FLCCC Alliance MATH+ ascorbic acid and I-MASK+ ivermectin protocols for COVID-19 – A Brief Review

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FLCCC Alliance MATH+ ascorbic acid and I-MASK+
ivermectin protocols for COVID-19 — a brief review
Mika Turkia
M.Sc., mika.turkia@alumni.helsinki.fi, November 10, 2020
Abstract
An alliance of established experts on critical care, Front Line Covid-19 Critical Care Alliance (FLCCC),
has published two protocols for treatment of COVID-19. The first one, MATH+, is intended for hospital
and intensive care unit treament of pulmonary phases of the disease. It is based on affordable, commonly
available components: anti-inflammatory corticosteroids (methylprednisolone, “M”), high-dose vitamin
C infusion (ascorbic acid, “A”), vitamin B1 (thiamine, “T”), anticoagulant heparin (“H”), antiparasitic
agent ivermectin, and supplemental components (“+”) including melatonin, vitamin D, elemental zinc
and magnesium.
The MATH+ protocol has received scarce attention due to the World Health Organization advising
against the use of corticosteroids in the beginning of the pandemic. In addition, randomized controlled
clinical trials were required as a condition for adoption of the protocol. As the hospital mortality rate
of MATH+ treated patients was less than a quarter of the rate of patients receiving a standard of care,
the authors of the protocol considered performing such trials unethical.
Later, other parties have performed clinical trials with e.g. corticosteroids and anticoagulants which has
led to their more widespread adoption. Other essential components of the protocol remain unadopted.
In October 2020, ivermectin was upgraded from an optional component to an essential component of the
protocol. According to the authors, ivermectin is considered the first agent effective for both prophylaxis
(prevention) of COVID-19 and for treatment of all phases of COVID-19 including outpatient treatment
of the early symptomatic phase. Therefore, at the end of October 2020, a separate ivermectin-based
I-MASK+ protocol for prophylaxis and early outpatient treatment of COVID-19 was published.
Keywords: COVID-19; SARS-CoV-2; ivermectin, methylprednisolone, ascorbic acid, thiamine, heparin
ORCID iD: 0000-0002-8575-9838
Early developments
The first version of the protocol was based on corticosteroid hydrocortisone, vitamin C and thiamine.1,2
This protocol had been used for treatment of sepsis for several years.3In January-February 2020, an
anticoagulant was added to the protocol. Hydrocortisone was upgraded to methylprednisolone in April.
Ivermectin was added as an optional component in May and upgraded to an essential component in
October.
In the beginning of the pandemic corticosteroids were a controversial subject, possibly due to the phase-
specific nature of COVID-19 not having been fully understood. In early 2020, the World Health Organi-
zation advised against the use of corticosteroids. This advisory was later proven to have been misguided.4
It was officially changed no earlier than September 2, 2020.5According to the current data, corticos-
teroids appear disadvantageous in the early symptomatic phase but necessary in the late pulmonary
phase.
1
This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3723854

Another generally accepted method have been anticoagulants. As an example, adoption of anticoagulants
in one US hospital reduced the need for mechanical ventilation from 30% to 8% and reduced the hospital
mortality rate from 63% to 29%.6
In the first half of 2020, hospital mortality rate of patients treated with MATH+ was 5%, in contrast
to a standard of care rate of over 20%.7In Europe, ICU mortality in the same period was 24% and in
Finland 13-15%.8,9
Due to the difference in mortality rates the authors of the MATH+ protocol did not consider performing
randomized controlled trials ethical. As other parties refused to overlook this requirement, widespread
adoption of the protocol did not occur.
The FLCCC alliance perspective on COVID-19
According to the MATH+ protocol, COVID-19 progresses in phases. Different phases require slightly
different, phase-specific treatment approaches.2Approximately 20 to 40 percent of the patients are
estimated to be symptom-free. For symptomatic patients, there are four phases. The first phase is an
approximately four-day symptomless incubation period. It is followed by an early symptomatic phase of
approximately six days. The third phase is an early pulmonary phase of approximately three days. It is
followed by a late pulmonary phase of approximately two weeks.
After a droplet or aerosol mediated infection through airways or eyes, a symptomless incubation period
follows, during which SARS-CoV-2 replicates predominantly in the nasal pharynx.10,11 In this phase,
antiviral agents such as quercetin or zinc may be beneficial.12,13,14,15,16
Infectivity is the highest in symptom-free individuals, during the incubation period, and in the beginning
of the early symptomatic phase.17,18 Masks reduce the inoculum size.19 A smaller viral load may enable
the innate immune system to overcome the infection or at least lessen its severity. Sufficient levels of
vitamin D have been observed to protect from SARS-CoV-2 infection to some degree.20,21
After the early pulmonary phase the patient is no longer considered infective. This is due to a fall in
viral replication and viral load resulting to only non-replicable virus particles remaining in the body.22,23
Regardless, even though the patient is no longer infective, tests based on detection of these virus particles
may give a positive result.
Since patients are typically not admitted to hospitals before the early pulmonary phase and because
antiviral pharmaceuticals have been tested on these hospital patients, the antivirals have failed in
trials.24 Patients do not die due to living viruses but due to a delayed, dysregulated immune response
triggered by the dead virus particles.25
It is essential to begin controlling this inflammatory immune response immediately at the onset of
symptoms before the inflammation causes organ damage that is difficult to repair.26 Therefore, it would
be essential to have an outpatient protocol for treatment of the early symptomatic phase, to be started
immediately at the onset of mild symptoms.
After the early symptomatic phase, approximately one-fifth of patients progress to the early pulmonary
phase,27 which typically includes inflammation and organizing pneumonia.28,29,30 Inflammation may
progress through redundant cell signaling pathways; therefore, blocking a single pathway with a single
pharmaceutical is unlikely to inhibit progression of the disease.31 Therefore, the presented protocols
utilize multiple agents to block multiple pathways and to gain synergistic effects.
Suppressing the immune response in the early and late pulmonary phases is partially performed with
corticosteroids.4Of those, methylprednisolone is considered especially suitable.32,33
Another component for controlling the immune response is ascorbic acid. The rationale for using vi-
tamin C infusion is that in the late pulmonary phase the vitamin C levels of the patients have been
observed to reach levels corresponding to scurvy.34,35 Vitamin C has broad-spectrum antiviral, antibac-
terial and anti-inflammatory effects.36,37 It may reduce the duration of mechanical ventilation and prevent
pneumonia.38,39,40 Methylprednisolone and vitamin C synergistically amplify each other’s effects.41 In
2014, vitamin C infusion for sepsis was proven safe in a US trial.42
2
This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3723854

A central component of the MATH+ protocol is heparin (more specifically, enoxaparin belonging to
the low molecular weight heparin family) which has also non-anticoagulant benefits.43,44,45 In addition,
MATH+ protocol utilizes thiamine which is often low in the elderly. Thiamine deficiency leads to
diminished ATP production in the cells and may contribute to e.g. mental confusion.46 Melatonin may
protect against multiorgan failure.47,48
Approximately half of recovered patients suffer from post-discharge persistent symptoms.49,50 These may
be partly due to above mentioned deficiencies of vitamins and trace elements and might be alleviated by
supplementation. Care should be taken to avoid e.g. excessive zinc supplementation which may cause
copper deficiency.51
Ascorbic acid protocols in Shanghai and the United States
For more than a decade, vitamin C infusion had already been used in Shanghai, China for severe illnesses
requiring intensive care.52 In late 2019, a combination of high-dose vitamin C, heparin, anticoagulants
and antivirals was adopted as the official treatment protocol of COVID-19 in the Shanghai area.53,54,55
In general, these findings raised scarce interest outside China, along with other options such as lian-
huaqingwen which has been proven effective in clinical trials.56,57,58
The difference between the Shanghai protocol and the Marik protocol appears to be that the Shanghai
recommendation was cautious towards corticosteroids and did not include e.g. thiamine, zinc or quercetin.
The national guideline of China published in English in March 2020 recommended heparin and corti-
costeroids, did not mention ascorbic acid but included anti-inflammatory traditional Chinese medicine
preparations.59 Similarly, guidelines for children included corticosteroids and TCM preparations.60
A randomized clinical trial of vitamin C for COVID-19 was started in China in February but due to
the successful early containment of the epidemic only 56 patients could be recruited.61 Regardless, the
treatment was shown to statistically significantly improve oxygenation (P=0.01). On a 5% significance
level (P=0.05), groups differed with respect to IL-6 and bilirubin levels and, importantly, with respect
to mortality of most severely ill patients. The hospital mortality rate of patients with a sequential organ
failure assessment score of equal or larger than 3 was 22%, in contrast to 52% in the control group. If
the study had not ended early due to lack of patients, the results would likely have been indisputable.
Ascorbic acid protocols in evidence-based medicine
As mentioned above, the MATH+ protocol had its origins in a vitamin C protocol developed for sepsis.3
The historical developments related to general adoption of this method promoted by another research
group appear interesting. The adoption process seems to have been hindered by dogmatic adherence to
formal requirements, an approach in which formalities seems to have mattered more than actual clinical
outcomes or common sense. In the case of a decisive phase III sepsis trial,62 this meant funding body
influenced selection of primary endpoints that in retrospect appeared poor, and a methodological error
which turned these endpoints statistically insignificant, resulting in the study being labeled negative and
the method continuing to be largely ignored.63,64
Disregarding what had been chosen for endpoints and looking at the actual data,62 it can be seen that
during the vitamin C infusion all-cause mortality rate was 5% in comparison to 23% in the control group,
and that the difference remained after discontinuation of the infusion until the end of the observation
period of 28 days. Yet in the world of misunderstood or misapplied evidence-based medicine this evidence
was deemed irrelevant on a technicality. It should be noted that these kind of research practices result
not only in inferior science but also in huge societal inefficiencies. These historical biases have likely also
hindered adoption of vitamin C for COVID-19.
The role of ivermectin
A systematic review from June states that ivermectin has known antiviral effects on a broad range of
RNA and DNA viruses, including those with positive-sense single-stranded RNA, the class of viruses
3
This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3723854

that includes SARS-CoV-2.65 The authors note that significant effectiveness of ivermectin is seen in the
early stages of infection, thus indicating that ivermectin administration may be effective in the early
stages or prevention.
In June, a single treatment with ivermectin was shown to effect approximately 5000-fold reduction in virus
at 48 h in cell culture.66 The relevance of this observation has been disputed by the fact that the dose was
35-fold higher than the maximal concentration achieved with the approved clinical dose. With regard to
overdosing, ascorbic acid has been shown to protect from side effects of ivermectin overdose.67 However,
it has been suggested that ivermectin’s mechanism of action may be predominantly anti-inflammatory
or ionophoric.68,69,70 In addition, a new mechanism of action has recently been identified.71
Despite the exact mechanism of action being unknown, trials continue to indicate an effect. A random-
ized controlled trial published in August indicated that ivermectin prevented appearance of symptoms
in outpatients’ family members by a factor of seven (7.4% vs 58.4%).72 In another trial, ivermectin
prophylaxis reduced COVID-19 infections among healthcare workers by 73%.73
A randomized controlled trial published in October with ivermectin and doxycycline indicated shortened
course of disease, reduction in the number of patients that remained persistently positive for RT-PCR of
COVID-19, and prevention of clinical deterioration.74 Another clinical trial with ivermectin and doxy-
cycline yielded similar results.75
An earlier a retrospective study in May indicated lower mortality among ivermectin-treated patients
with severe pulmonary involvement (32.0% vs 81.8%, P=0.002).76 Overall mortality rates were 13.3%
vs 24.5%, P=0.045, respectively. Corticosteroids were used for 25.5% of patients in the ivermectin group
and 21.4% in the control group. Ivermectin group had 25.5% severe cases vs 22.4% in the control group.
There was no mention of anticoagulants; lack of their use might explain the high overall mortality.
In Peru, despite lack of randomized controlled trials at the time, ivermectin was officially adopted and
nationally distributed already since May 8, 2020. Regardless of the rationale behind the official adoption,
the idea seems to have emerged from successful grassroots experimentation in Iquitos,77 a city better
known for ayahuasca.78,79,80 Epidemiological statistics indicate a declining trend in excess mortality.81
Ivermectin has subsequently been distributed in some areas of Brazil and Bolivia. Veterinary formulas
appear to have been administered parenterally (injection) and orally without significant issues.82
Almost 70 clinical trials are being planned or ongoing.83 For example, a combination therapy trial with
ivermectin, doxycycline, zinc and vitamins C and D3 is being planned in Australia (NCT04482686).
A trial with three times the conventional dose of ivermectin finished in Argentina (NCT04381884),
reportedly confirming expectations of effectiveness.84,85 In Europe, studies are ongoing in Spain
(NCT04390022), Italy (NCT04438850), Bulgaria (EudraCT 2020-002091-12) and Israel (NCT04429711).
Finally, it may be pointed out that while the promising results about e.g. ivermectin may be considered
preliminary, abundant available data about expensive alternatives such as remdesivir indicate proven
inefficiency.86,87 It is unclear whether in the early phases of the pandemic the public has been intentionally
misled to ignore more suitable options.
Conclusions
Two of the main components of the MATH+ protocol presented in January-March 2020, corticosteroids
and heparin, have been generally adopted in the second half of 2020. Also thiamine is often being
supplemented. Ascorbic acid remains unadopted. Considering that it has been shown safe, that patients
with severe disease have been shown to essentially suffer from scurvy, that ascorbic acid has successfully
been used for COVID-19 in Shanghai area to the extent of it having been adopted as a standard of
care, and that it has been used for hundreds of patients in two US hospitals with significant benefits
on mortality, it is difficult to see a rationale behind non-adoption. Considering the roughly four-fold
difference in mortality rates in the first half of 2020, it seems unfortunate that the protocol has been
ignored.
Concerning ivermectin, it might be even more unfortunate to repeat the same mistake as with MATH+,
and continue exacerbating the societal costs of the pandemic by not reacting in time. The main interests
4
This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3723854

with ivermectin are prophylaxis and outpatient treatment. Preliminary data suggests significant benefits.
Considering that the early predictions of the authors about corticosteroids and anticoagulants have later
been proven correct, and as there are no concerns regarding safety or cost, it might be unadvisable to
wait for more results from ongoing clinical trials. In an emergency situation, dogmatic adherence to
extremely slow and inflexible evidence-based medicine practices may result in exactly the kind of harm
it was intended to protect the society from.
Even if ivermectin unexpectedly would not live up to the promise, at this point it would appear to be an
affordable insurance policy. In summary, adoption of the suggested measures might significantly reduce
the need for vaccinations, lockdowns and other societal restrictions, easing also the financial burden of
COVID-19.
Funding: None.
Conflict of Interest: None.
Ethical Approval: Not applicable.
Additional information:
https://covid19criticalcare.com
https://www.evms.edu/covidcare
http://covidcare.fi
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