Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial | Critical Care Medicine | JAMA Network Open | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Audio Editors' Summary (14:42)

Steven M. Bradley, MD, MPH joins JAMA Network editors to discuss a randomized clinical trial evaluating the safety and efficacy of 2 chloroquine diphosphate dosages in patients with severe coronavirus disease 2019 (COVID-19). JNOLive is a weekly broadcast featuring conversations about the latest research being published in JAMA Network Open. Follow JAMA Network Open on Facebook, Twitter and YouTube.

Wang  C, Horby  PW, Hayden  FG, Gao  GF.  A novel coronavirus outbreak of global health concern.   Lancet. 2020;395(10223):470-473. doi:10.1016/S0140-6736(20)30185-9PubMedGoogle ScholarCrossref
Holshue  ML, DeBolt  C, Lindquist  S,  et al; Washington State 2019-nCoV Case Investigation Team.  First case of 2019 novel coronavirus in the United States.   N Engl J Med. 2020;382(10):929-936. doi:10.1056/nejmoa2001191PubMedGoogle ScholarCrossref
Rodriguez-Morales  AJ, Gallego  V, Escalera-Antezana  JP,  et al.  COVID-19 in Latin America: the implications of the first confirmed case in Brazil.   Travel Med Infect Dis. 2020:101613. doi:10.1016/j.tmaid.2020.101613PubMedGoogle Scholar
Ling  Z, Xu  X, Gan  Q,  et al.  Asymptomatic SARS-CoV-2 infected patients with persistent negative CT findings.   Eur J Radiol. 2020;126:108956. doi:10.1016/j.ejrad.2020.108956PubMedGoogle Scholar
Shi  Y, Yu  X, Zhao  H, Wang  H, Zhao  R, Sheng  J.  Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan.   Crit Care. 2020;24(1):108. doi:10.1186/s13054-020-2833-7PubMedGoogle ScholarCrossref
Yang  X, Yu  Y, Xu  J,  et al.  Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.   Lancet Respir Med. 2020:S2213-2600(20)30079-5. doi:10.1016/S2213-2600(20)30079-5PubMedGoogle Scholar
Zhou  F, Yu  T, Du  R,  et al.  Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.   Lancet. 2020;395(10229):1054-1062. doi:10.1016/s0140-6736(20)30566-3PubMedGoogle ScholarCrossref
Vincent  MJ, Bergeron  E, Benjannet  S,  et al.  Chloroquine is a potent inhibitor of SARS coronavirus infection and spread.   Virol J. 2005;2:69. doi:10.1186/1743-422X-2-69PubMedGoogle ScholarCrossref
Keyaerts  E, Vijgen  L, Maes  P, Neyts  J, Van Ranst  M.  In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine.   Biochem Biophys Res Commun. 2004;323(1):264-268. doi:10.1016/j.bbrc.2004.08.085PubMedGoogle ScholarCrossref
Multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia.  Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia.   Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(3):185-188.PubMedGoogle Scholar
Wang  M, Cao  R, Zhang  L,  et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.   Cell Res. 2020;30(3):269-271. doi:10.1038/s41422-020-0282-0PubMedGoogle ScholarCrossref
Gao  J, Tian  Z, Yang  X.  Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.   Biosci Trends. 2020;14(1):72-73. doi:10.5582/bst.2020.01047PubMedGoogle ScholarCrossref
Gautret  P, Lagier  J-C, Parola  P,  et al.  Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.   Int J Antimicrob Agents. 2020:105949. doi:10.1016/j.ijantimicag.2020.105949PubMedGoogle Scholar
Lim  HS, Im  JS, Cho  JY,  et al.  Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax.   Antimicrob Agents Chemother. 2009;53(4):1468-1475. doi:10.1128/AAC.00339-08PubMedGoogle ScholarCrossref
Science Direct. Chloroquine retinopathy. Accessed March 20, 2020. https://www.sciencedirect.com/topics/medicine-and-dentistry/chloroquine-retinopathy
Kazi  MS, Saurabh  K, Rishi  P, Rishi  E.  Delayed onset chloroquine retinopathy presenting 10 years after long-term usage of chloroquine.   Middle East Afr J Ophthalmol. 2013;20(1):89-91. doi:10.4103/0974-9233.106404PubMedGoogle ScholarCrossref
Mavrikakis  I, Sfikakis  PP, Mavrikakis  E,  et al.  The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine: a reappraisal.   Ophthalmology. 2003;110(7):1321-1326. doi:10.1016/S0161-6420(03)00409-3PubMedGoogle ScholarCrossref
Silva  JA, Silva  MB, Skare  TL.  Chloroquine and QTc interval.   Clin Exp Rheumatol. 2007;25(5):795.PubMedGoogle Scholar
Inglot  AD.  Comparison of the antiviral activity in vitro of some non-steroidal anti-inflammatory drugs.   J Gen Virol. 1969;4(2):203-214. doi:10.1099/0022-1317-4-2-203PubMedGoogle ScholarCrossref
Miller  DK, Lenard  J.  Antihistaminics, local anesthetics, and other amines as antiviral agents.   Proc Natl Acad Sci U S A. 1981;78(6):3605-3609. doi:10.1073/pnas.78.6.3605PubMedGoogle ScholarCrossref
Schulz  KF, Altman  DG, Moher  D; CONSORT Group.  CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials.   BMC Med. 2010;8:18. doi:10.1186/1741-7015-8-18PubMedGoogle ScholarCrossref
Lu  X, Zhang  L, Du  H,  et al; Chinese Pediatric Novel Coronavirus Study Team.  SARS-CoV-2 infection in children.   N Engl J Med. 2020. Published online March 18, 2020. doi:10.1056/NEJMc2005073PubMedGoogle Scholar
Chen  T, Wu  D, Chen  H,  et al.  Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.   BMJ. 2020;368:m1091. doi:10.1136/bmj.m1091PubMedGoogle ScholarCrossref
Grasselli  G, Zangrillo  A, Zanella  A,  et al; COVID-19 Lombardy ICU Network.  Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy.   JAMA. 2020. Published April 6, 2020. doi:10.1001/jama.2020.5394PubMedGoogle Scholar
Karasic  TB, O’Hara  MH, Loaiza-Bonilla  A,  et al.  Effect of gemcitabine and nab-paclitaxel with or without hydroxychloroquine on patients with advanced pancreatic cancer: a phase 2 randomized clinical trial.   JAMA Oncol. 2019;5(7):993-998. doi:10.1001/jamaoncol.2019.0684PubMedGoogle ScholarCrossref
Rangwala  R, Leone  R, Chang  YC,  et al.  Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.   Autophagy. 2014;10(8):1369-1379. doi:10.4161/auto.29118PubMedGoogle ScholarCrossref
Nti  AA, Serrano  LW, Sandhu  HS,  et al.  Frequent subclinical macular changes in combined BRAF/MEK inhibition with high-dose hydroxychloroquine as treatment for advanced metastatic BRAF mutant melanoma: preliminary results from a phase i/ii clinical treatment trial.   Retina. 2019;39(3):502-513. doi:10.1097/IAE.0000000000002027PubMedGoogle ScholarCrossref
US Centers for Disease Control and Prevention. CDC 2019-novel coronavirus (2019-nCoV): real-time RT-PCR diagnostic panel. Updated March 15, 2020. Accessed April 21, 2020. https://www.fda.gov/media/134922/download
ClinicalTrials.gov. Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease (ORCHID). Accessed April 21, 2020. https://clinicaltrials.gov/ct2/show/NCT04332991?term=NCT04332991&draw=2&rank=1
ClinicalTrials.gov. Chloroquine Diphosphate in the Prevention of SARS in Covid-19 Infection (CloroCOVID19II). Accessed April 21, 2020. https://clinicaltrials.gov/ct2/show/NCT04342650?term=NCT04342650&draw=2&rank=1
Chorin  E, Dai  M, Shulman  E,  et al. The QT interval in patients with SARS-CoV-2 infection treated with hydroxychloroquine/azithromycin. Published April 3, 2020. Accessed April 20, 2020. https://www.medrxiv.org/content/10.1101/2020.04.02.20047050v1
Keyaerts  E, Vijgen  L, Maes  P, Neyts  J, Van Ranst  M.  In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine.   Biochem Biophys Res Commun. 2004;323(1):264-268. doi:10.1016/j.bbrc.2004.08.085PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    5 Comments for this article
    Primum Non Nocere
    Gordon Rubenfeld, MD MSc | Intensivist, Epidemiologist, Gadfly
    Pro tip: if you are prescribing HCQ after these JAMA results, do yourself and your defense lawyer a favor. Document in your medical record that you informed the patient of the potential risks of HCQ including sudden death and its benefits (???). Document their consent to this experimental therapy.

    The standard of care is not derived from tweets, rumors, hunches or presidential press conferences.
    Lack of equipoise?
    Jeanne Lenzer | independent journalist and author
    The initial protocol for this study seems to assume that chloroquine is beneficial at one dose or another.
    1.) Since we don't know if chloroquine is beneficial there should be a placebo arm
    2.) Since one dose is likely to do better than another, it'd be a win-win no matter what; if the higher dose did better the authors would conclude that the lower dose was simply ineffective; and if the lower dose does better, then it's just assumed that it's good and the higher dose is simply too toxic - when in truth we have no idea at all
    whether it helps or harms patients at any dose thanks to the absence of a placebo arm. 
    Chloroquine Dosing Phosphate salt vs. Base
    Judith Jacobi, PharmD | Visante, Inc.
    Borba report that 600mg chloroquine base twice daily targeting a total dose of 12 gm led to safety concerns regarding QTc interval prolongation and increased lethality. One contributing factor to the adverse event risk may be related to the regimen selected. In China, guidelines for chloroquine describe 500 mg chloroquine phosphate twice daily for 10 days, targeting a total dose of 10 gm of the phosphate salt. This is equivalent to a total dose of 6 gm chloroquine base. While it remains unclear whether any chloroquine regimen contributes to the recovery of patients with COVID-19, greater attention to the specific doses used in clinical trials is advised, to minimize the risk of adverse events. This trial is ongoing with a regimen of 450 mg chloroquine base twice daily on the first day, followed by 450mg daily for 4 days for a total of 2.7 gm chloroquine base or 4.5 gm total chloroquine phosphate, a dose slightly lower than used in China. If not effective, it will hopefully be safe.
    Dry powder inhalations of chloroquine diphosphate
    Hasham Shafi, PhD Pharmaceutics | CSIR- Central Drug Research Institute
    While this study and others have established that chloroquine base or its salt have a profound effect on QT interval prolongation in a dose dependent manner especially when doses have been titrated against COVID-19 treatment. As formulation experts, we suggest that chloroquine should be administered in the form of a dry powder inhalation. This route of drug delivery will deploy the drug directly to the respiratory epithelium as compared to the administration of this drug by oral and parental routes. Chloroquine delivered by inhalation will target the disease site (lungs) directly before entering the systemic circulation. This will prevent the dilution of the drug at the actual site as occurs in oral or injectable routes. Interestingly, this will allow the clinicians to titrate the actual dose that will be efficacious in treating COVID-19. Inhalation delivery will thus reduce the chloroquine dose required for lowering viral dissemination. This will also help in minimizing other side effects like retinal toxicity and myopathy by minimizing distribution to non-target tissues.
    Difference in ICU enrollment?
    Marc Imbert | I am a winemaker
    Finding: In figure 2b the number of patient in intensive Care (ICU) at enrollment shows a higher number in the high dose CQ group: 23 against 14. This represents 56% (23/41) in ICU for the higher dose of CQ with only 35% (14/40) for the low dosage. Further, the high dose CQ group has more older men with heart conditions; both of these factors may contribute to the higher lethality and CK rates from high dose CQ. This is interesting given the statement by study that "higher dosage was no longer associated with death when controlled by age." This is all said with respect; I thank the authors for their ongoing studies.
    Original Investigation
    Infectious Diseases
    April 24, 2020

    Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial

    Author Affiliations
    • 1Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil
    • 2Universidade do Estado do Amazonas, Manaus, Brazil
    • 3Fundação de Vigilância em Saúde do Amazonas, Manaus, Brazil
    • 4Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
    • 5Instituto Leônidas and Maria Deane, Fiocruz Amazonas, Manaus, Brazil
    • 6Programa de Computação Científica, Fiocruz, Rio de Janeiro, Brazil
    • 7Universidade Federal do Amazonas, Manaus, Brazil
    • 8Instituto Nacional de Infectologia Carlos Chagas–Fiocruz, Rio de Janeiro, Brazil
    • 9Universidade Federal de Santa Maria, Rio Grande do Sul, Brazil
    • 10Faculdade de Medicina da Universidade Federal do Mato Grosso do Sul, Campo Grande, Brazil
    • 11Fundação Oswaldo Cruz, Mato Grosso do Sul, Campo Grande, Brazil
    • 12Faculdade de Medicina de São José do Rio Preto, São Paulo, Brazil
    • 13Universidade de Brasília, Brasília, Brazil
    • 14ISGlobal, Hospital Clínic–Universitat de Barcelona, Barcelona, Spain
    • 15Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique
    • 16Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
    • 17Pediatric Infectious Diseases Unit, Pediatrics Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
    • 18Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública, Madrid, Spain
    • 19Universidade Federal de Mato Grosso, Mato Grosso, Brazil
    • 20Faculdade de Medicina da Universidade Federal do Amazonas, Manaus, Brazil
    • 21Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
    JAMA Netw Open. 2020;3(4):e208857. doi:10.1001/jamanetworkopen.2020.8857
    Key Points español 中文 (chinese)

    Question  How safe and effective are 2 different regimens of chloroquine diphosphate in the treatment of severe coronavirus disease 2019 (COVID-19)?

    Findings  In this phase IIb randomized clinical trial of 81 patients with COVID-19, an unplanned interim analysis recommended by an independent data safety and monitoring board found that a higher dosage of chloroquine diphosphate for 10 days was associated with more toxic effects and lethality, particularly affecting QTc interval prolongation. The limited sample size did not allow the study to show any benefit overall regarding treatment efficacy.

    Meaning  The preliminary findings from the CloroCovid-19 trial suggest that higher dosage of chloroquine should not be recommended for the treatment of severe COVID-19, especially among patients also receiving azithromycin and oseltamivir, because of safety concerns regarding QTc interval prolongation and increased lethality.


    Importance  There is no specific antiviral therapy recommended for coronavirus disease 2019 (COVID-19). In vitro studies indicate that the antiviral effect of chloroquine diphosphate (CQ) requires a high concentration of the drug.

    Objective  To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19.

    Design, Setting, and Participants  This parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon.

    Interventions  Patients were allocated to receive high-dosage CQ (ie, 600 mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450 mg twice daily on day 1 and once daily for 4 days).

    Main Outcomes and Measures  Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4.

    Results  Out of a predefined sample size of 440 patients, 81 were enrolled (41 [50.6%] to high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%).

    Conclusions and Relevance  The preliminary findings of this study suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir. These findings cannot be extrapolated to patients with nonsevere COVID-19.

    Trial Registration  ClinicalTrials.gov Identifier: NCT04323527