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Investigators are evaluating a variety of medications for the novel coronavirus disease 2019 (COVID- 19), and the possible treatment landscape is rapidly evolving.
Investigators are evaluating a variety of medications for the novel coronavirus disease 2019 (COVID- 19), and the possible treatment landscape is rapidly evolving. There are no FDA-approved medications for the treatment of COVID- 19. Currently, medical management consists of infection prevention and supportive care, which includes supplemental oxygen and mechanical ventilator support when indicated.1 At least 181 clinical trials were being conducted as of April 14, 2020, comprising studies at the recruiting stage and those that have already begun.2
COVID-19 Investigational Treatment Options
Remdesivir is an intravenous (IV) drug with broad antiviral activity (eg, severe acute respiratory syndrome [SARS] virus and Middle East respiratory syndrome) that has been used for the treatment of Ebola virus, and it works by inhibiting viral replication through premature termination of RNA transcription.3,4 Additionally, remdesivir appears to have a favorable safety profile based on its having been used to treat approximately 500 individuals, including healthy volunteers and those with acute Ebola virus infection.4 Remdesivir is being studied by Gilead Sciences for the treatment of COVID-19, and evidence suggests that it is currently one of the most promising investigational drugs.3
Results of a cohort study were published in the New England Journal of Medicine on April 10, examining compassionate use of remdesivir in 61 patients hospitalized with COVID-19 with an oxygen saturation of 94% or less while breathing ambient air or who required oxygen support.4 Patients received a 10-day treatment of IV remdesivir 200 mg on day 1 followed by 100 mg for the remaining 9 days of therapy. Fifty-three patients had data analyzed (7 lacked posttreatment data, 1 had dosing error), and clinical improvement was seen in 68% of patients.4 A total of 32 patients (60%) reported adverse events (AEs) during follow-up.4 The most common AEs were increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension. Twelve patients (23%) experienced serious AEs, including multiple organ dysfunction syndrome, septic shock, acute kidney injury, and hypotension, with most occurring in those receiving invasive ventilation.4 The results are promising; however, more robust studies are needed to determine the safety and efficacy of remdesivir for patients with COVID-19. Study limitations included the drug not being randomized and lacking a control, missing data, and a short follow-up duration.4
There are currently 2 phase 3 randomized clinical trials, known as the SIMPLE studies, for patients with severe COVID-19 symptoms (NCT04292899) and for those with moderate symptoms (NCT04292730).5,6 Gilead released topline results from the SIMPLE trial studying patients with severe COVID-19, which demonstrated similar improvement with the 5- and 10-day treatment regimens of remdesivir.5 Time to improvement for 50% of study participants was 10 days in the 5-day treatment group, and more than half of patients in both groups were discharged from the hospital by 14 days.5 Results are expected by May 2020 for the study evaluating patients with moderate COVID-19.6 Gilead is currently working on transitioning to expanded access of remdesivir for patients with severe symptoms and will collect and analyze treatment data.7
On May 1, the FDA issued an emergence use authroziation (EUA) for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in hospitalized adults and children.
HYDROXYCHLOROQUINE, CHLOROQUINE, AND AZITHROMYCIN
The FDA recently issued an EUA for the anti-malarial drugs chloroquine and hydroxychloroquine (Plaquenil) for the treatment of hospitalized adult and adolescent patients with COVID-19 who are unable to participate in a clinical trial and who weigh 50 kg or more. These medications have immunomodulatory activity that could contribute to an anti-inflammatory response, which is the theoretical mechanism of action for the proposed treatment of COVID- 19.8 The dosage of hydroxychloroquine recommended by the EUA is 800 mg on the first day of treatment followed by 400 mg daily for 4 to 7 days of total therapy, based on clinical evaluation.9 Chloroquine’s EUA recommends 1 g on day 1 followed by 500 mg daily for 4 to 7 days of total treatment, based on clinical evaluation.10 However, there is much controversy surrounding these drugs, as their safety and efficacy for the treatment of COVID-19 have not been established. Limited evidence suggests that these medications may have clinical benefits in patients with COVID-19.3
Hydroxychloroquine with azithromycin was examined in observational and nonrandomized studies in France for the treatment of COVID-19, but data were limited, as many individuals were considered to be low risk and only a small number of patients were included.11 Azithromycin has immunomodulatory and anti-inflammatory properties, but there are currently in- sufficient data for its adjunctive use in the management of COVID-19.3 Both hydroxychloroquine and azithromycin are associated with QT prolongation. A jointly published guidance was released April 8 by the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society regarding possible serious health risks associated with hydroxychloroquine and azithromycin use.12 Recommendations include QT interval monitoring, withholding hydroxychloroquine and azithromycin in patients with baseline QT prolongation or known congenital long QT syndrome, correcting hypokalemia and hypomagnesemia, and avoiding other QTc-pro- longing medications.12
Treatment guidelines released by the NIH recommended against the use of hydroxychloroquine in combination with azithromycin, except in the context of a clinical trial, due the potential for toxicities.
The safety and efficacy of hydroxychloroquine for the treatment of COVID- 19 will be further evaluated in the ORCHID Study by the National Heart, Lung, and Blood Institute.13 This phase 3 multicenter, placebo-controlled, ran- domized trial aims to enroll approximately 500 patients and is estimated to have initial results by April 2021.13,14 Chloroquine studies are also underway in China and other countries, as there is currently limited evidence regarding the drug’s effectiveness for COVID-19. One randomized phase 2b clinical trial compared high-dose chloroquine (600 mg twice daily for 10 days) with low- dose chloroquine (450 mg for 5 days, twice daily only on first day) in 81 patients with severe COVID-19 in Brazil.15 All patients also received azithromycin and ceftriaxone. The fatality rate was 13.5%, with more deaths and QTc prolongation occurring in the high-dose treatment group.15 The study halted the high-dose treatment arm and results were posted to medRxiv, but the study has not yet been peer reviewed. These results shed light on cardiac AEs potentially being dose dependent.
Tocilizumab (Actemra), manufactured by Genentech, is a recombinant humanized monoclonal antibody that is an interleukin receptor antagonist, with a proposed mechanism of action that combats cytokine release syndrome symptoms in severe cases of COVID-19.3 The drug is currently approved to treat various conditions such as rheumatoid arthritis; however, there are limited data demonstrating that tocilizumab shows benefit for severe COVID-19 symptoms. and results in fever reduction and a decreased need for supplemental oxygen.3 As tocilizumab is an immunosuppressive drug, it can increase the risk of serious infections. A phase 3 randomized multicenter study is underway to evaluate the safety and efficacy of tocilizumab in hospitalized patients with severe COVID-19 pneumonia.16
Investigators are evaluating other drugs for the treatment of COVID-19 (see Table).
1. Information for clinicians on therapeutic options for patients with COVID-19. CDC. Updated April 13, 2020. Accessed April 15, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html
2. COVID-19 treatment. ClinicalTrials.gov. Accessed April 15, 2020. https://clinicaltrials.gov/ct2/results?recrs=&cond=COVID-19+treatment&term=&cntry=&state=&city=&dist
3. Assessment of evidence for COVID-19-related treatments. American Society of Health-System Pharmacists. Updated April 15, 2020. Accessed April 15, 2020. https://www.ashp.org/-/media/8CA43C674C6D4335B6A19852843C4052.ashx
4. Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe COVID-19. N Engl J Med. Published online April 10, 2020. doi:10.1056/NEJMoa2007016
5. Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734TM) in Participants With Severe Coronavirus Disease (COVID-19). Updated April 14, 2020. Accessed April 15, 2020. https://clinicaltrials.gov/ct2/show/NCT04292899
6. Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734TM) in Participants With Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment. ClinicalTrials.gov. Updated April 14, 2020. Accessed April 15, 2020. https://clinicaltrials.gov/ct2/show/NCT04292730
7. Gilead Sciences statement on access to remdesivir outside of clinical trials. Gilead Sciences. Accessed April 16, 2020. https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-access-to-remdesivir-outside-of-clinical-trials
8. Request for emergency use authorization for use of chloroquine phosphate or hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of 2019 coronavirus disease. FDA. March 28, 2020. Accessed April 16, 2020. https://www.fda.gov/media/136534/download
9. Fact sheet for health care providers emergency use authorization (EUA) of hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of COVID-19 in certain hospitalized patients. FDA. April 3, 2020. Accessed April 16, 2020. https://www.fda.gov/media/136537/download
10. Fact sheet for health care providers emergency use authorization (EUA) of chloroquine phosphate supplied from the strategic national stockpile for treatment of COVID-19 in certain hospitalized patients. FDA. April 3, 2020. Accessed April 16, 2020. https://www.fda.gov/media/136535/download
11. Gautret P, Lagier JC, 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. Published online March 20, 2020. doi:10.1016/j.ijantimicag.2020.105949
12. Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for drug interactions on QTc in exploratory COVID-19 (coronavirus disease 2019) treatment. Circulation. Published online April 8, 2020. doi:10.1161/CIRCULATIONAHA.120.047521
13. NIH clinical trial of hydroxychloroquine, a potential therapy for COVID-19, begins. News release. National Institutes of Health; April 9, 2020. Accessed April 16, 2020. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-hydroxychloroquine-potential-therapy-covid-19-begins
14. Outcomes Related to COVID-19 Treated with Hydroxychloroquine Among In-patients With Symptomatic Disease (ORCHID). ClinicalTrials.gov. Updated April 7, 2020. Accessed April 16, 2020. https://clinicaltrials.gov/ct2/show/NCT04332991
15. Borba M, Val FA, Sampaio VS, et al; CloroCovid-19 Team. Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). Preprint. Posted online April 11, 2020. medRxiv 2020.04.07.20056424. doi:10.1101/2020.04.07.20056424
16. Waldrop T, Alsup D, McLaughlin EC. Fearing coronavirus, Arizona man dies after taking a form of chloroquine used to treat aquariums. CNN. March 25, 2020. Accessed April 16, 2020. https://www.cnn.com/2020/03/23/health/arizona-coronavirus-chloroquine-death/index.html
17. American Association of Poison Control Centers on hydroxychloroquine side effects. News release. American Association of Poison Control Centers; March 25, 2020. Accessed April 16, 2020. https://piper.filecamp.com/uniq/Klk1IGw3Mzt29mhN.pdf
18. A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia (COVACTA). ClinicalTrials.gov. Updated April 8, 2020. Accessed April 16, 2020. https://clinicaltrials.gov/ct2/show/NCT04320615
19. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. Published online March 18, 2020. doi:10.1056/NEJMoa2001282
20. RECOVERY randomised evaluation of COVID-19 therapy. Nuffield Department of Population Health. Accessed April 16, 2020. https://www.recoverytrial.net/
21. Sheahan TP, Sims AC, Zhou S, et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. Published online April 6, 2020. doi:10.1126/scitranslmed.abb5883
22. FDA: human trials can begin for Emory COVID-19 antiviral. News release. Emory University; April 7, 2020. Accessed April 16, 2020. https://news.emory.edu/stories/2020/04/covid_eidd2801_fda/index.html
23. FDA grants Bellerophon emergency expanded access for INOpulse for the treatment of COVID-19 virus. News release. Bellerophon Therapeutics; March 20, 2020. Accessed April 16, 2020. http://investors.bellerophon.com/news-releases/news-release-details/fda-grants-bellerophon-emergency-expanded-access-inopulser
24. Bellerophon Therapeutics submits investigational new drug application to study INOpulse inhaled nitric oxide therapy for the treatment of COVID-19. News release. Bellerophon Therapeutics; April 8, 2020. Accessed April 16, 2020. http://investors.bellerophon.com/news-releases/news-release-details/bellerophon-therapeutics-submits-investigational-new-drug