirin plus lopinavir/ritonavir plus interferon alpha [ 62 ], darunavir/cobicistat plus interferon alpha-2b versus interferon alpha-2b alone [ 61 ], lincomycin HCl versus azitromycin [ 63 ], 99mTc-methyl diphosphonate (99mTc-MDP) injection added to standard care versus standard care alone [ 64 ], and interferon alpha-2b plus gamma versus interferon alpha-2b alone [ 65 ].…”

“…We identified 8 trials comparing hydroxychloroquine added to standard care versus standard care alone [ 35 , 36 , 43 , 49 , 55 , 56 , 59 , 60 ]. We also identified one trial that used placebo as an additional control intervention [ 54 ]. All trials were assessed as at high risk of bias ( S3 Table ).…”

“…Visual inspection of the forest plot and measures to quantify heterogeneity (I 2 = 90%) indicated large heterogeneity. The assessment time points varied from 5 [ 35 , 36 , 54 ] to 28 [ 49 , 56 ] days after randomization. It was not possible to perform trial sequential analysis due to high diversity [ 9 ].…”

Cytokine Storm in COVID-19: “When You Come Out of the Storm, You Won’t Be the Same Person Who Walked in”

“…Based on ongoing analysis and emerging scientific data, however, the Food and Drug Administration (FDA) has revoked the emergency use authorization (EUA) to use chloroquine and hydroxychloroquine to treat COVID-19 in specific hospitalized patients under careful heart monitoring. FDA made this decision based on recent findings from a large, randomized clinical trial in hospitalized and non-hospitalized patients that revealed that these drugs had no benefit for improving the recovery and decreasing the death ( 91 , 92 ).…”

How useful is serology for COVID-19?

“…The second major interest that these serological studies could have, would be to confirm a posteriori that patients who were included in studies based on purely clinical criteria were actually infected with SARS-CoV-2. Indeed, several studies, including the Recovery study in England and that of Skipper et al [4] , [5] , have included in their evaluation patients who had not been tested, or tested negative, at the time of inclusion. Performing serology retrospectively, as in one recent study for example [6] , ensures that the patients included were indeed affected with SARS-CoV-2.…”