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

Caleb P Skipper, Katelyn A. Pastick, Nicole S Engen, Ananta S Bangdiwala, Mahsa Abassi, Sarah M Lofgren, Darlisha A Williams, Elizabeth C. Okafor, Matthew F Pullen, Melanie R. Nicol, Alanna A. Nascene, Katherine Huppler Hullsiek, Matthew P. Cheng, Darlette Luke, Sylvain A. Lother, Lauren J. MacKenzie, Glen Drobot, Lauren E. Kelly, Ilan S. Schwartz, Ryan ZarychanskiEmily G. McDonald, Todd C. Lee, Radha Rajasingham, David R. Boulware

Research output: Contribution to journalArticlepeer-review

383 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)623-631
Number of pages9
JournalAnnals of Internal Medicine
Issue number8
StatePublished - Oct 20 2020


  • Adult
  • Antimalarials/therapeutic use
  • Betacoronavirus
  • COVID-19
  • Coronavirus Infections/drug therapy
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Humans
  • Hydroxychloroquine/therapeutic use
  • Male
  • Middle Aged
  • Outpatients
  • Pandemics
  • Pneumonia, Viral/drug therapy
  • Retrospective Studies
  • Risk Factors
  • SARS-CoV-2
  • Time Factors

PubMed: MeSH publication types

  • Randomized Controlled Trial
  • Multicenter Study
  • Journal Article


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