Introduction
Various treatments for COVID-19 are in clinical trials around the world.
Global coronavirus COVID-19 clinical trial tracker
external link opens in a new window There are several treatments being used off-label on a compassionate-use basis, or as part of a clinical trial.
WHO: off-label use of medicines for COVID-19
external link opens in a new window It is important to note that there may be serious adverse effects associated with these drugs, and that these adverse effects may overlap with the clinical manifestations of COVID-19. These drugs may also increase the risk of death in an older patient or a patient with an underlying health condition (e.g., drugs that prolong the QT interval may increase the risk of cardiac death).[677]Kalil AC. Treating COVID-19: off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA Mar 24 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2763802
http://www.ncbi.nlm.nih.gov/pubmed/32208486?tool=bestpractice.com
Drug-drug interactions with the patient’s existing medication(s), and drug-disease interactions (e.g., impact of inflammation on drug metabolism in COVID-19 patients), must also be considered.[678]Marzolini C, Battegay M, Sendi P, et al. Prescribing in COVID-19 patients: should we take into account inflammation? Br J Clin Pharmacol. 2020 Aug 20 [Epub ahead of print].
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bcp.14524
http://www.ncbi.nlm.nih.gov/pubmed/32820554?tool=bestpractice.com
International trials to identify treatments that may be beneficial, such as the World Health Organization’s (WHO) Solidarity trial (the world’s largest randomized controlled trial on COVID-19 therapeutics across 30 countries), and the UK’s randomized evaluation of COVID-19 therapy (RECOVERY) trial, are ongoing.
WHO: “Solidarity” clinical trial for COVID-19 treatments
external link opens in a new window
RECOVERY trial
external link opens in a new window
Remdesivir
Remdesivir is a broad-spectrum investigational antiviral agent. There are conflicting recommendations across international guidelines about the use of remdesivir, so it is important that you check local guidance and protocols. Remdesivir may not reduce mortality (low-certainty evidence) or time to symptom resolution (moderate-certainty evidence) compared with standard of care.[620]Siemieniuk RA, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ. 2020 Jul 30;370:m2980.
https://www.bmj.com/content/370/bmj.m2980
http://www.ncbi.nlm.nih.gov/pubmed/32732190?tool=bestpractice.com
[676]Siemieniuk RA, Bartoszko JJ, Ge L, et al. Update to living systematic review on drug treatments for covid-19. BMJ. 2020 Dec 17;371:m4852.
https://www.bmj.com/content/371/bmj.m4852
http://www.ncbi.nlm.nih.gov/pubmed/33334735?tool=bestpractice.com
The WHO recommends against the use of remdesivir in hospitalized patients in addition to standard care, regardless of disease severity. This is a weak or conditional recommendation.[575]World Health Organization. Therapeutics and COVID-19: living guideline. 2020 [internet publication].
https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guideline
[619]Lamontagne F, Agoritsas T, Macdonald H, et al. A living WHO guideline on drugs for covid-19: update 3. BMJ. 2020 Dec 17;370:m3379.
https://www.bmj.com/content/370/bmj.m3379
The recommendation is based on a systematic review and network meta-analysis of four randomized trials with 7333 hospitalized patients, and included the NIAID-ACTT-1 trial (on which the original US approval of remdesivir was based) and the WHO Solidarity trial. There is currently no evidence that remdesivir improves patient outcomes such as time to clinical improvement, the need for mechanical ventilation, or mortality. However, the meta-analysis did not prove that remdesivir has no benefit.[619]Lamontagne F, Agoritsas T, Macdonald H, et al. A living WHO guideline on drugs for covid-19: update 3. BMJ. 2020 Dec 17;370:m3379.
https://www.bmj.com/content/370/bmj.m3379
The WHO Solidarity trial found that remdesivir appears to have little or no effect on hospitalized patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[679]WHO Solidarity Trial Consortium., Pan H, Peto R, et al. Repurposed antiviral drugs for Covid-19: interim WHO Solidarity trial results. N Engl J Med. 2020 Dec 2 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727327/
http://www.ncbi.nlm.nih.gov/pubmed/33264556?tool=bestpractice.com
In the US, the National Institutes of Health guidelines panel recommends remdesivir in hospitalized patients who require supplemental oxygen. It may be given alone (e.g., for patients who require minimal supplemental oxygen) or in combination with dexamethasone (e.g., for patients who require increasing amounts of supplemental oxygen). The panel also recommends remdesivir, in combination with dexamethasone, in hospitalized patients who require high-flow oxygen or noninvasive ventilation. It does not recommend remdesivir in patients who require invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). The panel acknowledges that remdesivir may also be appropriate in hospitalized patients who do not require oxygen, but who are at high risk of disease progression. The recommended treatment course is 5 days or until hospital discharge, whichever comes first. Some experts recommend a 10-day course in patients who have not shown substantial clinical improvement by day 5.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
The Infectious Diseases Society of America recommends remdesivir (5 days in patients on oxygen and 10 days in patients on mechanical ventilation or ECMO) over no antiviral treatment in hospitalized patients with severe disease based on moderate-certainty evidence. The panel recommends against the routine use of remdesivir in hospitalized patients who do not require oxygen and have an oxygen saturation >94% on room air, based on very low-certainty evidence.[623]Bhimraj A, Morgan RL, Hirsch Shumaker A, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. 2020 [internet publication].
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
The American College of Physicians recommends the use of remdesivir in hospitalized patients with moderate disease. This recommendation is based on low-certainty evidence that suggests remdesivir may slightly reduce mortality and serious adverse events, reduce time to clinical improvement and recovery, and reduce the need for invasive mechanical ventilation or ECMO compared with standard of care.[680]Qaseem A, Yost J, Etxeandia-Ikobaltzeta I, et al. Should remdesivir be used for the treatment of patients with COVID-19? Rapid, living practice points from the American College of Physicians (version 1). Ann Intern Med. 2020 Oct 5 [Epub ahead of print].
https://www.acpjournals.org/doi/10.7326/M20-5831
http://www.ncbi.nlm.nih.gov/pubmed/33017175?tool=bestpractice.com
[681]Wilt TJ, Kaka AS, MacDonald R, et al. Remdesivir for adults with COVID-19: a living systematic review for an American College of Physicians practice points. Ann Intern Med. 2020 Oct 5 [Epub ahead of print].
https://www.acpjournals.org/doi/10.7326/M20-5752
http://www.ncbi.nlm.nih.gov/pubmed/33017170?tool=bestpractice.com
In the UK and Europe, remdesivir is conditionally approved in adolescents ≥12 years of age and adults with pneumonia who require supplemental oxygen (usually classified as severe disease).[682]European Medicines Agency. First COVID-19 treatment recommended for EU authorisation. 2020 [internet publication].
https://www.ema.europa.eu/en/news/first-covid-19-treatment-recommended-eu-authorisation
However, the European Medicines Agency is reviewing the data from the WHO to see whether any changes are needed to the European marketing authorization, and has recommended a change to the marketing authorization to clarify it should only be used in patients on low- or high-flow oxygen or other noninvasive ventilation at start of treatment.[683]European Medicines Agency. Update on remdesivir: EMA will evaluate new data from Solidarity trial. 2020 [internet publication].
https://www.ema.europa.eu/en/news/update-remdesivir-ema-will-evaluate-new-data-solidarity-trial
[684]European Medicines Agency. Veklury. 2020 [internet publication].
https://www.ema.europa.eu/en/medicines/human/EPAR/veklury
The Food and Drug Administration (FDA) has approved remdesivir for the treatment of COVID-19 in hospitalized children (≥12 years of age and ≥40 kg) and adults. The approval does not cover the entire population that had previously been authorized under the original emergency-use authorization. The emergency-use authorization has now been revised to authorize use of remdesivir in hospitalized children who weigh between 3.5 kg and 40 kg, and children <12 years of age who weigh at least 3.5 kg.[685]US Food and Drug Administration. FDA approves first treatment for COVID-19. 2020 [internet publication].
https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19
Remdesivir can cause gastrointestinal symptoms, elevated transaminase levels, and an increase in prothrombin time. Hypersensitivity reactions have also been reported during and following administration. Remdesivir should not be used in patients with an estimated glomerular filtration rate <30 mL/minute, and it should be used with caution in patients with hepatic impairment. Safety and efficacy has not been evaluated in pregnant women, breastfeeding women, or children. Remdesivir should not be withheld from pregnant women if otherwise indicated. Remdesivir may interact with hydroxychloroquine/chloroquine, but is thought to be safe with corticosteroids.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
The European Medicines Agency has started a review of a safety signal to assess reports of acute kidney injury in some patients. At this stage, it has not been determined whether there is a causal relationship between remdesivir and acute kidney injury.[686]European Medicines Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 28 September - 1 October 2020. 2020 [internet publication].
https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-28-september-1-october-2020
Interleukin-6 (IL-6) inhibitors
IL-6 inhibitors (e.g., tocilizumab, siltuximab) are being trialed in patients for the treatment of virus-induced cytokine release syndrome. These drugs are already approved in some countries for other indications. There are conflicting recommendations across international guidelines about the use of these agents, so it is important that you check local guidance and protocols. UK guidance recommends considering tocilizumab (or sarilumab as an alternative) in critically ill adults admitted to the intensive care unit with severe pneumonia requiring respiratory support when infection is confirmed by microbiologic testing (or where a multidisciplinary team has a high level of confidence that the clinical and radiologic features suggest that COVID-19 is the most likely diagnosis) and patients do not meet specific exclusion criteria.[687]Medicines and Healthcare products Regulatory Agency. COVID-19 therapeutic alert: interleukin-6 inhibitors (tocilizumab or sarilumab) for patients admitted to ICU with COVID-19 pneumonia (adults). 2021 [internet publication].
https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=103134
This recommendation is based on evidence (yet to be peer reviewed) from the REMAP-CAP trial that showed a reduction in mortality of 24% when these drugs were given within 24 hours of intensive care unit admission, compared with standard of care (including corticosteroids). The treatment also reduced the time patients spent in the intensive care unit by more than 1 week on average. The effect is thought to be supplementary to those from corticosteroids.[688]Gordon AC, Mouncey PR, Al-Beidh F, et al; medRxiv. Interleukin-6 receptor antagonists in critically ill patients with Covid-19: preliminary report. 2021 [internet publication].
https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v2
It is possible that any benefit from tocilizumab is seen only in the most severely ill patients when it is given soon after organ support is started, when any developing organ dysfunction may be more reversible.[689]National Institute for Health and Care Excellence. COVID-19 rapid evidence summary: tocilizumab for COVID-19. 2021 [internet publication].
https://www.nice.org.uk/advice/es33/chapter/Product-overview
In the US, the National Institutes of Health guidelines panel recommends against the use of IL-6 inhibitors for the treatment of COVID-19 except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Likewise, the Infectious Diseases Society of America recommends against the routine use of tocilizumab in hospitalized patients based on low-certainty evidence.[623]Bhimraj A, Morgan RL, Hirsch Shumaker A, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. 2020 [internet publication].
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
A living systematic review and meta-analysis found that (as of 8 October 2020) there is moderate-certainty evidence that tocilizumab reduces the risk of mechanical ventilation in hospitalized patients. Low-certainty evidence from cohort studies suggests an association between tocilizumab and lower mortality.[690]Tleyjeh IM, Kashour Z, Damlaj M, et al. Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis. Clin Microbiol Infect. 2020 Nov 5 [Epub ahead of print].
https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30690-X/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/33161150?tool=bestpractice.com
The randomized controlled phase 3 EMPACTA trial found that tocilizumab reduced the need for mechanical ventilation in hospitalized patients compared with placebo, although there was no statistical difference in mortality between the two arms.[691]Genentech. Genentech’s phase III EMPACTA study showed Actemra reduced the likelihood of needing mechanical ventilation in hospitalized patients with COVID-19 associated pneumonia. 2020 [internet publication].
https://www.gene.com/media/press-releases/14881/2020-09-17/genentechs-phase-iii-empacta-study-showe
However, the randomized controlled phase 3 COVACTA trial failed to meet its primary end point of clinical status, and found that tocilizumab did not improve mortality.[692]Furlow B. COVACTA trial raises questions about tocilizumab's benefit in COVID-19. Lancet Rheumatol. 2020 Sep 9 [Epub ahead of print].
https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30313-1/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/32929415?tool=bestpractice.com
Full results of both trials are yet to be published. Other randomized trials also give conflicting results.[693]Gupta S, Wang W, Hayek SS, et al. Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19. JAMA Intern Med. 2020 Oct 20 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772185
http://www.ncbi.nlm.nih.gov/pubmed/33080002?tool=bestpractice.com
[694]Salvarani C, Dolci G, Massari M, et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA Intern Med. 2020 Oct 20 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772186
http://www.ncbi.nlm.nih.gov/pubmed/33080005?tool=bestpractice.com
[695]Hermine O, Mariette X, Tharaux PL, et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med. 2020 Oct 20 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772187
http://www.ncbi.nlm.nih.gov/pubmed/33080017?tool=bestpractice.com
[696]Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med. 2020 Oct 21 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2028836
http://www.ncbi.nlm.nih.gov/pubmed/33085857?tool=bestpractice.com
[697]Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 2021 Jan 7;384(1):20-30.
https://www.nejm.org/doi/full/10.1056/NEJMoa2030340
http://www.ncbi.nlm.nih.gov/pubmed/33332779?tool=bestpractice.com
Monoclonal antibodies
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies have the potential to be used for prophylaxis and treatment of COVID-19. These antibodies bind to the SARS-CoV-2 surface spike protein receptor-binding domain, which blocks the binding of the virus to the angiotensin-converting enzyme-2 (ACE2) host cell surface receptor.[698]Marovich M, Mascola JR, Cohen MS. Monoclonal antibodies for prevention and treatment of COVID-19. JAMA. 2020 Jun 15 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2767383
http://www.ncbi.nlm.nih.gov/pubmed/32539093?tool=bestpractice.com
The combination of casirivimab and imdevimab (formerly known as REGN-COV2) has been issued an emergency-use authorization by the FDA for the treatment of mild to moderate disease in children and adults. The authorization covers patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe disease and/or hospitalization. This includes patients who are 65 years of age or older, or who have certain chronic medical conditions. The authorization was based on a randomized, double-blind, placebo-controlled trial in nonhospitalized adults with mild to moderate symptoms. The trial found that the monoclonal antibody combination reduced COVID-19-related hospitalization or emergency department visits in patients at high risk for disease progression within 28 days after treatment, when compared with placebo. The study is yet to be published.[699]US Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes monoclonal antibodies for treatment of COVID-19. 2020 [internet publication].
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19
An interim analysis of an ongoing, randomized, double-blind, phase 1-3 trial in nonhospitalized patients found that casirivimab/imdevimab reduced viral load from baseline through to day 7, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline.[700]Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med. 2020 Dec 17 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2035002
http://www.ncbi.nlm.nih.gov/pubmed/33332778?tool=bestpractice.com
Casirivimab/imdevimab is not authorized for use in hospitalized patients or those who require oxygen as it has not shown benefit in these patients. Further enrolment of patients requiring high-flow oxygen or mechanical ventilation has been placed on hold due to a potential safety signal and an unfavorable risk/benefit profile at this time. However, enrolment of hospitalized patients requiring either no or low-flow oxygen is being continued.[701]Regeneron Pharmaceuticals, Inc. REGN-COV2 independent data monitoring committee recommends holding enrollment in hospitalized patients with high oxygen requirements and continuing enrollment in patients with low or no oxygen requirements. 2020 [internet publication].
https://investor.regeneron.com/news-releases/news-release-details/regn-cov2-independent-data-monitoring-committee-recommends
The UK RECOVERY trial is investigating whether adding casirivimab/imdevimab to usual standard of care (versus standard care alone) has any impact on all-cause 28-day mortality.[702]Mahase E. Covid-19: RECOVERY trial will evaluate "antiviral antibody cocktail". BMJ. 2020 Sep 15;370:m3584.
https://www.bmj.com/content/370/bmj.m3584
http://www.ncbi.nlm.nih.gov/pubmed/32933902?tool=bestpractice.com
The National Institutes of Health guidelines panel states that there are insufficient data to recommend either for or against the use of casirivimab/imdevimab for the treatment of outpatients with mild to moderate COVID-19, and that it should not be considered the standard of care. Patients at higher risk for disease progression should be prioritized for treatment, and patients who are hospitalized should not receive casirivimab/imdevimab outside of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
The treatment must be administered as an intravenous infusion. The FDA has issued an emergency-use authorization for bamlanivimab (LY-CoV555) for the treatment of mild to moderate disease in children and adults. The authorization covers patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe disease and/or hospitalization. This includes patients who are 65 years of age or older, or who have certain chronic medical conditions.[703]US Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes monoclonal antibody for treatment of COVID-19. 2020 [internet publication].
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibody-treatment-covid-19
Bamlanivimab, in combination with remdesivir, did not demonstrate efficacy among hospitalized patients who had COVID-19 without end-organ failure.[704]ACTIV-3/TICO LY-CoV555 Study Group; Lundgren JD, Grund B, Barkauskas CE, et al. A neutralizing monoclonal antibody for hospitalized patients with Covid-19. N Engl J Med. 2020 Dec 22 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2033130
http://www.ncbi.nlm.nih.gov/pubmed/33356051?tool=bestpractice.com
Another trial that was investigating the efficacy of bamlanivimab in hospitalized patients has been stopped based on trial data that suggests bamlanivimab is unlikely to help hospitalized patients recover from advanced disease. Other studies of bamlanivimab in recently diagnosed mild to moderate disease, recently diagnosed disease in the ambulatory setting, and prevention of disease in residents and staff at long-term care facilities remain ongoing.[705]Eli Lilly and Company. Lilly statement regarding NIH’s ACTIV-3 clinical trial. 2020 [internet publication].
https://www.lilly.com/news/stories/statement-activ3-clinical-trial-nih-covid19
The National Institutes of Health guidelines panel states that there are insufficient data to recommend either for or against the use of bamlanivimab for the treatment of outpatients with mild to moderate COVID-19, and that it should not be considered the standard of care. Patients at higher risk for disease progression should be prioritized for treatment, and patients who are hospitalized should not receive bamlanivimab outside of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
The Infectious Diseases Society of America recommends against the routine use of bamlanivimab in ambulatory patients; however, it states that bamlanivimab may be a reasonable treatment option in patients at increased risk.[623]Bhimraj A, Morgan RL, Hirsch Shumaker A, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. 2020 [internet publication].
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
The combination AZD7442 (AZD8895 and AZD1061) is currently in phase 2 trials and is set to advance to phase 3 trials. This combination of long-acting antibodies derived from convalescent patients has been engineered to extend the half-life of the antibodies and increase protection to 6 to 12 months after administration.[706]AstraZeneca. COVID-19 long-acting antiBody (LAAB) combination AZD7442 rapidly advances into phase III clinical trials. 2020 [internet publication].
https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/covid-19-long-acting-antibody-laab-combination-azd7442-rapidly-advances-into-phase-iii-clinical-trials.html
Convalescent plasma
Clinical trials to determine the safety and efficacy of convalescent plasma that contains antibodies to SARS-CoV-2 in patients with COVID-19 are ongoing. In the US, the FDA has issued an emergency-use authorization for convalescent plasma for the treatment of COVID-19 in hospitalized patients.[707]US Food and Drug Administration. FDA issues emergency use authorization for convalescent plasma as potential promising COVID–19 treatment, another achievement in administration’s fight against pandemic. 2020 [internet publication].
https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment
This follows publication of a preprint (not peer reviewed) of an open-label, multicenter, expanded access program study of over 35,000 patients that found convalescent plasma lowered 7-day mortality by 9% in hospitalized patients when given within 3 days of diagnosis, and by 12% when given 4 or more days later.[708]Joyner MJ, Senefeld JW, Klassen SA, et al; medRxiv. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. 2020 [internet publication].
https://www.medrxiv.org/content/10.1101/2020.08.12.20169359v1
A meta-analysis and systematic review with a total of 5444 patients found that the use of convalescent plasma reduced mortality, increased viral clearance, and resulted in clinical improvement in patients with COVID-19; however, the evidence is of low quality and further randomized controlled trials are required.[709]Sarkar S, Soni KD, Khanna P. Convalescent plasma a clutch at straws in COVID-19 management! A systematic review and meta-analysis. J Med Virol. 2020 Aug 10 [Epub ahead of print].
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.26408
http://www.ncbi.nlm.nih.gov/pubmed/32776573?tool=bestpractice.com
An open-label, randomized controlled trial in hospitalized patients with moderate disease found that convalescent plasma was not associated with a reduction in progression to severe disease or all-cause mortality.[710]Agarwal A, Mukherjee A, Kumar G, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020 Oct 22;371:m3939.
https://www.doi.org/10.1136/bmj.m3939
http://www.ncbi.nlm.nih.gov/pubmed/33093056?tool=bestpractice.com
However, a randomized, double-blind, placebo-controlled trial in older patients with mild disease who received convalescent plasma within 72 hours after the onset of symptoms found that early administration reduced the progression to severe disease.[711]Libster R, Pérez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med. 2021 Jan 6 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2033700
http://www.ncbi.nlm.nih.gov/pubmed/33406353?tool=bestpractice.com
The authors of a Cochrane review were uncertain as to whether convalescent plasma is beneficial for hospitalized patients with COVID-19. The currently available evidence on the safety and efficacy of convalescent plasma for the treatment of hospitalized patients is of low or very low certainty.[712]Chai KL, Valk SJ, Piechotta V, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev. 2020 Oct 12;10:CD013600.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013600.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/33044747?tool=bestpractice.com
Anti-SARS-CoV-2 antibody levels in the plasma appear to affect outcome. Transfusion of plasma with higher anti–SARS-CoV-2 immunoglobulin G antibody levels was associated with a lower risk of death compared with transfusion of plasma with lower antibody levels in one retrospective study based on an US national registry.[713]Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent plasma antibody levels and the risk of death from Covid-19. N Engl J Med. 2021 Jan 13 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2031893
The National Institutes of Health guidelines panel says that there is currently insufficient evidence to recommend either for or against the use of convalescent plasma for the treatment of COVID-19.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
The Infectious Diseases Society of America recommends convalescent plasma only in the context of a clinical trial.[623]Bhimraj A, Morgan RL, Hirsch Shumaker A, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. 2020 [internet publication].
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
The UK RECOVERY trial is currently investigating whether convalescent plasma is effective in the treatment of COVID-19.
Baricitinib
Baricitinib, an oral Janus kinase inhibitor, may prevent the dysregulated production of proinflammatory cytokines observed in patients with severe/critical COVID-19. The FDA has issued an emergency-use authorization for baricitinib in combination with remdesivir for the treatment of suspected or confirmed COVID-19 in hospitalized adults and children ages 2 years and older who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation.[714]US Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes drug combination for treatment of COVID-19. 2020 [internet publication].
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-combination-treatment-covid-19
The authorization is based on a randomized, double-blind, placebo-controlled trial that found baricitinib plus remdesivir was shown to reduce time to recovery (defined as either being discharged from the hospital, or being hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care) within 29 days after initiating treatment compared with patients who received placebo plus remdesivir. The median time to recovery was 7 days for baricitinib plus remdesivir and 8 days for placebo plus remdesivir.[715]Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2020 Dec 11 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2031994
http://www.ncbi.nlm.nih.gov/pubmed/33306283?tool=bestpractice.com
The National Institutes of Health guidelines panel states that there are insufficient data to recommend either for or against the use of baricitinib in combination with remdesivir for the treatment of hospitalized patients in cases where corticosteroids can be used instead. In rare cases where corticosteroids cannot be used, the panel recommends baricitinib in combination with remdesivir for the treatment of hospitalized, nonintubated patients who require oxygen supplementation. The panel recommends against the use of baricitinib without remdesivir. There is insufficient data to recommend either for or against the use of baricitinib in combination with corticosteroids.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Ivermectin
Ivermectin, a broad-spectrum antiparasitic agent, has been shown to be effective against SARS-CoV-2 in vitro.[716]Caly L, Druce JD, Catton MG, et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787.
https://www.sciencedirect.com/science/article/pii/S0166354220302011
http://www.ncbi.nlm.nih.gov/pubmed/32251768?tool=bestpractice.com
Numerous registered clinical studies of ivermectin, either alone or in combination with other drugs (e.g., doxycycline), are ongoing in many countries for the treatment or prevention of COVID-19. A systematic review and meta-analysis found that adding ivermectin to usual care led to significant clinical improvement and a significant reduction in all-cause mortality compared with usual care; however, the quality of evidence was very low.[717]Padhy BM, Mohanty RR, Das S, et al. Therapeutic potential of ivermectin as add on treatment in COVID 19: a systematic review and meta-analysis. J Pharm Pharm Sci. 2020;23:462-9.
https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/31457/21594
http://www.ncbi.nlm.nih.gov/pubmed/33227231?tool=bestpractice.com
The results of several randomized trials and retrospective cohort studies have been published or made available as preliminary reports (not peer reviewed as yet). Some studies showed no benefits or worsening of disease after ivermectin use; others reported a shorter time to symptom resolution, shorter time to viral clearance, greater reduction in inflammatory markers, and lower mortality rates in patients who received ivermectin compared with patients who received a comparator drug or placebo. The National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of ivermectin for the treatment of COVID-19, and that results from adequately powered, well-designed, and well-conducted clinical trials are needed.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Hydroxychloroquine/chloroquine
Hydroxychloroquine and chloroquine are oral drugs that are indicated for the prophylaxis and treatment of malaria, as well as the treatment of some autoimmune conditions. Both drugs show in vitro activity against SARS-CoV-2; however, hydroxychloroquine has been used more commonly in trials due to its better adverse-effect profile.[718]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 Mar;30(3):269-71.
https://www.nature.com/articles/s41422-020-0282-0
http://www.ncbi.nlm.nih.gov/pubmed/32020029?tool=bestpractice.com
[719]Cortegiani A, Ingoglia G, Ippolito M, et al. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care. 2020 Jun;57:279-83.
https://www.sciencedirect.com/science/article/pii/S0883944120303907
http://www.ncbi.nlm.nih.gov/pubmed/32173110?tool=bestpractice.com
Initial data from clinical trials of hydroxychloroquine seemed promising.[720]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. 2020 Mar 20:105949.
https://www.sciencedirect.com/science/article/pii/S0924857920300996
http://www.ncbi.nlm.nih.gov/pubmed/32205204?tool=bestpractice.com
[721]Chen Z, Hu J, Zhang Z, et al; medRxiv. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. 2020 [internet publication].
https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v2.full.pdf
[722]Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020 May 14;369:m1849.
https://www.bmj.com/content/369/bmj.m1849
http://www.ncbi.nlm.nih.gov/pubmed/32409561?tool=bestpractice.com
However, a living systematic review of current evidence (as of 21 September) concludes that there is low-strength evidence from trials and cohort studies that hydroxychloroquine has no positive effect on all-cause mortality or the need for mechanical ventilation. Trials show low strength of evidence for no positive effect on intubation or death and discharge from the hospital, whereas evidence from cohort studies about these outcomes remains insufficient. Data are insufficiently strong to support a treatment benefit of hydroxychloroquine for other outcomes (e.g., intensive care unit admission, symptom resolution). In trials where hydroxychloroquine is initiated in the outpatient setting, there is low strength of evidence that it reduces hospitalization; however, there is insufficient evidence from cohort studies.[723]Hernandez AV, Roman YM, Pasupuleti V, et al. Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19: a living systematic review. Ann Intern Med. 2020 May 27 [Epub ahead of print].
https://www.acpjournals.org/doi/10.7326/M20-2496
http://www.ncbi.nlm.nih.gov/pubmed/32459529?tool=bestpractice.com
[724]Hernandez AV, Roman YM, Pasupuleti V, et al. Update alert 3: hydroxychloroquine or chloroquine for the treatment or prophylaxis of COVID-19. Ann Intern Med. 2020 Oct 21 [Epub ahead of print].
https://www.acpjournals.org/doi/10.7326/L20-1257
http://www.ncbi.nlm.nih.gov/pubmed/33085507?tool=bestpractice.com
A preprint meta-analysis found that early use of hydroxychloroquine in nonhospitalized patients reduced the risk of infection, hospitalization, and death (grouped together into a composite outcome – a limitation of the study) by 24%, with no serious adverse cardiac events reported.[725]Ladapo JA, McKinnon JE, McCullough PA, et al; medRxiv. Randomized controlled trials of early ambulatory hydroxychloroquine in the prevention of COVID-19 infection, hospitalization, and death: meta-analysis. 2020 [internet publication].
https://www.medrxiv.org/content/10.1101/2020.09.30.20204693v1
A systematic review of 43 mainly retrospective or prospective observational preprint studies also found it is effective when used early in the outpatient setting.[726]Prodromos C, Rumschlag T. Hydroxychloroquine is effective, and consistently so used early, for Covid-19: a systematic review. New Microbes New Infect. 2020 Oct 5:100776.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534595/
http://www.ncbi.nlm.nih.gov/pubmed/33042552?tool=bestpractice.com
Hydroxychloroquine is in trials for the prevention of COVID-19 (mainly in healthcare workers). A randomized, double-blind, placebo-controlled trial with 132 healthcare workers found that there was no significant difference in infection rates in participants receiving daily hydroxychloroquine for 8 weeks compared with placebo, and mild adverse effects were more common in the hydroxychloroquine arm. However, this trial was terminated early and may have been underpowered to detect a clinically important difference.[727]Abella BS, Jolkovsky EL, Biney BT, et al. Efficacy and safety of hydroxychloroquine vs placebo for pre-exposure SARS-CoV-2 prophylaxis among health care workers: a randomized clinical trial. JAMA Intern Med. 2020 Sep 30 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2771265
http://www.ncbi.nlm.nih.gov/pubmed/33001138?tool=bestpractice.com
Post-exposure prophylaxis with hydroxychloroquine has not been shown to be effective in other trials.[728]Mitjà O, Corbacho-Monné M, Ubals M, et al. A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19. N Engl J Med. 2020 Nov 24 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2021801
[729]Barnabas RV, Brown ER, Bershteyn A, et al. Hydroxychloroquine as postexposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 infection : a randomized trial. Ann Intern Med. 2020 Dec 8 [Epub ahead of print].
https://www.acpjournals.org/doi/10.7326/M20-6519
http://www.ncbi.nlm.nih.gov/pubmed/33284679?tool=bestpractice.com
The WHO and the National Institutes of Health have prematurely discontinued their clinical trials of hydroxychloroquine citing a lack of efficacy. The WHO Solidarity trial found that hydroxychloroquine appears to have little or no effect on hospitalized patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[679]WHO Solidarity Trial Consortium., Pan H, Peto R, et al. Repurposed antiviral drugs for Covid-19: interim WHO Solidarity trial results. N Engl J Med. 2020 Dec 2 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727327/
http://www.ncbi.nlm.nih.gov/pubmed/33264556?tool=bestpractice.com
Results from the UK RECOVERY trial found that hydroxychloroquine does not reduce the risk of death at 28 days compared with usual care.[730]RECOVERY Collaborative Group; Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020 Oct 8 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2022926
http://www.ncbi.nlm.nih.gov/pubmed/33031652?tool=bestpractice.com
The WHO strongly recommends against the use of hydroxychloroquine or chloroquine, regardless of disease severity, based on low- to moderate-certainty evidence.[575]World Health Organization. Therapeutics and COVID-19: living guideline. 2020 [internet publication].
https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guideline
[619]Lamontagne F, Agoritsas T, Macdonald H, et al. A living WHO guideline on drugs for covid-19: update 3. BMJ. 2020 Dec 17;370:m3379.
https://www.bmj.com/content/370/bmj.m3379
The National Institutes of Health guidelines panel recommends against the use of hydroxychloroquine or chloroquine for the treatment of COVID-19 in hospitalized patients. The panel recommends against the use of both drugs in nonhospitalized patients except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
The Infectious Diseases Society of America strongly recommends against the use of hydroxychloroquine or chloroquine (with or without azithromycin) for the treatment of COVID-19 in hospitalized patients based on moderate-quality evidence.[623]Bhimraj A, Morgan RL, Hirsch Shumaker A, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. 2020 [internet publication].
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
The FDA has revoked its emergency-use authorization for hydroxychloroquine and chloroquine as it believes the potential benefits no longer outweigh the known and potential risks.[610]Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST guideline and expert panel report. Chest. 2020 Jun 2 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265858/
http://www.ncbi.nlm.nih.gov/pubmed/32502594?tool=bestpractice.com
If used, hydroxychloroquine and chloroquine should be used with caution in patients with preexisting cardiovascular disease due to the risk of arrhythmias, and a baseline echocardiogram is recommended before treatment, particularly in patients who are critically ill.[731]Roden DM, Harrington RA, Poppas A, et al. Considerations for drug interactions on QTc in exploratory COVID-19 (coronavirus disease 2019) treatment. Circulation. 2020 Jun 16;141(24):e906-7.
https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.120.047521
http://www.ncbi.nlm.nih.gov/pubmed/32267732?tool=bestpractice.com
[732]Kamp TJ, Hamdan MH, January CT. Chloroquine or hydroxychloroquine for COVID-19: is cardiotoxicity a concern? J Am Heart Assoc. 2020 May 28:e016887.
https://www.ahajournals.org/doi/pdf/10.1161/JAHA.120.016887
http://www.ncbi.nlm.nih.gov/pubmed/32463308?tool=bestpractice.com
Caution is recommended when using these drugs with other drugs that prolong the QT interval (e.g., azithromycin) due to an increased risk of QT interval prolongation and/or ventricular tachycardia (including Torsades de Pointes).[733]Bessière F, Roccia H, Delinière A, et al. Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit. JAMA Cardiol. 2020 May 1 [Epub ahead of print].
https://jamanetwork.com/journals/jamacardiology/fullarticle/2765633
http://www.ncbi.nlm.nih.gov/pubmed/32356858?tool=bestpractice.com
[734]Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020 May 1 [Epub ahead of print].
https://jamanetwork.com/journals/jamacardiology/fullarticle/2765631
http://www.ncbi.nlm.nih.gov/pubmed/32356863?tool=bestpractice.com
[735]Nguyen LS, Dolladille C, Drici MD, et al. Cardiovascular toxicities associated with hydroxychloroquine and azithromycin: an analysis of the World Health Organization pharmacovigilance database. Circulation. 2020 May 22 [Epub ahead of print].
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.048238
http://www.ncbi.nlm.nih.gov/pubmed/32442023?tool=bestpractice.com
A phase 1 trial of inhaled liposomal hydroxychloroquine has been approved.[736]TLC. TLC receives Australian and Taiwan approval to initiate phase I clinical trial of TLC19 inhalable liposomal hydroxychloroquine for COVID-19. 2020 [internet publication].
https://www.tlcbio.com/en-global/press-releases/detail/News_20201007
Lopinavir/ritonavir
An oral antiretroviral protease inhibitor currently approved for the treatment of HIV infection. Results from the UK RECOVERY trial found that there is no beneficial effect of lopinavir/ritonavir in hospitalized patients with COVID-19. There was no significant difference in 28-day mortality, risk of progression to mechanical ventilation or death, or duration of hospital stay between the two treatment arms (lopinavir/ritonavir versus usual care alone).[737]RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020 Oct 5 [Epub ahead of print].
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32013-4/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/33031764?tool=bestpractice.com
The WHO Solidarity trial found that lopinavir/ritonavir appears to have little or no effect on hospitalized patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[679]WHO Solidarity Trial Consortium., Pan H, Peto R, et al. Repurposed antiviral drugs for Covid-19: interim WHO Solidarity trial results. N Engl J Med. 2020 Dec 2 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727327/
http://www.ncbi.nlm.nih.gov/pubmed/33264556?tool=bestpractice.com
A systematic review and meta-analysis found that lopinavir/ritonavir had no significant advantage in efficacy over standard care, no antivirals, or other antiviral treatments.[738]Alhumaid S, Mutair AA, Alawi ZA, et al. Efficacy and safety of lopinavir/ritonavir for treatment of COVID-19: a systematic review and meta-analysis. Trop Med Infect Dis. 2020 Nov 28;5(4):E180.
https://www.mdpi.com/2414-6366/5/4/180/htm
http://www.ncbi.nlm.nih.gov/pubmed/33260553?tool=bestpractice.com
The WHO strongly recommends against the use of lopinavir/ritonavir, regardless of disease severity, based on low- to moderate-certainty evidence.[575]World Health Organization. Therapeutics and COVID-19: living guideline. 2020 [internet publication].
https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guideline
[619]Lamontagne F, Agoritsas T, Macdonald H, et al. A living WHO guideline on drugs for covid-19: update 3. BMJ. 2020 Dec 17;370:m3379.
https://www.bmj.com/content/370/bmj.m3379
The National Institutes of Health guidelines panel recommends against the use of lopinavir/ritonavir for the treatment of COVID-19 except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
The Infectious Diseases Society of America recommends against the use of lopinavir/ritonavir based on moderate-certainty evidence.[623]Bhimraj A, Morgan RL, Hirsch Shumaker A, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. 2020 [internet publication].
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
Lopinavir/ritonavir causes QT interval prolongation and may increase the risk of bradycardia, especially in older, critically ill patients.[739]Beyls C, Martin N, Hermida A, et al. Lopinavir-ritonavir treatment for COVID-19 infection in intensive care unit: risk of bradycardia. Circ Arrhythm Electrophysiol. 2020 Aug;13(8):e008798.
https://www.ahajournals.org/doi/10.1161/CIRCEP.120.008798
http://www.ncbi.nlm.nih.gov/pubmed/32809882?tool=bestpractice.com
Intravenous immune globulin
Intravenous immune globulin (IVIG) is being trialed in some patients with COVID-19.[49]Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-13.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30211-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/32007143?tool=bestpractice.com
[740]Jawhara S. Could intravenous immunoglobulin collected from recovered coronavirus patients protect against COVID-19 and strengthen the immune system of new patients? Int J Mol Sci. 2020 Mar 25;21(7).
https://www.mdpi.com/1422-0067/21/7/2272/htm
http://www.ncbi.nlm.nih.gov/pubmed/32218340?tool=bestpractice.com
A retrospective study of 58 patients with severe COVID-19 found that IVIG, when used as an adjuvant treatment within 48 hours of admission, may reduce the use of mechanical ventilation, reduce hospital/intensive care unit stay, and reduce 28-day mortality; however, this study had several limitations.[741]Xie Y, Cao S, Li Q, et al. Effect of regular intravenous immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19. J Infect. 2020 Apr 10 [Epub ahead of print].
https://www.journalofinfection.com/article/S0163-4453(20)30172-9/pdf
http://www.ncbi.nlm.nih.gov/pubmed/32283154?tool=bestpractice.com
There is currently insufficient evidence to recommend IVIG for the treatment of COVID-19.[742]Zhang J, Yang Y, Yang N, et al. Effectiveness of intravenous immunoglobulin for children with severe COVID-19: a rapid review. Ann Transl Med. 2020 May;8(10):625.
http://atm.amegroups.com/article/view/43600/html
http://www.ncbi.nlm.nih.gov/pubmed/32566562?tool=bestpractice.com
The National Institutes of Health guidelines panel recommends against the use of non-SARS-CoV-2-specific IVIG for the treatment of COVID-19 except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Anakinra
Anakinra, an interleukin-1 inhibitor, is being trialed in COVID-19 patients for the treatment of virus-induced cytokine release syndrome. It is already approved in some countries for other indications. Addition of high-dose intravenous anakinra to noninvasive ventilation and standard care (which included hydroxychloroquine and lopinavir/ritonavir) in COVID-19 patients with moderate to severe acute respiratory distress syndrome and hyperinflammation was associated with a higher survival rate at 21 days in a small retrospective study.[743]Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020 Jun;2(6):e325-31.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252085/
http://www.ncbi.nlm.nih.gov/pubmed/32501454?tool=bestpractice.com
A small prospective cohort study found that anakinra significantly reduced the need for invasive mechanical ventilation and mortality in patients with severe disease.[744]Huet T, Beaussier H, Voisin O, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol. 2020 Jul;2(7):e393-400.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259909/
http://www.ncbi.nlm.nih.gov/pubmed/32835245?tool=bestpractice.com
A small retrospective case series found that anakinra could be beneficial in patients with cytokine release syndrome when initiated early after the onset of acute hypoxic respiratory failure.[745]Navarro-Millán I, Sattui SE, Lakhanpal A, et al. Use of anakinra to prevent mechanical ventilation in severe COVID-19: a case series. Arthritis Rheumatol. 2020 Jun 30 [Epub ahead of print].
https://onlinelibrary.wiley.com/doi/abs/10.1002/art.41422
http://www.ncbi.nlm.nih.gov/pubmed/32602262?tool=bestpractice.com
A phase 3 trial comparing anakinra with optimized standard of care in hospitalized patients has been suspended due to excess mortality in the intervention arm.[746]ClinicalTrials.gov. Anakinra for COVID-19 respiratory symptoms (ANACONDA). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04364009
The National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of anakinra for the treatment of COVID-19.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
The National Institute for Health and Care Excellence in the UK states that there is no evidence available to determine whether anakinra is effective, safe, or cost-effective for treating adults and children with secondary hemophagocytic lymphohistiocytosis triggered by SARS-CoV-2 or a similar coronavirus.[747]National Institute for Health and Care Excellence. COVID 19 rapid evidence summary: anakinra for COVID-19 associated secondary haemophagocytic lymphohistiocytosis. 2020 [internet publication].
https://www.nice.org.uk/advice/es26/chapter/Key-messages
Antigranulocyte–macrophage colony-stimulating factor (GM-CSF) monoclonal antibodies
Mavrilimumab was associated with improved clinical outcomes compared with standard care in nonmechanically ventilated patients with severe disease and systemic hyperinflammation in a single-center prospective cohort study.[748]De Luca G, Cavalli G, Campochiaro C, et al. GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study. Lancet Rheumatol. 2020 Aug;2(8):e465-73.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430344/
http://www.ncbi.nlm.nih.gov/pubmed/32835256?tool=bestpractice.com
Lenzilumab was associated with a reduction in the relative risk of progression to invasive mechanical ventilation and/or death in high-risk COVID-19 patients with severe pneumonia compared with a matched control cohort of patients who received standard care alone in a small study of 39 patients.[749]Temesgen Z, Assi M, Shweta FNU, et al. GM-CSF neutralization with lenzilumab in severe COVID-19 pneumonia: a case-control study. Mayo Clin Proc. 2020 Aug [Epub ahead of print].
https://els-jbs-prod-cdn.jbs.elsevierhealth.com/pb/assets/raw/Health%20Advance/journals/jmcp/jmcp_ft95_8_7.pdf
[750]Temesgen Z, Assi M, Vergidis P, et al. First clinical use of lenzilumab to neutralize GM-CSF in patients with severe COVID-19 pneumonia. medRxiv. 2020 Jun 14 [Epub ahead of print].
https://www.medrxiv.org/content/10.1101/2020.06.08.20125369v2
http://www.ncbi.nlm.nih.gov/pubmed/32587983?tool=bestpractice.com
Tumor necrosis factor (TNF)-alpha inhibitors
A trial has been launched in the UK to investigate whether adalimumab is effective for treating patients in the community, including care homes. The trial will test two dose levels of adalimumab, and patients will be followed up for 4 months. The trial comes after a recent study reported that TNF inhibitors were associated with a decreased odds of hospitalization in people with rheumatic disease and COVID-19.[751]Mahase E. Covid-19: Anti-TNF drug adalimumab to be trialled for patients in the community. BMJ. 2020 Oct 1;371:m3847.
https://www.bmj.com/content/371/bmj.m3847
http://www.ncbi.nlm.nih.gov/pubmed/33004419?tool=bestpractice.com
Stem cell therapy
Stem cell therapy is being investigated to treat patients with COVID-19 in clinical trials. It is thought that mesenchymal stem cells can reduce the pathologic changes that occur in the lungs, and inhibit the cell-mediated immune inflammatory response.[752]ClinicalTrials.gov. Mesenchymal stem cell treatment for pneumonia patients infected with 2019 novel coronavirus. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04252118
Remestemcel-L (ex vivo cultured adult human mesenchymal stem cells from the bone marrow of healthy adult donors) is currently in phase 3 trials for the treatment of moderate to severe acute respiratory distress syndrome in ventilator-dependent COVID-19 patients; however, an interim analysis of data found that the trial is not likely to meet its 30-day mortality reduction end point and has stopped enrolment, although the trial will be completed with the patients currently enrolled, with follow-up as planned.[753]Mesoblast Limited. Mesoblast update on COVID-19 ARDS trial. 2020 [internet publication].
http://investorsmedia.mesoblast.com/static-files/bc0ce366-1c50-46ce-a9d4-d06b7ce403e5
The National Institutes of Health guidelines panel recommends against the use of mesenchymal stem cells for the treatment of COVID-19 except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Adipose-derived mesenchymal stem cells have been approved by the FDA for the treatment of severe COVID-19.
Granulocyte colony-stimulating factor (G-CSF)
Recombinant G-CSF plus usual care did not accelerate clinical improvement compared with usual care alone according to preliminary findings from a randomized clinical trial in patients with lymphopenia and no comorbidities. Larger studies are needed to determine whether G-CSF, which increases peripheral blood leukocyte and lymphocyte cell counts, is beneficial in COVID-19 patients.[754]Cheng LL, Guan WJ, Duan CY, et al. Effect of recombinant human granulocyte colony-stimulating factor for patients with coronavirus disease 2019 (COVID-19) and lymphopenia: a randomized clinical trial. JAMA Intern Med. 2020 Sep 10 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2770680
http://www.ncbi.nlm.nih.gov/pubmed/32910179?tool=bestpractice.com
Very low-certainty evidence suggests that recombinant G-CSF may reduce risk of death and need for mechanical ventilation compared with standard care.[620]Siemieniuk RA, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ. 2020 Jul 30;370:m2980.
https://www.bmj.com/content/370/bmj.m2980
http://www.ncbi.nlm.nih.gov/pubmed/32732190?tool=bestpractice.com
[676]Siemieniuk RA, Bartoszko JJ, Ge L, et al. Update to living systematic review on drug treatments for covid-19. BMJ. 2020 Dec 17;371:m4852.
https://www.bmj.com/content/371/bmj.m4852
http://www.ncbi.nlm.nih.gov/pubmed/33334735?tool=bestpractice.com
Bacille Calmette-Guerin (BCG) vaccine
The BCG vaccine is being trialed in some countries for the prevention of COVID-19, including in healthcare workers. There is some evidence that BCG vaccination prevents other respiratory tract infections in children and older people mediated by induction of innate immune memory.[755]Centre for Evidence-Based Medicine; Soliman R, Brassey J, Plüddemann A, et al. Does BCG vaccination protect against acute respiratory infections and COVID-19? A rapid review of current evidence. 2020 [internet publication].
https://www.cebm.net/covid-19/does-bcg-vaccination-protect-against-acute-respiratory-infections-and-covid-19-a-rapid-review-of-current-evidence/
However, there is no evidence to support its use in COVID-19, and the WHO does not recommend it for the prevention of COVID-19.[756]World Health Organization. Bacille Calmette-Guérin (BCG) vaccination and COVID-19: scientific brief. 2020 [internet publication].
https://www.who.int/news-room/commentaries/detail/bacille-calmette-guérin-(bcg)-vaccination-and-covid-19
Bemcentinib
An experimental small molecule that inhibits AXL kinase. Bemcentinib has previously demonstrated a role in the treatment of cancer, but has also been reported to have antiviral activity in preclinical models, including activity against SARS-CoV-2. It was the first candidate to be selected as part of the UK’s Accelerating COVID-19 Research and Development (ACCORD) study.[757]Department of Health and Social Care. COVID-19 treatments could be fast-tracked through new national clinical trial initiative. 2020 [internet publication].
https://www.gov.uk/government/news/covid-19-treatments-could-be-fast-tracked-through-new-national-clinical-trial-initiative
The study has stopped recruiting new patients into the trial due to the reduction of new COVID-19 cases in the UK. Patients already recruited will continue on treatment as per the study protocol.
Angiotensin-II receptor antagonists
Angiotensin-II receptor antagonists such as losartan are being investigated as a potential treatment because it is thought that the angiotensin-converting enzyme-2 (ACE2) receptor is the main binding site for the virus.[758]Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020 Mar 4 [Epub ahead of print].
https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.21656
http://www.ncbi.nlm.nih.gov/pubmed/32129518?tool=bestpractice.com
[759]ClinicalTrials.gov. Losartan for patients with COVID-19 requiring hospitalization. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04312009
[760]ClinicalTrials.gov. Losartan for patients with COVID-19 not requiring hospitalization. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04311177
However, some experts believe that these drugs may worsen COVID-19 due to overexpression of ACE2 in people taking these drugs.
Angiotensin-II receptor agonists
C21, a first-in-class oral low molecular weight angiotensin-II receptor agonist, demonstrated efficacy in a randomized, double-blind, placebo-controlled phase 2 trial. C21 reduced the risk of needing oxygen or mechanical ventilation in hospitalized patients compared with placebo.[761]ClinicalTrials.gov. Safety and efficacy of C21 in subjects with COVID-19. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04452435
[762]Vicore Pharma. Vicore Pharma reports positive top line data from the ATTRACT clinical study in patients with COVID-19. 2020 [internet publication].
https://vicorepharma.com/investors/press-releases/press/?releaseID=82FD41BA3EBA3689
Interferons
A randomized, placebo-controlled, phase 2 study found that nebulized interferon beta-1a was associated with a higher odds of clinical improvement and more rapid recovery.[763]Monk PD, Marsden RJ, Tear VJ, et al. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med. 2020 Nov 12 [Epub ahead of print].
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30511-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/33189161?tool=bestpractice.com
The WHO Solidarity trial found that interferon beta-1a appears to have little or no effect on hospitalized patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[679]WHO Solidarity Trial Consortium., Pan H, Peto R, et al. Repurposed antiviral drugs for Covid-19: interim WHO Solidarity trial results. N Engl J Med. 2020 Dec 2 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727327/
http://www.ncbi.nlm.nih.gov/pubmed/33264556?tool=bestpractice.com
Triple therapy with interferon beta-1b, lopinavir/ritonavir, and ribavirin has been tested in hospitalized COVID-19 patients in a small open-label randomized phase 2 trial. Patients who received triple therapy had a significantly shorter median time to a negative nasopharyngeal swab result compared with the control group (lopinavir/ritonavir only). Patients had mild to moderate disease at the time of enrolment.[764]Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020 May 30;395(10238):1695-704.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211500/
http://www.ncbi.nlm.nih.gov/pubmed/32401715?tool=bestpractice.com
A phase 2 trial found that peginterferon lambda reduced viral load and increased the number of participants with a negative nasopharyngeal swab at day 7 in outpatients with mild to moderate disease compared with placebo.[765]ClinicalTrials.gov. Interferon lambda for immediate antiviral therapy at diagnosis in COVID-19 (ILIAD). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04354259
[766]Eiger BioPharmaceuticals. Eiger BioPharmaceuticals announces positive results of investigator sponsored randomized controlled trial at University of Toronto with peginterferon lambda in outpatients with mild to moderate COVID-19. 2020 [internet publication].
https://ir.eigerbio.com/news-releases/news-release-details/eiger-biopharmaceuticals-announces-positive-results-investigator
Clinical trials of inhaled remdesivir, and remdesivir plus interferon beta-1a, have started.[767]National Institutes of Health. NIH clinical trial testing remdesivir plus interferon beta-1a for COVID-19 treatment begins. 2020 [internet publication].
https://www.nih.gov/news-events/news-releases/nih-clinical-trial-testing-remdesivir-plus-interferon-beta-1a-covid-19-treatment-begins
The National Institutes of Health guidelines panel recommends against the use of interferons for the treatment of severe or critically ill patients, except in the context of a clinical trial.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Antibiotics
The PRINCIPLE trial in the UK is currently evaluating three treatment strategies in older people (people ages over 65 years, or people ages over 50 years with an underlying health condition): usual care alone; usual care plus azithromycin; and usual care plus doxycycline.[768]University of Oxford. PRINCIPLE trial. 2020 [internet publication].
https://www.principletrial.org
The UK RECOVERY trial found that azithromycin showed no significant clinical benefit (i.e., length of hospital stay, need for invasive mechanical ventilation, 28-day mortality) in hospitalized patients compared with usual standard care alone. The UK Medicines and Healthcare products Regulatory Agency recommends that azithromycin should not be used in the management of confirmed or suspected COVID-19 in hospitalized patients unless there are additional indications for which its use remains appropriate.[769]Medicines and Healthcare products Regulatory Agency. Azithromycin in the management of COVID-19 (SARS-CoV-2). 2020 [internet publication].
https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=103125
Brilacidin
An investigational drug that belongs to a new class of antibiotics called host defense protein mimetics. Brilacidin has antibacterial, antiviral, and anti-inflammatory properties, and exhibits potent in vitro activity against SARS-CoV-2.[770]Bakovic A, Risner K, Bhalla N, et al. Brilacidin, a COVID-19 drug candidate, exhibits potent in vitro antiviral activity against SARS-CoV-2. bioRxiv. 2020 Oct 30 [Epub ahead of print].
https://www.biorxiv.org/content/10.1101/2020.10.29.352450v1.full
The FDA has granted fast-track designation to the drug, and a phase 2 trial is due to start soon.[771]Innovation Pharmaceuticals. Brilacidin. 2021 [internet publication].
http://www.ipharminc.com/brilacidin-1
Favipiravir
A meta-analysis found that there was significant clinical and radiologic improvement following treatment with favipiravir compared with standard of care.[772]Shrestha DB, Budhathoki P, Khadka S, et al. Favipiravir versus other antiviral or standard of care for COVID-19 treatment: a rapid systematic review and meta-analysis. Virol J. 2020 Sep 24;17(1):141.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512218/
http://www.ncbi.nlm.nih.gov/pubmed/32972430?tool=bestpractice.com
Colchicine
Colchicine, an anti-inflammatory agent that is used for the management of gout and other inflammatory conditions, is being tested in various clinical trials. The UK RECOVERY trial is currently investigating whether colchicine is effective in the treatment of COVID-19. The main outcome the trial will assess is mortality after 28 days. Other outcomes include the impact on hospital stay and the need for ventilation.[773]Nuffield Department of Population Health. Colchicine to be investigated as a possible treatment for COVID-19 in the RECOVERY trial. 2020 [internet publication].
https://www.recoverytrial.net/news/colchicine-to-be-investigated-as-a-possible-treatment-for-covid-19-in-the-recovery-trial
Aspirin
Although it is not currently recommended, aspirin may be effective for the prevention of blood clots in patients with COVID-19. The UK RECOVERY trial is currently investigating whether aspirin plus usual standard of care reduces mortality at 28 days, length of hospital stay, or the need for ventilation in hospitalized patients with COVID-19 compared with standard of care alone.[774]Nuffield Department of Population Health. Aspirin to be investigated as a possible treatment for COVID-19 in the RECOVERY trial. 2020 [internet publication].
https://www.recoverytrial.net/news/aspirin-to-be-investigated-as-a-possible-treatment-for-covid-19-in-the-recovery-trial
Vitamin C
Vitamin C supplementation has shown promise in the treatment of viral infections.[775]Boretti A, Banik BK. Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome. PharmaNutrition. 2020 Apr 21:100190.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172861/
http://www.ncbi.nlm.nih.gov/pubmed/32322486?tool=bestpractice.com
High-dose intravenous vitamin C is being trialed in some centers for the treatment of severe COVID-19.[776]ClinicalTrials.gov. Vitamin C infusion for the treatment of severe 2019-nCoV infected pneumonia. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04264533
There is no evidence to support or refute the use of vitamin C in the treatment of patients with COVID-19; however, a substantial number of trials are ongoing.[777]Baladia E, Pizarro AB, Ortiz-Muñoz L, et al. Vitamin C for COVID-19: a living systematic review. Medwave. 2020 Jul 28;20(6):e7978.
https://www.medwave.cl/link.cgi/English/Original/SystReviews/7978.act
http://www.ncbi.nlm.nih.gov/pubmed/32759894?tool=bestpractice.com
A pilot randomized controlled trial found high-dose intravenous vitamin C may show potential benefit in improving oxygenation and reducing mortality in critically ill patients; however, the trial was underpowered.[778]Zhang J, Rao X, Li Y; Research Square. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. 2020 [internet publication].
https://www.researchsquare.com/article/rs-52778/v2
The National Institutes of Health guidelines panel states that there is insufficient data to recommend either for or against vitamin C for the treatment of COVID-19 in noncritically ill or critically ill patients.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Vitamin D
Vitamin D supplementation has been associated with a reduced risk of acute respiratory infections such as influenza.[779]Grant WB, Lahore H, McDonnell SL, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients. 2020 Apr 2;12(4).
https://www.mdpi.com/2072-6643/12/4/988/htm
http://www.ncbi.nlm.nih.gov/pubmed/32252338?tool=bestpractice.com
[780]McCartney DM, Byrne DG. Optimisation of vitamin D status for enhanced immuno-protection against Covid-19. Ir Med J. 2020 Apr 3;113(4):58.
http://imj.ie/optimisation-of-vitamin-d-status-for-enhanced-immuno-protection-against-covid-19/
http://www.ncbi.nlm.nih.gov/pubmed/32268051?tool=bestpractice.com
[781]Jakovac H. COVID-19 and vitamin D: is there a link and an opportunity for intervention? Am J Physiol Endocrinol Metab. 2020 May 1;318(5):E589.
https://journals.physiology.org/doi/full/10.1152/ajpendo.00138.2020
http://www.ncbi.nlm.nih.gov/pubmed/32297519?tool=bestpractice.com
[782]Jolliffe DA, Camargo CA, Sluyter JD, et al. Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials. medRxiv. 2020 Nov 25 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709175/
http://www.ncbi.nlm.nih.gov/pubmed/33269357?tool=bestpractice.com
Vitamin D is being trialed in patients with COVID-19.[783]ClinicalTrials.gov. Vitamin D on prevention and treatment of COVID-19 (COVITD-19). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04334005
[784]ClinicalTrials.gov. COVID-19 and vitamin D supplementation: a multicenter randomized controlled trial of high dose versus standard dose vitamin D3 in high-risk COVID-19 patients (CoVitTrial). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04344041
However, there is no evidence to recommend vitamin D for the prophylaxis or treatment of COVID-19 as yet.[785]Centre for Evidence-Based Medicine; Lee J, van Hecke O, Roberts N. Vitamin D: a rapid review of the evidence for treatment or prevention in COVID-19. 2020 [internet publication].
https://www.cebm.net/covid-19/vitamin-d-a-rapid-review-of-the-evidence-for-treatment-or-prevention-in-covid-19/
A pilot randomized controlled trial found that high-dose calcifediol, a vitamin D3 analog, significantly reduced the need for intensive care unit treatment in hospitalized patients, and may improve clinical outcomes.[786]Castillo ME, Entrenas Costa LM, Vaquero Barrios JM, et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: a pilot randomized clinical study. J Steroid Biochem Mol Biol. 2020 Aug 29;105751.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456194/
http://www.ncbi.nlm.nih.gov/pubmed/32871238?tool=bestpractice.com
The UK National Institute for Health and Care Excellence recommends vitamin D supplementation in adults (including pregnant and breastfeeding women), young people, and children over 4 years of age between October and early March (and at other times of the year if at risk of vitamin D deficiency) to maintain bone and muscle health. However, it does not recommend supplementation to solely prevent or treat COVID-19, except as part of a clinical trial.[787]National Institute for Health and Care Excellence. COVID-19 rapid guideline: vitamin D. Dec 2020 [internet publication].
https://www.nice.org.uk/guidance/ng187
The National Institutes of Health guidelines panel states that there is insufficient data to recommend either for or against vitamin D.[3]National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020 [internet publication].
https://covid19treatmentguidelines.nih.gov/
Probiotics
There is emerging evidence that gut dysbiosis may have a role in the pathogenesis of COVID-19.[300]Dhar D, Mohanty A. Gut microbiota and Covid-19- possible link and implications. Virus Res. 2020 May 13;285:198018.
https://www.sciencedirect.com/science/article/pii/S0168170220304603?via%3Dihub
http://www.ncbi.nlm.nih.gov/pubmed/32430279?tool=bestpractice.com
[301]Zuo T, Zhang F, Lui GCY, et al. Alterations in gut microbiota of patients with COVID-19 during time of hospitalization. Gastroenterology. 2020 Sep;159(3):944-55.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237927/
http://www.ncbi.nlm.nih.gov/pubmed/32442562?tool=bestpractice.com
[302]Gu S, Chen Y, Wu Z, et al. Alterations of the gut microbiota in patients with COVID-19 or H1N1 influenza. Clin Infect Dis. 2020 Jun 4 [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/pubmed/32497191?tool=bestpractice.com
Probiotics may represent a complementary approach for the prevention or treatment of mucosal damage or inflammation through the modulation of gut microbiota; however, further research is required.[788]Mak JWY, Chan FKL, Ng SC. Probiotics and COVID-19: authors' reply. Lancet Gastroenterol Hepatol. 2020 Aug;5(8):722-3.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357987/
http://www.ncbi.nlm.nih.gov/pubmed/32673605?tool=bestpractice.com
Traditional Chinese medicine
Traditional Chinese medicine is being used in patients with COVID-19 in China according to local guidelines and as part of clinical trials.[789]Yang Y, Islam MS, Wang J, et al. Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): a review and perspective. Int J Biol Sci. 2020 Mar 15;16(10):1708-17.
https://www.ijbs.com/v16p1708.htm
http://www.ncbi.nlm.nih.gov/pubmed/32226288?tool=bestpractice.com
A meta-analysis found that Chinese medicine combined with conventional treatment significantly improved clinical efficacy compared with conventional treatment alone; however, high-quality, multiple-center, large-sample randomized controlled trials are needed.[790]Sun CY, Sun YL, Li XM. The role of Chinese medicine in COVID-19 pneumonia: a systematic review and meta-analysis. Am J Emerg Med. 2020 Jul 8 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342052/
http://www.ncbi.nlm.nih.gov/pubmed/33071103?tool=bestpractice.com
Fluvoxamine
A selective serotonin-reuptake inhibitor with a strong affinity for the sigma-1 receptor. Sigma-1 agonism is a potential mechanism for immune modulation. Previous studies have shown that fluvoxamine reduces the damaging aspects of the inflammatory response during sepsis. A double-blind, randomized, preliminary trial of fluvoxamine versus placebo in adult outpatients with symptomatic COVID-19 found that patients treated with fluvoxamine had a lower likelihood of deterioration over 15 days. However, the study was limited by sample size and short follow-up duration.[791]Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. JAMA. 2020 Nov 12 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2773108
http://www.ncbi.nlm.nih.gov/pubmed/33180097?tool=bestpractice.com
Hyperbaric oxygen
Preliminary evidence suggests that hyperbaric oxygen treatment has been successfully used to treat deteriorating, severely hypoxemic patients with severe COVID-19.[792]Harch PG. Hyperbaric oxygen treatment of novel coronavirus (COVID-19) respiratory failure. Med Gas Res. Apr-Jun 2020;10(2):61-2.
http://www.ncbi.nlm.nih.gov/pubmed/32541128?tool=bestpractice.com
[793]Thibodeaux K, Speyrer M, Raza A, et al. Hyperbaric oxygen therapy in preventing mechanical ventilation in COVID-19 patients: a retrospective case series. J Wound Care. 2020 May 1;29(sup5a):S4-8.
http://www.ncbi.nlm.nih.gov/pubmed/32412891?tool=bestpractice.com
Clinical trials are currently recruiting.[794]ClinicalTrials.gov. Hyperbaric oxygen for COVID-19 patients. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04332081
[795]ClinicalTrials.gov. Safety and efficacy of hyperbaric oxygen for ARDS in patients with COVID-19 (COVID-19-HBO). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04327505
Nitric oxide
Studies indicate that nitric oxide may help to reduce respiratory tract infection by inactivating viruses and inhibiting their replication in epithelial cells.[796]Martel J, Ko YF, Young JD, et al. Could nasal nitric oxide help to mitigate the severity of COVID-19? Microbes Infect. 2020 May 6 [Epub ahead of print].
https://www.sciencedirect.com/science/article/pii/S1286457920300800?via%3Dihub
http://www.ncbi.nlm.nih.gov/pubmed/32387333?tool=bestpractice.com
The FDA has approved an investigational drug application for inhaled nitric oxide to be studied in a phase 3 study of up to 500 patients with COVID-19. Other studies are currently recruiting.
Aviptadil
A synthetic form of vasoactive intestinal peptide (also known as RLF-100) has been granted an expanded access protocol (which makes the treatment available to patients who have exhausted approved therapies and who are not eligible for the current clinical trial of aviptadil) and fast-track designation by the FDA for the treatment of respiratory failure in patients with COVID-19. Intravenous and inhaled formulations are currently in phase 2 and 3 clinical trials in the US.[797]ClinicalTrials.gov. Intravenous aviptadil for critical COVID-19 with respiratory failure (COVID-AIV). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04311697
[798]ClinicalTrials.gov. Inhaled aviptadil for the treatment of non-acute lung injury in COVID-19 (AVINALI). 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04360096
The manufacturer has requested emergency-use authorization from the FDA for the treatment of patients with critical disease and respiratory failure who have exhausted approved therapies, based on the results of a small case-control study.[799]NeuroRx. NeuroRx submits request for emergency use authorization for RLF-100™ (aviptadil) in the treatment of patients with critical COVID-19 and respiratory failure who have exhausted approved therapy. 2020 [internet publication].
https://www.neurorxpharma.com/press-releases/neurorx-submits-request-for-emergency-use-authorization-for-rlf-100-aviptadil-in-the-treatment-of-patients-with-critical-covid-19-and-respiratory-failure-who-have-exhausted-approved-therapy/
Icatibant
A selective bradykinin B2 receptor antagonist. A small exploratory case-control study of 9 people found an association between the administration of icatibant and improved oxygenation, suggesting that administration in the early stages of disease when patients are hypoxic may be beneficial. Treatment strategies that target the kallikrein-kinin system require further investigation in randomized trials for patients with COVID-19.[800]van de Veerdonk FL, Kouijzer IJE, de Nooijer AH, et al. Outcomes associated with use of a kinin B2 receptor antagonist among patients with COVID-19. JAMA Netw Open. 2020 Aug 3;3(8):e2017708.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2769237
http://www.ncbi.nlm.nih.gov/pubmed/32789513?tool=bestpractice.com
Tradipitant
A neurokinin 1 antagonist that is being trialed for the treatment of neurogenic inflammation of the lung secondary to SARS-CoV-2 infection. Interim analysis of the ODYSSEY study found that hospitalized patients improved sooner when treated with tradipitant compared with placebo. The trial is ongoing.[801]Vanda Pharmaceuticals Inc. Vanda Pharmaceuticals' interim analysis from ODYSSEY study shows tradipitant may accelerate clinical improvement in patients with COVID-19 pneumonia. 2020 [internet publication].
https://vandapharmaceuticalsinc.gcs-web.com/node/14256/pdf
[802]ClinicalTrials.gov. ODYSSEY: a study to investigate the efficacy of tradipitant in treating severe or critical COVID-19 infection. 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04326426