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
Mayla Gabriela Silva Borba, Fernando Fonseca Almeida Val, Vanderson Souza Sampaio, Marcia Almeida Araújo Alexandre, Gisely Cardoso Melo, MSc Marcelo Brito, Maria Paula Gomes Mourão, MSc José Diego Brito-Sousa, PhD; Djane Baía-Da-Silva, Marcus Vinitius Farias Guerra, Ludhmila Abrahão Hajjar, BSc Rosemary Costa Pinto, Antonio Alcirley Silva Balieiro, Antônio Guilherme Fonseca Pacheco, James Dean Oliveira Santos, Felipe Gomes Naveca, MSc Mariana Simão Xavier, André Machado Siqueira, MD Alexandre Schwarzbold, MD; Maurício Júlio Croda, Maurício Lacerda Nogueira, Gustavo Adolfo Sierra Romero, MD; Cor Quique Bassat, Cor Jesus Fontes, Bernardino Cláudio Albuquerque, Cláudio-Tadeu Daniel-Ribeiro, Wuelton Marcelo Monteiro, Marcus Vinícius Guimarães Lacerda
JAMA Network Open, doi:10.1001/jamanetworkopen.2020.8857
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 highdosage 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 highdosage 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 (continued) Key Points 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..
Abbreviation: CK, creatine phosphokinase; CKMB, creatinine phosphokinase-MB; COVID-19, coronavirus disease 2019; QTcF, QT interval corrected by the Fridericia method. a Not all patients completed day 13 visit before this article was finalized. b Low-dosage group received chloroquine for 5 days (450 mg twice daily on the first day and 450 mg once daily for 4 days). c High-dosage group received chloroquine for 10 days (600 mg twice daily for 10 days). d Decreases in hemoglobin level of more than 3 g/dL or 30% or greater from baseline are shown. e Increases in creatinine serum levels of 30% or more from baseline are shown. f Serious adverse events related to the trial regimen were prolongation of the QTcF. Lethality among critically ill patients in the present study seemed to be even higher than among similar patients not receiving CQ in a large historical sample-size cohort of patients in Lombardy, Italy. 24 That could reflect the quality of intensive care units in both countries or the possible lack of or deleterious effect of CQ in such patients with COVID-19. The occurrence of myocarditis in our sample, with the confirmed QTcF prolongation, warrants caution regarding this drug's safety, particularly considering the eventual increase in fatal arrythmias, such as ventricular tachycardia.
Strengths and Limitations This study had some strengths. It was double-masked; performed in a public hospital, which will manage most cases in countries like Brazil; compliant with good..
References
Acquisition, Sampaio, Alexandre, Brito, Mourão et al., Critical revision of the manuscript for important intellectual content
Administrative, Brito, Mourão, Brito-Sousa, Guerra et al., None
Affiliations, Dourado, Manaus, Brazil (borba, Val et al., Universidade do Estado do Amazonas
Alves, None, MSc
Azevedo, None, BSc
Barbosa Oliveira, Luiz, Ferreira, Henrique, Maciel et al., None, BSc
Bezerra, Maciel, None, MSc
Chen, Wu, Chen, Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study, BMJ,
doi:10.1136/bmj.m1091Chorin, Dai, Shulman, The QT interval in patients with SARS-CoV-2 infection treated with hydroxychloroquine/azithromycin, Published,
doi:10.1101/2020.04.02.20047050v1Clinicaltrials, Gov, Chloroquine Diphosphate in the Prevention of SARS in Covid-19 Infection
Clinicaltrials, Gov, Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease (ORCHID)
Esthefani, Cirino, None, BSc
Ferreira Melo, None
Ferreira, Marins, Bsc, Kelly, Costa, None, BSc
Francisca, Melo, None, BSc
Gabriela, Santos, Michael, Sousa, Leonam et al., None, BSc
Gao, Tian, Yang, Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Biosci Trends,
doi:10.5582/bst.2020.01047Gautret, Lagier, Parola, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.105949Grasselli, Zangrillo, Zanella, 2 admitted to ICUs of the Lombardy region
Grosso, Sul, None
Holshue, Debolt, Lindquist, Washington State 2019-nCoV Case Investigation Team. First case of 2019 novel coronavirus in the United States, N Engl J Med,
doi:10.1056/nejmoa2001191Kazi, Saurabh, Rishi, Rishi, Delayed onset chloroquine retinopathy presenting 10 years after long-term usage of chloroquine, Middle East Afr J Ophthalmol,
doi:10.4103/0974-9233.106404Keyaerts, Vijgen, Maes, Neyts, Van Ranst, In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine, Biochem Biophys Res Commun,
doi:10.1016/j.bbrc.2004.08.085Keyaerts, Vijgen, Maes, Neyts, Van Ranst, In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine, Biochem Biophys Res Commun,
doi:10.1016/j.bbrc.2004.08.085Lacerda, Monteiro ; Borba, Val, Sampaio, Melo et al., data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis
Lim, Im, Cho, Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax, Antimicrob Agents Chemother,
doi:10.1128/AAC.00339-08Lima, None
Lins, Vitor-Silva, None
Lu, Zhang, Du, Chinese Pediatric Novel Coronavirus Study Team. SARS-CoV-2 infection in children, N Engl J Med,
doi:10.1056/NEJMc2005073Maria, Jeronimo, Garcia, Silva, Fátima et al., None, BSc
Mavrikakis, Sfikakis, Mavrikakis, The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine: a reappraisal, Ophthalmology,
doi:10.1016/S0161-6420(03)00409-3Medeiros, Almeida, Emanuelle, Silva, Frota et al., None
Miller, Antihistaminics, local anesthetics, and other amines as antiviral agents, Proc Natl Acad Sci U S A,
doi:10.1073/pnas.78.6.3605Morais Rocha, Guedes, Silva, None, BSc
Nti, Serrano, Sandhu, 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,
doi:10.1097/IAE.0000000000002027Nélio Brutus, Bsc, Kelry, Oliveira Dinelly, Bsc et al., None, BSc
Oliveira Trindade, None
Oliveira, João, Neto, None, BSc
Pereira Souza, None
Rangwala, Leone, Chang, Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma, Autophagy,
doi:10.4161/auto.29118Rodriguez-Morales, Gallego, Escalera-Antezana, COVID-19 in Latin America: the implications of the first confirmed case in Brazil, Travel Med Infect Dis,
doi:10.1016/j.tmaid.2020.101613Santana, None
Schulz, Altman, Moher, Group, CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials, BMC Med,
doi:10.1186/1741-7015-8-18Shi, Yu, Zhao, Wang, Zhao et al., Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan, Crit Care,
doi:10.1186/s13054-020-2833-7Silva Pereira, None
Silva, Silva, Skare, Chloroquine and QTc interval, Clin Exp Rheumatol
Soares Freire, Abreu-Netto, None, BSc
Soares, Debora, Duarte, None, BSc
Souza Dias, Lima, Corado, None, MSc
Thaliê, Santos, None
Vincent, Bergeron, Benjannet, Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol J,
doi:10.1186/1743-422X-2-69Vitória, Printes, Bsc, Wanessa, Barbosa, None, BSc
Wang, Cao, Zhang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res,
doi:10.1038/s41422-020-0282-0Yang, Yu, Xu, 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,
doi:10.1016/S2213-2600(20)30079-5Zhou, Yu, Du, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, Lancet,
doi:10.1016/s0140-6736(20)30566-3DOI record:
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