TY - JOUR
T1 - Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults
T2 - A randomized clinical trial
AU - for the COVID-19 Early Treatment Study Team
AU - Johnston, Christine
AU - Brown, Elizabeth R.
AU - Stewart, Jenell
AU - Karita, Helen C.Stankiewicz
AU - Kissinger, Patricia J.
AU - Dwyer, John
AU - Hosek, Sybil
AU - Oyedele, Temitope
AU - Paasche-Orlow, Michael K.
AU - Paolino, Kristopher
AU - Heller, Kate B.
AU - Leingang, Hannah
AU - Haugen, Harald S.
AU - Dong, Tracy Q.
AU - Bershteyn, Anna
AU - Sridhar, Arun R.
AU - Poole, Jeanne
AU - Noseworthy, Peter A.
AU - Ackerman, Michael J.
AU - Morrison, Susan
AU - Greninger, Alexander L.
AU - Huang, Meei Li
AU - Jerome, Keith R.
AU - Wener, Mark H.
AU - Wald, Anna
AU - Schiffer, Joshua T.
AU - Celum, Connie
AU - Chu, Helen Y.
AU - Barnabas, Ruanne V.
AU - Baeten, Jared M.
N1 - Funding Information:
We thank the volunteers who participated in this study for their altruism and dedication. We are grateful to the members of the trial's Data and Safety Monitoring Board (Drs. David Glidden, Michael Boeckh, and Robert Coombs), local advisors at each trial site, and overseeing ethics review committees for their expertise and guidance. We appreciate assistance from Drs. Nathaniel Davenport, Ann Jarris and Gregory Morlin for recruitment, from Drs. Jairam Lingappa and Florian Hladik for laboratory equipment, from Dr. David Albert and the AliveCor team for rapidly creating a real-time QTc monitoring system, and from Drs. Peter Dull and Scott Miller from the Bill & Melinda Gates Foundation who provided input and guidance. We are indebted to the members of the HCQ COVID-19 Early Treatment Study team for their outstanding work and dedication.
Funding Information:
Declaration of interests: Grants from BMGF for conduct of the study (CJ, ERB, AS, SM, HL, AW, RVB, JMB), Declaration of interests outside of the submitted work: grants from BMGF (AB), grants from CDC (CJ), and NIH (CJ, ERB, HSK, SH, AB, AW), personal fees from Gilead (CJ, CC, AW, JMB) or grants from Gilead (ALG), personal fees from Merck (CC, AW, HYC) or grants from Merck (ALG), grants from Abbott (ALG) grants from Sanofi Pasteur (AW, HYC), grant from GSK (AW), travel from Innovative Molecules (AW), personal fees from Crozet, Aicuris, and X-vax (AW), personal fees from Medpace and AbbVie (CJ), personal fees from Gates Ventures (AB), personal fees for Pfizer, GSK, grant from Ellume (HYC), non-financial support Cepheid (HYC), JMB became an employee at Gilead outside and subsequent to the work.PAN and MJA have a potential financial relationship with AliveCor related to QT assessment using the device, however the investigators would receive no financial benefit for use of the technology for patients at Mayo Clinic or for its use in the current study. All other authors declare nothing.
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/3
Y1 - 2021/3
N2 - 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 (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 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
AB - 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 (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 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
KW - Azithromycin
KW - COVID-19
KW - Coronavirus
KW - Early treatment
KW - Hydroxychloroquine
KW - Randomized controlled trial
KW - Remote enrollment
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85101669241&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101669241&partnerID=8YFLogxK
U2 - 10.1016/j.eclinm.2021.100773
DO - 10.1016/j.eclinm.2021.100773
M3 - Article
AN - SCOPUS:85101669241
SN - 2589-5370
VL - 33
JO - EClinicalMedicine
JF - EClinicalMedicine
M1 - 100773
ER -