Hydroxychloroquine with or Without Azithromycin for Treatment of Early SARS-CoV-2 Infection Among High-Risk Outpatient Adults: A Randomized Clinical Trial
Johnston et al.
, Hydroxychloroquine with or Without Azithromycin for Treatment of Early SARS-CoV-2 Infection Among High-Risk..
, EClinicalMedicine, doi:10.1016/j.eclinm.2021.100773 (date from earlier preprint), NCT04354428
Small early terminated late treatment RCT comparing vitamin C + folic acid, HCQ + folic acid, and HCQ+AZ, showing non-statistically significantly lower hospitalization with HCQ/HCQ+AZ, and faster viral clearance with HCQ. Enrollment was a median of 5.9 days after onset (6.2 and 6.3 in the treatment arms).
The median time to viral clearance for vitamin C + folic acid was 8 days in the preprint but changed to 7 days in the published paper without explanation.
Low risk patients, median age 37, no deaths (not matching the title which claims "high risk"). Post hoc addition of a new Ct threshold to obscure the statistically significant faster clearance. No analysis for time from symptom onset. Authors identify (relatively) low and high risk cohorts, but do not provide either viral shedding or symptom resolution results for the cohorts. NCT04354428 (history)
. For other issues see 
risk of hospitalization, 29.9% lower, RR 0.70, p = 0.73, treatment 5 of 148 (3.4%), control 4 of 83 (4.8%), NNT 69, HCQ + folic acid and HCQ + AZ vs. vitamin C + folic acid.
risk of no recovery, 2.0% lower, RR 0.98, p = 0.95, treatment 30 of 60 (50.0%), control 34 of 72 (47.2%), adjusted per study, inverted to make RR<1 favor treatment, HCQ + folic acid vs. vitamin C + folic acid.
risk of no recovery, 9.9% higher, RR 1.10, p = 0.70, treatment 34 of 65 (52.3%), control 34 of 72 (47.2%), adjusted per study, inverted to make RR<1 favor treatment, HCQ + AZ vs. vitamin C + folic acid.
time to viral-, 28.6% lower, relative time 0.71, treatment 49, control 52, median time, HCQ + folic acid vs. vitamin C + folic acid.
time to viral-, 14.3% lower, relative time 0.86, treatment 51, control 52, median time, HCQ + AZ vs. vitamin C + folic acid.
risk of no viral clearance, 38.3% lower, RR 0.62, p = 0.047, treatment 6 of 49 (12.2%), control 12 of 52 (23.1%), NNT 9.2, adjusted per study, inverted to make RR<1 favor treatment, HCQ + folic acid vs. vitamin C + folic acid.
risk of no viral clearance, 20.0% lower, RR 0.80, p = 0.49, treatment 11 of 51 (21.6%), control 12 of 52 (23.1%), adjusted per study, inverted to make RR<1 favor treatment, HCQ + AZ vs. vitamin C + folic acid.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Johnston et al., 9 Dec 2020, Randomized Controlled Trial, USA, peer-reviewed, 30 authors, average treatment delay 5.9 days, dosage 400mg bid day 1, 200mg bid days 2-10, trial NCT04354428 (history)
Abstract: EClinicalMedicine 33 (2021) 100773
Contents lists available at ScienceDirect
journal homepage: https://www.journals.elsevier.com/eclinicalmedicine
Hydroxychloroquine with or without azithromycin for treatment of early
SARS-CoV-2 infection among high-risk outpatient adults: A randomized
Christine Johnstona,b,h,*, Elizabeth R. Brownc,h,i, Jenell Stewarta,e, Helen C.Stankiewicz Karitaa,
Patricia J. Kissingerj, John Dwyerk, Sybil Hosekl,m, Temitope Oyedelel,m,
Michael K. Paasche-Orlown,o, Kristopher Paolinop, Kate B. Hellere, Hannah Leingange,
Harald S. Haugene, Tracy Q. Dongh, Anna Bershteynq, Arun R. Sridharf, Jeanne Poolef,
Peter A. Noseworthyr, Michael J. Ackermanr, Susan Morrisone, Alexander L. Greningerb,h,
Meei-Li Huangh, Keith R. Jeromeb,h, Mark H. Wenerb,g, Anna Walda,b,d,h, Joshua T. Schiffera,h,
Connie Celuma,d,e, Helen Y. Chua,d,e, Ruanne V. Barnabasa,b,d,h, Jared M. Baetena,d,e, for the
COVID-19 Early Treatment Study Team
Division of Allergy and Infectious Diseases, University of Washington, United States
Department of Laboratory Medicine and Pathology, University of Washington, United States
Department of Biostatistics, University of Washington, United States
Department of Epidemiology, University of Washington, United States
Department of Global Health, University of Washington, United States
Division of Cardiology, University of Washington, United States
Division of Rheumatology, University of Washington, Seattle, WA, United States
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, United States
School of Medicine, Tulane University, New Orleans, LA, United States
John H. Stroger, Jr., Hospital of Cook County, Chicago, IL, United States
Rush University Medical Center, Chicago, IL, United States
Boston University School of Medicine, Boston, MA, United States
Boston Medical Center, Boston, MA, United States
State University of New York Upstate Medical University, Syracuse, NY, United States
New York University Grossman School of Medicine, NY, NY, United States
Mayo Clinic, Rochester, MN, United States
A R T I C L E
I N F O
Received 23 December 2020
Revised 8 February 2021
Accepted 10 February 2021
Available online 27 February 2021
Randomized controlled trial
A B S T R A C T
Background: Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARSCoV-2 transmission.
Methods: In this randomized, double-blind, three-arm (1:1:1) 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..
is less effective
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