• 1.

    Yao X et al. 2020. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis. https://doi.org/10.1093/cid/ciaa237.

    • Search Google Scholar
    • Export Citation
  • 2.

    Weston S, Haupt R, Logue J, Matthews K, Frieman BM, 2020. FDA approved drugs with broad anti-coronaviral activity inhibit SARS-CoV-2 in vitro . bioRXiv.

    • Search Google Scholar
    • Export Citation
  • 3.

    Dowall SD et al. 2015. Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo Guinea pig model. J Gen Virol 96: 34843492.

    • Search Google Scholar
    • Export Citation
  • 4.

    De Lamballerie X, Boisson V, Reynier JC, Enault S, Charrel RN, Flahault A, Roques P, Le Grand R, 2008. On chikungunya acute infection and chloroquine treatment. Vector Borne Zoonotic Dis 8: 837839.

    • Search Google Scholar
    • Export Citation
  • 5.

    Paton NI, Lee L, Xu Y, Ooi EE, Cheung YB, Archuleta S, Wong G, Wilder-Smith A, 2011. Chloroquine for influenza prevention: a randomized, double-blind, placebo controlled trial. Lancet Infect Dis 11: 677683.

    • Search Google Scholar
    • Export Citation
  • 6.

    Sperber K, Louie M, Kraus T, Proner J, Sapira E, Lin S, Stecher V, Mayer L, 1995. Hydroxychloroquine treatment of patients with human immunodeficiency virus type 1. Clin Ther 17: 622636.

    • Search Google Scholar
    • Export Citation
  • 7.

    Tricou V, Minh NN, Van TP, Lee SJ, Farrar J, Wills B, Tran HT, Simmons CP, 2010. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. PLoS Negl Trop Dis 4: e785.

    • Search Google Scholar
    • Export Citation
  • 8.

    Gautret P et al. 2020. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. https://doi.org/10.1016/j.ijantimicag.2020.105949.

    • Search Google Scholar
    • Export Citation
  • 9.

    Gao J, Tian Z, Yang X, 2020. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 14: 7273.

    • Search Google Scholar
    • Export Citation
  • 10.

    National Academies of Sciences, Engineering, and Medicine, 2017. Integrating Clinical Research into Epidemic Response: the Ebola Experience. Washington DC: The National Academies Press.

    • Search Google Scholar
    • Export Citation
  • 11.

    ClinicalTrials.gov, 2020 (NCT04315896). Hydroxychloroquine Treatment for Severe COVID-19 Pulmonary Infection (HYDRA Trial) (HYDRA). Available at: https://clinicaltrials.gov/ct2/show/NCT04315896?cond=NCT04315896&draw=2&rank=1. Accessed March 27, 2020.

    • Search Google Scholar
    • Export Citation
  • 12.

    ClinicalTrials.gov, 2020 (NCT04318015). Hydroxychloroquine Chemoprophylaxis in Healthcare Personnel in Contact with COVID-19 Patients (PHYDRA Trial) (PHYDRA). Available at: https://clinicaltrials.gov/ct2/show/NCT04318015?term=NCT04318015&draw=2&rank=1. Accessed March 27, 2020.

    • Search Google Scholar
    • Export Citation
  • 13.

    ClinicalTrials.gov, 2020 (NCT04318444). Hydroxychloroquine Post Exposure Prophylaxis for Coronavirus Disease (COVID-19). Available at: https://clinicaltrials.gov/ct2/show/NCT04318444?term=NCT04318444&draw=2&rank=1. Accessed March 27, 2020.

    • Search Google Scholar
    • Export Citation
  • 14.

    ClinicalTrials.gov, 2020 (NCT04321278). Safety and Efficacy of Hydroxychloroquine Associated with Azithromycin in SARS-CoV2 Virus (Alliance Covid-19 Brasil II). Available at: https://clinicaltrials.gov/ct2/show/NCT04321278?term=NCT04321278&draw=2&rank=1. Accessed March 27, 2020.

    • Search Google Scholar
    • Export Citation
  • 15.

    ClinicalTrials.gov, 2020 (NCT04308668). Post-exposure Prophylaxis/Preemptive Therapy for SARS-Coronavirus-2 (COVID-19 PEP). Available at: https://clinicaltrials.gov/ct2/show/NCT04308668?term=NCT04308668&draw=2&rank=1. Accessed March 27, 2020.

    • Search Google Scholar
    • Export Citation
  • 16.

    ClinicalTrials.gov, 2020 (NCT04304053). Treatment of COVID-19 Cases and Chemoprophylaxis of Contacts as Prevention (HCQ4COV19). Available at: https://clinicaltrials.gov/ct2/show/NCT04304053?term=NCT04304053&draw=2&rank=1. Accessed March 27, 2020.

    • Search Google Scholar
    • Export Citation
  • 17.

    ClinicalTrials.gov, 2020 (NCT04316377). Norwegian Coronavirus Disease 2019 Study (NO COVID-19). Available at: https://clinicaltrials.gov/ct2/show/NCT04316377?term=NCT04316377&draw=2&rank=1. Accessed March 27, 2020.

    • Search Google Scholar
    • Export Citation
  • 18.

    ClinicalTrials.gov, 2020. (NCT043032990). Various Combination of Protease Inhibitors, Oseltamivir, Favipiravir, and Hydroxychloroquine for Treatment of COVID19: A Randomized Control Trial (THDMS-COVID19). Available at: https://clinicaltrials.gov/ct2/show/NCT04303299?term=NCT04303299&draw=2&rank=1. Accessed March 27, 2020.

    • Search Google Scholar
    • Export Citation
  • 19.

    Nord JE, Shah PK, Rinaldi RZ, Weisman MH, 2004. Hydroxychloroquine cardiotoxicity in systemic lupus erythematosus: a report of 2 cases and review of the literature. Semin Arthritis Rheum 33: 336351.

    • Search Google Scholar
    • Export Citation
  • 20.

    Chen C, Zhou Y, Wang DW, 2020. SARS-CoV-2: a potential novel etiology of fulminant myocarditis. Herz. https://doi.org/10.1007/s00059-020-04909-z.

    • Search Google Scholar
    • Export Citation
  • 21.

    Taylor WR, White NJ, 2004. Antimalarial drug toxicity: a review. Drug Saf 27: 2561.

  • 22.

    ClinicalTrials.gov, 2020 (NCT04280705). Adaptive COVID-19 Treatment Trial (ACTT). Available at: https://clinicaltrials.gov/ct2/show/NCT04280705?cond=NCT04280705&draw=2&rank=1. Accessed March 30, 2020.

    • Search Google Scholar
    • Export Citation
  • 23.

    Kupferschmidt K, Cohen J, 2020. Race to find COVID-19 treatments accelerates, WHO launches megatrial to test repurposed drugsand experimental drug candidates. Science 367: 14121413.

    • Search Google Scholar
    • Export Citation
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A Call for Randomized Controlled Trials to Test the Efficacy of Chloroquine and Hydroxychloroquine as Therapeutics against Novel Coronavirus Disease (COVID-19)

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  • 1 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland;
  • | 2 Edge BioInnovation Consulting, Frederick, Maryland

Novel coronavirus disease (COVID-19) is spreading fast around the world, with many uncertainties about treatment and prevention. Currently, there are no U.S. Food and Drug Administration (FDA)–approved drugs for the treatment of patients with COVID-19. A great deal of effort is ongoing to find effective therapeutics and preventive measures against this transmissible virus with high mortality. Available data are limited, and there are minimal randomized controlled trial (RCT) data on the efficacy of antiviral or immunomodulatory agents for the treatment of COVID-19.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used to treat malaria for 70 years. Recently, triggered in part by media reports on potential efficacy, CQ and HCQ have been widely used off-label for treatment and prevention of COVID-19. These drugs were suggested for clinical usage after in vitro activity was observed against COVID-19.1,2 The molecular mechanism is believed to involve action at multiple steps in the viral pathway, including cellular entry and exit. These drugs alter intracellular pH, and may induce endoplasmic reticulum stress, causing misformation of essential viral proteins. However, in vitro activity of these drugs should not be interpreted as proof of clinical efficacy against COVID-19. Similar in vitro activity of CQ and HCQ was identified against multiple other viruses, but follow-up clinical trials did not show significant clinical efficacy of these drugs, for example, against Ebola virus disease,3 chikungunya,4 influenza,5 HIV infection,6 and dengue.7

A report of a nonrandomized trial of 20 COVID-19 patients in France who received HCQ alone or in combination with azithromycin showed that, compared with untreated controls, HCQ reduced nasopharyngeal viral carriage 6 days after the initiation of therapy.8 Another preliminary report containing limited information noted that, in 100 COVID-19 patients in China, CQ offered superior clinical efficacy than controls.9 Based on these limited data, the National Health Commission of the People’s Republic of China is considering CQ in their national guidelines to treat COVID-19.9 If efficacy of CQ and HCQ are demonstrated by RCTs, this would be the first time they are found to be effective for the treatment of a viral infection.

An analysis of the clinical trials conducted during the 2014–2015 Ebola outbreak in West Africa showed that an RCT was an ethical, appropriate, and efficient path toward identification of safe and efficacious therapeutics.10 The equipoise for a placebo-controlled RCT for the treatment of COVID-19 derives from the absence of proven therapy for COVID-19 and the need to establish benefit versus harm caused by any experimental therapeutic. This ethical consideration justifies initiation of clinical trials; many are planned or are underway to study CQ and HCQ for treating or preventing COVID-19 in different countries (as examples: NCT04315896,11 NCT04318015,12 NCT04318444,13 NCT04321278,14 NCT04308668,15 NCT04304053,16 NCT04316377,17 and NCT0430329918). In the meantime, significant off-label use is occurring globally, including in many U.S. hospitals, with not only potential benefit but also potential risk of harm, whereas adequate data on efficacy and safety are not yet available.

Many academic institutions in the United States and overseas have drafted institutional guidelines for off-label use of drugs for COVID-19, including CQ and HCQ with different dosages and duration for either treatment or prophylaxis, but there is no standard recommendation for prescribing these medications for this disease. Moreover, CQ and HCQ may cause harm, with narrow therapeutic windows, and many side effects, including cardiac toxicity (QT prolongation, torsade de pointes, and ventricular arrhythmia), which may be particularly problematic in the elderly, who are also most likely to suffer from severe COVID-19.19 Coronavirus disease also appears to cause cardiac effects, including myocarditis.20 Other side effects associated with CQ and/or HCQ include retinopathy, nausea, vomiting, bone marrow suppression, psychosis, seizure, emotional lability, vertigo, dizziness, and myopathy.21 The known toxicities of CQ and HCQ raise concern regarding toxicity of self-administered drugs, with overdoses, severe toxicity, and death described recently in the popular press.

Although the COVID-19 pandemic is global, it may be a particular burden for developing countries with limited infrastructure. Given a lack of evidence and intense pressure to try something in COVID-19 patients, clinicians may increasingly turn to off-label usage of drugs. We call on public health organizations to urgently consider creating or expanding partnerships with local governments to support unified RCTs to test the efficacies of potential therapeutics against COVID-19. Leveraging the previously developed adaptive RCT design from the National Institute of Allergy and Infectious Diseases (NIAID) PALM trial, which efficiently assesses multiple arms against a common comparator, the NIAID, National Institute of Health, and the WHO have already launched COVID-19 RCTs. The NIAID trial is a multinational placebo-controlled trail of 440 hospitalized COVID-19 patients, initially comparing remdesivir with placebo.22 The WHO solidarity trial is a large, adaptive, five-arm trial comparing four promising COVID-19 regimens: remdesevir, CQ, lopinavir–ritonavir, and lopinavir–ritonavir plus interferon beta, all compared with standard of care, with mortality as the primary end point.23 Both trials require close data and safety monitoring board oversight and allow for dropping poorly performing arms and adding promising putative therapeutics as they are developed. So far, many countries, including Argentina, Bahrain, Canada, France, Iran, Norway, South Africa, Spain, Switzerland, and Thailand have signed up for the trial. Both trials are examples of robust efforts to generate high-quality evidence to identify medicines that may potentially save lives in the global battle against COVID-19.

The off-label use of CQ and HCQ to treat or prevent COVID-19 must be cautious, considering potential serious toxicities. Global multicenter RCTs testing safety and efficacy of CQ or HCQ seem to be the most reasonable plan to urgently gather data on the efficacy and safety of these medications in the treatment of COVID-19. Before the availability of robust data from RCTs, we highly recommend that off-label use of medications to treat COVID-19, including CQ or HCQ, be accompanied by careful observation for potential toxicity.

Acknowledgment:

Publication charges for this article were waived due to the ongoing pandemic of COVID-19.

REFERENCES

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    • Search Google Scholar
    • Export Citation
  • 2.

    Weston S, Haupt R, Logue J, Matthews K, Frieman BM, 2020. FDA approved drugs with broad anti-coronaviral activity inhibit SARS-CoV-2 in vitro . bioRXiv.

    • Search Google Scholar
    • Export Citation
  • 3.

    Dowall SD et al. 2015. Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo Guinea pig model. J Gen Virol 96: 34843492.

    • Search Google Scholar
    • Export Citation
  • 4.

    De Lamballerie X, Boisson V, Reynier JC, Enault S, Charrel RN, Flahault A, Roques P, Le Grand R, 2008. On chikungunya acute infection and chloroquine treatment. Vector Borne Zoonotic Dis 8: 837839.

    • Search Google Scholar
    • Export Citation
  • 5.

    Paton NI, Lee L, Xu Y, Ooi EE, Cheung YB, Archuleta S, Wong G, Wilder-Smith A, 2011. Chloroquine for influenza prevention: a randomized, double-blind, placebo controlled trial. Lancet Infect Dis 11: 677683.

    • Search Google Scholar
    • Export Citation
  • 6.

    Sperber K, Louie M, Kraus T, Proner J, Sapira E, Lin S, Stecher V, Mayer L, 1995. Hydroxychloroquine treatment of patients with human immunodeficiency virus type 1. Clin Ther 17: 622636.

    • Search Google Scholar
    • Export Citation
  • 7.

    Tricou V, Minh NN, Van TP, Lee SJ, Farrar J, Wills B, Tran HT, Simmons CP, 2010. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. PLoS Negl Trop Dis 4: e785.

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    • Export Citation
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    • Export Citation
  • 9.

    Gao J, Tian Z, Yang X, 2020. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 14: 7273.

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    ClinicalTrials.gov, 2020 (NCT04318015). Hydroxychloroquine Chemoprophylaxis in Healthcare Personnel in Contact with COVID-19 Patients (PHYDRA Trial) (PHYDRA). Available at: https://clinicaltrials.gov/ct2/show/NCT04318015?term=NCT04318015&draw=2&rank=1. Accessed March 27, 2020.

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  • 13.

    ClinicalTrials.gov, 2020 (NCT04318444). Hydroxychloroquine Post Exposure Prophylaxis for Coronavirus Disease (COVID-19). Available at: https://clinicaltrials.gov/ct2/show/NCT04318444?term=NCT04318444&draw=2&rank=1. Accessed March 27, 2020.

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    ClinicalTrials.gov, 2020 (NCT04308668). Post-exposure Prophylaxis/Preemptive Therapy for SARS-Coronavirus-2 (COVID-19 PEP). Available at: https://clinicaltrials.gov/ct2/show/NCT04308668?term=NCT04308668&draw=2&rank=1. Accessed March 27, 2020.

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  • 17.

    ClinicalTrials.gov, 2020 (NCT04316377). Norwegian Coronavirus Disease 2019 Study (NO COVID-19). Available at: https://clinicaltrials.gov/ct2/show/NCT04316377?term=NCT04316377&draw=2&rank=1. Accessed March 27, 2020.

    • Search Google Scholar
    • Export Citation
  • 18.

    ClinicalTrials.gov, 2020. (NCT043032990). Various Combination of Protease Inhibitors, Oseltamivir, Favipiravir, and Hydroxychloroquine for Treatment of COVID19: A Randomized Control Trial (THDMS-COVID19). Available at: https://clinicaltrials.gov/ct2/show/NCT04303299?term=NCT04303299&draw=2&rank=1. Accessed March 27, 2020.

    • Search Google Scholar
    • Export Citation
  • 19.

    Nord JE, Shah PK, Rinaldi RZ, Weisman MH, 2004. Hydroxychloroquine cardiotoxicity in systemic lupus erythematosus: a report of 2 cases and review of the literature. Semin Arthritis Rheum 33: 336351.

    • Search Google Scholar
    • Export Citation
  • 20.

    Chen C, Zhou Y, Wang DW, 2020. SARS-CoV-2: a potential novel etiology of fulminant myocarditis. Herz. https://doi.org/10.1007/s00059-020-04909-z.

    • Search Google Scholar
    • Export Citation
  • 21.

    Taylor WR, White NJ, 2004. Antimalarial drug toxicity: a review. Drug Saf 27: 2561.

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    ClinicalTrials.gov, 2020 (NCT04280705). Adaptive COVID-19 Treatment Trial (ACTT). Available at: https://clinicaltrials.gov/ct2/show/NCT04280705?cond=NCT04280705&draw=2&rank=1. Accessed March 30, 2020.

    • Search Google Scholar
    • Export Citation
  • 23.

    Kupferschmidt K, Cohen J, 2020. Race to find COVID-19 treatments accelerates, WHO launches megatrial to test repurposed drugsand experimental drug candidates. Science 367: 14121413.

    • Search Google Scholar
    • Export Citation

Author Notes

Address correspondence to Maryam Keshtkar-Jahromi, Johns Hopkins Bayview Medical Center, Mason F. Lord Bldg., Center Tower, 3rd Floor, 5200 Eastern Ave., Baltimore, MD 21224. E-mail: maryam.keshtkar@jhmi.edu

Authors’ addresses: Maryam Keshtkar-Jahromi, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, E-mail: maryam.keshtkar@jhmi.edu. Sina Bavari, Edge BioInnovation Consulting, Frederick MD, E-mail: sinabavari@comcast.net.

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