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Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial.
Johnston, Christine; Brown, Elizabeth R; Stewart, Jenell; Karita, Helen C Stankiewicz; Kissinger, Patricia J; Dwyer, John; Hosek, Sybil; Oyedele, Temitope; Paasche-Orlow, Michael K; Paolino, Kristopher; Heller, Kate B; Leingang, Hannah; Haugen, Harald S; Dong, Tracy Q; Bershteyn, Anna; Sridhar, Arun R; Poole, Jeanne; Noseworthy, Peter A; Ackerman, Michael J; Morrison, Susan; Greninger, Alexander L; Huang, Meei-Li; Jerome, Keith R; Wener, Mark H; Wald, Anna; Schiffer, Joshua T; Celum, Connie; Chu, Helen Y; Barnabas, Ruanne V; Baeten, Jared M.
  • Johnston C; Division of Allergy and Infectious Diseases, University of Washington, United States.
  • Brown ER; Department of Laboratory Medicine and Pathology, University of Washington, United States.
  • Stewart J; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
  • Karita HCS; Department of Biostatistics, University of Washington, United States.
  • Kissinger PJ; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
  • Dwyer J; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
  • Hosek S; Division of Allergy and Infectious Diseases, University of Washington, United States.
  • Oyedele T; Department of Global Health, University of Washington, United States.
  • Paasche-Orlow MK; Division of Allergy and Infectious Diseases, University of Washington, United States.
  • Paolino K; School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, United States.
  • Heller KB; School of Medicine, Tulane University, New Orleans, LA, United States.
  • Leingang H; John H. Stroger, Jr., Hospital of Cook County, Chicago, IL, United States.
  • Haugen HS; Rush University Medical Center, Chicago, IL, United States.
  • Dong TQ; John H. Stroger, Jr., Hospital of Cook County, Chicago, IL, United States.
  • Bershteyn A; Rush University Medical Center, Chicago, IL, United States.
  • Sridhar AR; Boston University School of Medicine, Boston, MA, United States.
  • Poole J; Boston Medical Center, Boston, MA, United States.
  • Noseworthy PA; State University of New York Upstate Medical University, Syracuse, NY, United States.
  • Ackerman MJ; Department of Global Health, University of Washington, United States.
  • Morrison S; Department of Global Health, University of Washington, United States.
  • Greninger AL; Department of Global Health, University of Washington, United States.
  • Huang ML; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
  • Jerome KR; New York University Grossman School of Medicine, NY, NY, United States.
  • Wener MH; Division of Cardiology, University of Washington, United States.
  • Wald A; Division of Cardiology, University of Washington, United States.
  • Schiffer JT; Mayo Clinic, Rochester, MN, United States.
  • Celum C; Mayo Clinic, Rochester, MN, United States.
  • Chu HY; Department of Global Health, University of Washington, United States.
  • Barnabas RV; Department of Laboratory Medicine and Pathology, University of Washington, United States.
  • Baeten JM; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
EClinicalMedicine ; 33: 100773, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1103840
ABSTRACT

BACKGROUND:

Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission.

METHODS:

In this randomized, double-blind, three-arm (111) placebo-equivalent controlled trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive hydroxychloroquine (HCQ) (400 mg BID x1day, followed by 200 mg BID x9days) with or without azithromycin (AZ) (500 mg, then 250 mg daily x4days) or placebo-equivalent (ascorbic acid (HCQ) and folic acid (AZ)), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs were collected daily. Primary endpoints were (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility.

FINDINGS:

Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Among 129 high-risk participants, incident LRTI occurred in six (4.7%) participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in seven (5.4%) (four control, one HCQ, two HCQ/AZ); no LRTI and two (2%) hospitalizations occurred in the 102 low-risk participants (one HCQ, one HCQ/AZ). There were no deaths. Among 152 participants with viral shedding at enrollment, median time to clearance was 5 days (95% CI=4-6) in HCQ, 6 days (95% CI=4-8) in HCQ/AZ, and 8 days (95% CI=6-10) in control. Viral clearance was faster in HCQ (HR=1.62, 95% CI=1.01-2.60, p = 0.047) but not HCQ/AZ (HR=1.25, p = 0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group (HCQ HR=1.02, 95% CI-0.63-1.64, p = 0.95, HCQ/AZ HR=0.91, 95% CI=0.57-1.45, p = 0.70).

INTERPRETATION:

Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection.

FUNDING:

The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.Trial registration ClinicalTrials.gov number NCT04354428.
Keywords

Full text: Available Collection: International databases Database: MEDLINE Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Variants Language: English Journal: EClinicalMedicine Year: 2021 Document Type: Article Affiliation country: J.eclinm.2021.100773

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Variants Language: English Journal: EClinicalMedicine Year: 2021 Document Type: Article Affiliation country: J.eclinm.2021.100773