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    5 Comments for this article
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    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.
    CONFLICT OF INTEREST: JAMA Editor
    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. 
    CONFLICT OF INTEREST: None Reported
    READ MORE
    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.
    CONFLICT OF INTEREST: None Reported
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    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.
    CONFLICT OF INTEREST: None Reported
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    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.
    CONFLICT OF INTEREST: None Reported
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    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.

    Abstract

    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

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