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COVID-19 Protocols

Medical Evidence

This page contains the medical evidence in support of the individual medical therapies that make up our MATH+ Hospital Treatment Protocol for COVID-19 as well as the I-MASK+ and I-MASS Preventive and Early Outpatient Treatment Protocols and the medicines included in our more recent I-RECOVER protocol for long-haul COVID syndrome.  In October 2020, we added ivermectin to our COVID-19 protocols, which we regard as a core medication in the prevention and treatment of COVID-19.  That evidence has its own section: Ivermectin in COVID-19.

Corticosteroid therapy is one of the most effective interventions in COVID-19 and MATH+. From early March 2020, when the FLCCC team of physicians first came together to study and create treatment protocols for fighting the novel disease, the team, guided by Dr. G. Umberto Meduri’s expertise in corticosteroid use, placed methylprednisolone at the head — as the “M” — in its MATH+ hospital treatment formula. As a result, the two hospitals using the MATH+ formula had mortality rates of no higher than 6%, when most hospitals lost as many as 80% of their seriously ill COVID patients. This was months before the landmark RECOVERY trial convinced world authorities to allow and advocate for the use of steroids in treating the inflammatory stage of the disease. Publications listed below range from large scale observational studies demonstrating large impacts on mortality in the prior pandemics of SARS and H1N1, through the landmark RECOVERY trial done in the United Kingdom against COVID-19, to numerous and increasing COVID-19 retrospective cohort studies published from Italy, China, Spain, and the United States. In addition, a scientific review of the evidence supporting methylprednisolone in COVID-19 authored by FLCCC Alliance member Dr. G. Umberto Meduri can be found here.

June 17, 2021
Efficacy of a Low Dose of Melatonin… in Hospitalized Patients with COVID-19
https://doi.org/10.1016/j.arcmed.2021.06.006

June 1, 2021 | NEJM Journal Watch
Is Methylprednisolone Better than Dexamethasone for Severe COVID-19?
Daniel D. Dressler, MD, MSc, MHM, FACP
https://www.jwatch.org/na53560/2021/06/01/methylprednisolone-better-dexamethasone-severe-covid-19

October 7, 2020 | Springer
The ten reasons why corticosteroid therapy reduces mortality in severe COVID-19
Yaseen M. Arabi, George P. Chrousos & G. Umberto Meduri
https://link.springer.com/article/10.1007/s00134-020-06223-y

September 22, 2020 | USA (BMJ Open Respiratory Research)
SARS-CoV-2 organising pneumonia: ‘Has there been a widespread failure to identify and treat this prevalent condition in COVID-19?’
Pierre Kory (FLCCC Alliance) and Jeffrey P. Kanne
https://bmjopenrespres.bmj.com/content/7/1/e000724.full

September 12 | Open Forum Infectious Diseases
Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia
Francesco Salton, Paola Confalonieri, G. Umberto Meduri et al.
https://doi.org/10.1093/ofid/ofaa421

September 2, 2020 | USA
Timing is crucial and hydrocortisone should be started within the first 12 hours after shock onset
Cohort study: “Evaluation of the Initiation Timing of Hydrocortisone in Adult Patients With Septic Shock”
http://doi.org/10.1097/SHK.0000000000001651

September 2, 2020 | worldwide
Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19
The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial
https://jamanetwork.com/journals/jama/fullarticle/2770278?utm_campaign=articlePDF

September 2, 2020 | France
Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19
A Randomized Clinical Trial
https://jamanetwork.com/journals/jama/fullarticle/2770276tm_medium=articlePDFlink&utm_source=ar…

September 2, 2020 | Brazil
Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19
The CoDEX Randomized Clinical Trial
https://jamanetwork.com/journals/jama/fullarticle/2770277

June 25, 2020 | Italy/USA/UK
Treatment with Methylprednisolone leads to significant mortality reduction in COVID-19
“Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia” (Clinical Trial)
https://doi.org/10.1101/2020.06.17.20134031

June 18, 2020 | Spain
Methylprednisolone decreases risk of ICU, NIV, or death in Covid-19
“GLUCOCOVID: A controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia” (Clinical Trial)
https://doi.org/10.1101/2020.06.17.20133579

May 19, 2020 | USA
Early CST (corticosteroid treatment) reduces mortality, need for ICU beds, ventilators in COVID-19
“Early short course corticosteroids in hospitalized patients with COVID-19” (Multi-center quasi-experimental study)
https://doi.org/10.1093/cid/ciaa601

May 15, 2020 | USA
Methylprednisolone counteracts SARS-CoV-2 gene activation pattern
“COVID-19: disease pathways and gene expression changes predict methylprednisolone can improve outcome in severe cases” (Clinical Study)
https://dx.doi.org/10.21203/rs.3.rs-29392/v1

May 13, 2020 | France
CST reduces the risk of intubation in COVID-19 patients
“Beneficial effect of corticosteroids in severe COVID-19 pneumonia: A propensity score matching analysis” (Case-control Study)
https://doi.org/10.1101/2020.05.08.20094755

April 28, 2020 | Spain/Italy et al.
CST reduced mortality during SARS and H1N1 pandemics
“Rationale for Prolonged Corticosteroid Treatment in the Acute Respiratory Distress Syndrome Caused by Coronavirus Disease 2019”
https://doi.org/10.1097/cce.0000000000000111

April 28, 2020 | China
Early CST reduces need for mechanical ventilation, ICU and hospital LOS, and oxygen support
“A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia”
https://doi.org/10.1038/s41392-020-0158-2

April 22, 2020 | USA/Greece
The role of Glucocorticoid receptors in critical illness
“General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections”
https://doi.org/10.3389/fendo.2020.00161

April 20, 2020 | USA
Timed & titrated use of steroid in COVID-19?
Josh Farkas of PulmCrit reviews need for steroids in COVID-19
https://emcrit.org/pulmcrit/steroid-covid/

April 2020 | Critical Care Explorations
Rationale for Prolonged Corticosteroid Treatment in the Acute Respiratory Distress Syndrome Caused by Coronavirus Disease 2019
Jesús Villar, Marco Confalonieri, Stephen M. Pastores, G. Umberto Meduri
http://doi.org/10.1097/CCE.0000000000000111

March 13, 2020 | China
CST in COVID ARDS associated with lower mortality
“Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China” (Cohort Study)
https://doi.org/10.1001/jamainternmed.2020.0994

Numerous studies of the profound physiologic and clinical impacts of intravenous ascorbic acid (AA) in critical illness states have been published over the past two decades. The publications below range from multiple studies in septic shock demonstrating large outcome improvements, to CITRIS-ALI, the NIH funded multi-center randomized controlled trial in ARDS which found that high dose intravenous AA led to a statistically significant reduction in mortality. Timeliness of administration, i.e. the need for early infusion at the onset of critical illness, is a variable that has been poorly accounted for in many trials of intravenous AA and is well-illustrated in multiple studies below.

June 19, 2020 | USA/Italy/UK
Quercetin & Vitamin C: A synergistic therapy for prevention and treatment of COVID-19
“Quercetin and Vitamin C: An experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19)”
https://doi.org/10.3389/fimmu.2020.01451

April, 2020 | USA
Impact of intravenous ascorbic acid in critical illness, database of all published trials
“Clinical trials of IV Ascorbic Acid, Thiamine RX, or HAT therapy in ICU patients with septic shock or ARDS” (spreadsheet)
https://docs.google.com/spreadsheets/d/e/2PACX-1vTc9ySK-KTeaylouVkYEto9an8kZehJ5dG6LwBAFgKj12_wtk4cd…

March 30, 2020 | USA
Importance of the timeliness of IV ascorbic acid initiation and relation to survival in shock patients
“Relationship between delays in iHAT administration and ICU mortality in shock patients” (graph)
/wp-content/uploads/2020/06/TIME-TO-HAT-INITIATION-AND-MORTALITY-ANALYSIS-IN-SEPTIC-SHOCK-N139.png

March 26, 2020 | China
High dose intravenous ascorbic acid used successfully in Covid-19
“Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?” (Article on ScienceDirect)
https://doi.org/10.1016/j.medidd.2020.100028

March 17, 2020 | USA
Faster resolution of shock with early HAT treatment in sepsis
“The ORANGES trial – Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis”
https://doi.org/10.1016/j.chest.2020.02.049

January 9, 2020 | USA
HAT therapy reduces mortality in septic children
“Hydrocortisone–ascorbic acid–thiamine use associated with lower mortality in pediatric septic shock”
https://doi.org/10.1164/rccm.201908-1543le

December 23, 2019 | USA
The anti-viral properties of Vitamin C
Editorial on Taylor & Francis Online by Ruben M. L. Colunga Biancatelli, Max Berrill and Paul E. Marik (FLCCC)
https://doi.org/10.1080/14787210.2020.1706483

October 1, 2019 | USA
Intravenous ascorbic acid reduces mortality in ARDS
The CITRIS-ALI Randomized Clinical Trial – “Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure”
https://doi.org/10.1001/jama.2019.11825

July 21, 2017 | USA
Corticosteroid and ascorbic acid act synergistically in protecting the pulmonary endothelial barrier
“Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction” (Study)
https://doi.org/10.1016/j.chest.2017.07.014

June, 2017 | USA
HAT therapy for treatment of severe sepsis & septic shock
A retrospective before-after study
https://doi.org/10.1016/j.chest.2016.11.036

Thiamine is another cornerstone in the concept of “metabolic resuscitation,” an approach based on the concept that once severe or critical illness develops, multiple deficiencies in key vitamins and hormones are created via “consumption” induced via the body’s attempts to fight off the insult or invader. Immediate and aggressive repletion of such substances are critical to strengthening the immune system’s ability to maintain balance and prevent the onset-of-multi-organ failure. The studies below detail the critical functions of thiamine, the deleterious consequences and high incidence of thiamine deficiency, and also include several key studies demonstrating improvements in survival with aggressive intravenous thiamine repletion.

June 30, 2021 | USA
Evaluation of thiamine as adjunctive therapy in COVID‑19 critically ill patients
https://doi.org/10.1186/s13054-021-03648-9

December 6, 2019 | USA
Thiamine in septic shock: A targeted therapy
Journal of Thoracic Disease
https://doi.org/10.21037/jtd.2019.12.82

November, 2018 | USA
IV Thiamine reduces mortality in septic shock
“Effect of Thiamine administration on lactate clearance and mortality in patients with septic shock” (Critical Care Magazine – Nov 2018 – Vol. 46 – Issue 11)
https://doi.org/10.1097/CCM.0000000000003311

February, 2016 | USA
Thiamine deficiency common in sepsis, IV repletion improves survival
Randomized, double-blind, placebo-controlled trial of Thiamine as a metabolic resuscitator in septic shock – A pilot study (Critical Care Magazine – Feb 2016 – Vol. 44 – Issue 2)
https://doi.org/10.1097/CCM.0000000000001572

One of the earliest and most profound insights into the pathophysiology of COVID-19 disease was that of it’s extreme “hypercoagulability,” found the most severely ill patients suffering severe inflammation. The studies below detail both the high incidences and types of clotting complications seen in critically ill COVID-19 patients, along with studies demonstrating associations between anti-coagulant treatment and improvements in survival.

April 9, 2020 | China
High rates of VTE in severe Covid-19
“Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia”
https://doi.org/10.1111/jth.14830

May 6, 2020 | USA
Mt. Sinai Hospital: Systemic anticoagulation improved survival
“Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19”
https://doi.org/10.1016/j.jacc.2020.05.001

May 4, 2020 | France
VTE incidence in Covid-19 ARDS is 5x that of non-Covid ARDS
“High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study”
https://doi.org/10.1007/s00134-020-06062-x

April 20, 2020 | China
Chinese experts recommend full anti-coagulation in Covid-19
“Chinese expert consensus on diagnosis and treatment of coagulation dysfunction in COVID-19”
https://doi.org/10.1186/s40779-020-00247-7

May 5, 2020 | The Netherlands
Daily VTE incidence increases rapidly over time in hospital, associated with death
“Incidence of venous thromboembolism in hospitalized patients with COVID‐19”
https://doi.org/10.1111/jth.14888

March 27, 2020 | China
Anticoagulation is associated with decreased mortality in Covid-19
“Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy”
https://doi.org/10.1111/jth.14817

The studies below detail both the biologic plausibility supporting each adjunctive medicine, and the emerging clinical evidence base, demonstrating their impacts on survival in multiple critical illness states, including the emerging evidence for their use in COVID-19.

June 24, 2020 | China
Statin use is associated with a lower risk of all-cause mortality
“In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19” (Retrospective Study)
https://doi.org/10.1016/j.cmet.2020.06.015

June 10, 2020 | Singapore
Vitamin-Magnesium combo may reduce severity of COVID-19 in seniors
A cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients
https://doi.org/10.1101/2020.06.01.20112334

May 22, 2020 | USA
Famotidine associated with improved clinical outcomes in hospitalized COVID-19 patients
“Famotidine Use is Associated with Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study”
https://pubmed.ncbi.nlm.nih.gov/32446698/?from_term=famotidine+COVID-19&from_pos=2

May 15, 2020 | USA/Spain
Therapeutic algorithm for use of Melatonin in patients with COVID-19
Review of the evidence for a role of Melatonin as a COVID-19 treatment
https://doi.org/10.3389/fmed.2020.00226

April 28, 2020 | USA
Vitamin D insufficiency is prevalent in severe COVID-19
Retrospective review
https://www.medrxiv.org/content/10.1101/2020.04.24.20075838v1

April, 2020 | USA
The role of Vitamin D in suppressing cytokine storm and mortality in COVID-19
A retrospective review of the relationship between Vitamin D and Covid-19 infection and mortality
https://www.medrxiv.org/content/10.1101/2020.04.08.20058578v4

April 2, 2020 | USA/Hungary
Evidence that Vitamin D could reduce risk of COVID-19 infections and deaths
Review on the role of Vitamin D in reducing the risk of respiratory tract infections
https://pubmed.ncbi.nlm.nih.gov/32252338/

December 15, 2019 | USA/Italy/UK
Melatonin for the treatment of sepsis: the scientific rationale
Review on the evidence for the role of Melatonin in sepsis, its pharmacokinetic profile and the virtual absence of side effects
http://dx.doi.org/10.21037/jtd.2019.12.85

May 4, 2017 | Germany
Persistent low serum Zinc associated with recurrent sepsis in critically ill
A pilot study
https://pubmed.ncbi.nlm.nih.gov/28472045/

March 24, 2016 | USA/Thailand
Hypomagnesemia and mortality in patients admitted to intensive care unit
A systematic review and meta-analysis
https://doi.org/10.1093/qjmed/hcw048

November 4, 2010 | Netherlands
Zinc inhibits Coronavirus activity in vitro and blocks viral replication
“Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture”
https://pubmed.ncbi.nlm.nih.gov/21079686/

June, 2006 | Saudi Arabia
Aggressive Magnesium supplementation associated with improved survival
“Magnesium supplementation and the potential association with mortality rates among critically ill non-cardiac patients”
https://pubmed.ncbi.nlm.nih.gov/16758043/

April, 2003 | Belgium
Development of ionized hypomagnesemia is associated with higher mortality rates
Prospective observational study
https://doi.org/10.1097/01.ccm.0000060867.17556.a0

A founding principle underlying our treatment protocols is that they evolve in accordance with both emerging therapeutic trials evidence as well as new pathophysiologic insights. When sufficient supportive evidence for a new therapeutic against COVID-19 emerges, we first add these medicines as “optional” components until such a time when we can better clarify their additive or synergistic efficacy to the existing core therapies.

The most compelling recent therapeutic evidence suggests a role for the following therapies (last updated on May 17, 2021):

  • Inhaled budesonide: The typical dose used for asthma and obstructive lung diseases is 180 to 360 micrograms inhaled twice a day, but effectiveness at these doses is not well-established. Based on the STOIC Trial (open label Phase 2), 800 micrograms inhaled twice a day shortened self reported time to recovery as well as the need for urgent care or hospital visits. Side effects were mild and self-limited and occurred among 5 subjects. With interim results from the PRINCIPLE Trial on budesonide 800micrograms twice a day, time to recovery in outpatients was reported to be reduced. Inhaled steroids are believed to reduce expression of cellular proteins that SARS-Cov2 must bind, and may explain why asthmatics did not have worse Covid19 outcomes than the general population, despite being initially anticipated. Cost may be a barrier for some patients in the US, including some insured patients whose plans favor alternate inhaled steroids that have not been tested in covid19.
  • Nitazoxanide: An antiparasitic drug typically used for infectious diarrhea, it is believed to interfere with multiple mechanisms of viral entry. Well-designed clinical trials have demonstrated its ability to reduce viral replication and accelerate time to viral clearance when used as early monotherapy, but its clinical benefits have not been well-established. It may be synergistic in multidrug regimens, including a combination with ivermectin, as shown in one trial where it was combined with ivermectin, ribavirin and zinc, in which 58% of treatment and zero controls cleared the virus by day 7 (p< 0.001). It has an extremely favorable safety profile and no contraindications in immunocompetent patients, but can be expensive in some cases.

  • Colchicine: Early outpatient use only – 0.6 mg BID for 3 days then reduce to 0.6 mg daily for total of 30 days. In the COLCORONA study colchicine reduced the need for hospitalization (4.5 vs 5.7%) in high risk patients. The drug was associated with an increased risk of side effects most notably diarrhea and pulmonary embolism. It is unclear if colchicine has any benefit in patients receiving ivermectin and whether the addition of colchicine to ivermectin has additive effects.

Recently added to our I-MASK+,MATH+, and I-RECOVER protocols:

  • Fluvoxamine: 50 mg PO twice daily for 10–14 days. Selective serotonin reuptake inhibitor (SSRI) that activates sigma-1 receptors decreasing cytokine production. Two randomized controls trials have found decreased risk of hospitalization and time to clinical recovery. Larger trials are ongoing.

Recently added to our MATH+ protocol:

  • Cyproheptadine: 6–8 mg PO TID, monitor for drowsiness. Mounting evidence has identified the clear pathophysiologic role of excess platelet activation with serotonin release in COVID-19, thus explaining multiple physiologic abnormalties observed (hyperpnea, pulmonary vasodilation, renal vasoconstriction, neurologic dysfunction etc) which often quickly reverse in the presence of the anti-serotonin agent cyproheptadine.
  • Dutasteride: Men who develop COVID-19 have a significantly worse outcome than women (independent of other risk factors). This effect may be mediated in part by testosterone. Testosterone increases the expression of the transmembrane protease, serine 2 (TMPRSS2) which is required for priming of the spike protein for cell fusion. The antiandrogens dutasteride 0.5 mg/day and proxalutamide 200 mg /day (NCT 04446429) have been demonstrated to reduce time to viral clearance, improve time to recovery and reduce hospitalization in men with COVID-19 in the outpatient setting. It should be noted that proxalutamide in not available in the USA.

November 9, 2021
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE: Correlation between 25-hydroxy vitamin D levels and COVID-19 severity in pregnant women: a cross-sectional study
Conclusion: There is a relationship between vitamin D status and the severity of COVID-19 in pregnant women. During the pandemic period, vitamin D supplementation for pregnant women should gain more importance.
https://pubmed.ncbi.nlm.nih.gov/34812699/

October 14, 2021
Nutrients: COVID-19 Mortality Risk Correlates Inversely with Vitamin D3 Status, and a Mortality Rate Close to Zero Could Theoretically Be Achieved at 50 ng/mL 25(OH)D3: Results of a Systematic Review and Meta-Analysis
Conclusion: The datasets provide strong evidence that low D3 is a predictor rather than just a side effect of the infection. Despite ongoing vaccinations, we recommend raising serum 25(OH)D levels to above 50 ng/mL to prevent or mitigate new outbreaks due to escape mutations or decreasing antibody activity.
https://pubmed.ncbi.nlm.nih.gov/34684596/

March 2021
Frontiers in Public Health: The Impact of Vitamin D Level on COVID-19 Infection: Systematic Review and Meta-Analysis
Conclusion: sufficient Vitamin D level in serum is associated with a significantly decreased risk of COVID-19 infection.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973108/