AUTHORS: Pierre Kory, MD1*, G. Umberto Meduri, MD2†, Jose Iglesias, DO3, Joseph Varon, MD4 , Keith Berkowitz, MD5 , Howard Kornfeld, MD6 , Eivind Vinjevoll, MD7 , Scott Mitchell, MBChB8 , Fred Wagshul, MD9, Paul E. Marik, MD10
Corresponding Author: Pierre Kory, MD, MPA – pkory@flccc.net
Abstract
In March 2020, the Front Line COVID-19 Critical Care Alliance (FLCCC) was created and led by Professor Paul E. Marik to continuously review the rapidly emerging basic science, translational, and clinical data to develop a treatment protocol for COVID-19. The FLCCC recently discovered that ivermectin, an anti-parasitic medicine, has highly potent anti-viral and anti-inflammatory properties against SARS-CoV-2 and COVID-19. This conclusion is based on the increasing study results reporting effectiveness, not only within in-vitro and animal models, but in numerous clinical trials
Review of the Emerging Evidence Supporting the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19 from around the world. Repeated, consistent, large magnitude improvements in clinical outcomes are reported when ivermectin is both as a prophylactic agent and in all phases of the disease from multiple, large, randomized and observational controlled trials. Further, data showing impacts on population wide health outcomes have resulted from multiple large “natural experiments” that appear to have occurred when various regional health ministries and governmental authorities within South American countries initiated “ivermectin distribution” campaigns to their citizen populations in the hopes the drug would prove effective. The tight, reproducible, temporally associated decreases in case counts and case fatality rates in each of those regions compared to nearby regions without such campaigns, suggest that ivermectin may prove to be a global solution to the pandemic.
To our knowledge, the current review is the earliest to compile sufficient clinical data to demonstrate the strong signal of therapeutic efficacy as it is based on numerous clinical trials in multiple disease phases. One limitation is that half the controlled trials have been published in peer-reviewed publications, with the remainder of the controlled trials results taken from manuscripts uploaded to medicine pre-print servers. Although it is now standard practice for trials data from pre-print servers to immediately influence therapeutic practices during the pandemic, given the controversial therapeutics adopted as a result of this practice, the FLCCC argues that it is imperative that our major national and international health care agencies devote the necessary resources to more quickly validate these studies and confirm the major, positive epidemiological impacts that have been recorded when ivermectin is widely distributed among populations with a high incidence of COVID-19 infections.
Introduction
In March 2020, an expert panel called the Front Line COVID-19 Critical Care Alliance (FLCCC) was created and led by Professor Paul E. Marik.1 The group of expert critical care physicians and thought leaders immediately began continuously reviewing the rapidly emerging basic science, translational, and clinical data in COVID-19 which then led to the early creation of a treatment protocol for hospi- talized patients called MATH+, based on the collective expertise of the group in both the research and treatment of multiple other severe infections causing lung injury.
Two manuscripts reviewing different aspects of both the scientific rationale and evolving published clinical evidence in support of the MATH+ protocol were published in major medical journals at two different time points in the pandemic (Kory et al., 2020;Marik et al., 2020). The most recent paper reported a 6.1% hospital mortality rate in COVID-19 patients measured in the two U.S hospitals that systematically adopted the MATH+ protocol (Kory et al., 2020). This was a markedly decreased mortality rate compared to the 23.0% hospital mortality rate calculated from a review of 45 studies including over 230,000 patients (unpublished data; available on request). For a review of the therapeutic interventions comprising the current MATH+ protocol, see Figure 1 below.
Review of the Emerging Evidence Supporting the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19
Although the adoption of MATH+ has been considerable, it largely occurred only after the treatment efficacy of the majority of the protocol components (corticosteroids, ascorbic acid, heparin, statins, Vitamin D, melatonin) were either validated in subsequent randomized controlled trials or more strongly supported with large observational data sets (Entrenas Castillo et al., 2020;Horby et al., 2020;Jehi et al., 2020;Nadkarni et al., 2020;Rodriguez-Nava et al., 2020;Zhang et al., 2020a;Zhang et al., 2020b). Despite the plethora of supportive evidence, the MATH+ protocol for hospitalized patients has not yet become widespread. Further, the world is in a worsening crisis with the potential of again overwhelming hospitals and ICU’s. As of December 16th, 2020, the number of deaths attributed to COVID-19 in the United States reached 311,073 with over 6.8 million active cases, the highest number to date.2 Multiple European countries have now begun to impose new rounds of restrictions and lockdowns.3
Further compounding these alarming developments was a wave of recently published results from therapeutic trials done on medicines thought effective for COVID-19 which found a lack of impact on mortality with use of remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, con- valescent plasma, tocilizumab, and mono-clonal antibody therapy (Agarwal et al., 2020;Consortium, 2020;Hermine et al., 2020;Salvarani et al., 2020).4 One year into the pandemic, the only therapy considered “proven” as a life-saving treatment in COVID-19 is the use of corticosteroids in patients with moderate to severe illness (Horby et al., 2020). Similarly, most concerning is the fact that little has proven effective to prevent disease progression to prevent hospitalization.
Fortunately, it now appears that ivermectin, a widely used anti-parasitic medicine with known anti-viral and anti-inflammatory properties is proving a highly potent and multi-phase effective treatment against COVID-19. Although growing numbers of the studies supporting this conclusion have passed through peer review, approximately half of the remaining trials data are from manuscripts uploaded to medical pre-print servers, a now standard practice for both rapid dissemination and adoption of new therapeutics throughout the pandemic. The FLCCC expert panel, in their prolonged and continued commitment to reviewing the emerging medical evidence base, and considering the impact of the recent surge, has now reached a consensus in recommending that ivermectin for both prophylaxis and treatment of COVID-19 should be systematically and globally adopted.
The FLCCC recommendation is based on the following set of conclusions derived from the existing data, which will be comprehensively reviewed below:
1) Since 2012, multiple in-vitro studies have demonstrated that Ivermectin inhibits the replication of many viruses, including influenza, Zika, Dengue and others (Mastrangelo et al., 2012;Wagstaff et al., 2012;Tay et al., 2013;Go?tz et al., 2016;Varghese et al., 2016;Atkinson et al., 2018;Lv et al., 2018;King et al., 2020;Yang et al., 2020).
https://www.worldometers.info/
https://www.npr.org/sections/
https://www.lilly.com/news/
- 2) Ivermectin inhibits SARS-CoV-2 replication and binding to host tissue via several observed and proposed mechanisms (Caly et al., 2020b).
- 3) Ivermectin has potent anti-inflammatory properties with in-vitro data demonstrating profound inhibition of both cytokine production and transcription of nuclear factor-?B (NF-?B), the most potent mediator of inflammation (Zhang et al., 2008;Ci et al., 2009;Zhang et al., 2009).
- 4) Ivermectin significantly diminishes viral load and protects against organ damage in multiple animal models when infected with SARS-CoV-2 or similar coronaviruses (Arevalo et al., 2020;de Melo et al., 2020).
- 5) Ivermectin prevents transmission and development of COVID-19 disease in those exposed to infected patients (Beher [remainder of message body omitted; too large]
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