Ivermectin, a classical antiparasitic and anti-scabies agent, has demonstrated antiviral activity for a variety of viruses including chikungunya virus, zyka virus and dengue virus and was tested as a potentially effective for COVID-19. Although ivermectin demonstrated potent in vitro action by reducing viral load by 5000x after 48 hours of incubation, simultaneous pharmacokinetics simulations suggested that the minimum effective concentrations would be unfeasible to be reached within safety range (EC-50 = 2 Micromol). However, despite the theoretical unfeasible concentrations to be achieved, preliminary observational yet well-structured studies followed by randomized clinical trials (RCTs) demonstrated ivermectin efficacy when combined with hydroxychloroquine, doxycycline or azithromycin, which was corroborated by a recent systematic review and metanalysis. In common, a dose-response effect for effectiveness was observed, and no adverse effects was reported at any dose between 0.2mg/kg/day and 1.0mg/kg/day. Based on the scientific rationale combined with the preliminary evidence, ivermectin has sufficient evidence to be tested in higher doses in a RCT for COVID-19. The investigators propose to test ivermectin at high doses as a treatment for patients recently diagnosed with COVID-19, aiming to explore the possible protective role of high-dose ivermectin in SARS-CoV-2 infection in terms of reduction of clinic and virologic disease duration, and prevention of oxygen use, hospitalization, mechanical ventilation, death, and post-COVID persisting symptoms.
Overall
COVID-19 is a multisystemic disease caused by SARS-CoV-2 that has become a pandemic largely
due to a combination of favorable transmission and infection characteristics for its spread,
including prolonged preclinical or also asymptomatic yet transmitting period, relatively
highly resistant to mechanical and physical barriers and prolonged survival in the air, and
transmission patterns not yet fully elucidated.
While vaccines are not widely available, the number of new cases should not decrease
dramatically, unfortunately, since a large percentage of the population has not been infected
by the SARS-CoV-2 yet, reinfection becomes increasingly plausible with mutations in the
virus, and virus contention policies failed to be 100% effective.
Considering potential antiviral approaches for COVID-19, their effectiveness only make sense
if tested and given early in the disease, during viral dissemination. The learning that
oseltamivir is only effective for Influenza A in the first three days of disease finds strong
plausibility, and reinforces the expected lack of effectiveness of any drug with in vitro or
preliminary antiviral activity reported when tested in hospitalized or non-mild patients,
once COVID-19 presents tend to present mild symptoms during the viral dissemination stage.
An actual early detection of COVID-19, i.e., before its progression to further inflammatory
stages, is challenging, once the earliest symptoms tend to be unspecific, mild, and hardly
attributable to COVID-19. By suspecting of COVID-19 in the presence of any symptom, specific
to COVID-19 or not, sensitivity was met to be above 90% while specificity was also relatively
high (above 50%). In addition, time-to-treat, rather than which drug to choose, could better
determine the effectiveness of a specific approach.
Ivermectin: potential antiviral activity for COVID-19
Among drugs potentially effective for COVID-19, despite the classical antiparasitic and
anti-scabies use, ivermectin has demonstrated antiviral activity for a variety of viruses by
inhibiting and reducing the viral shedding duration, including chikungunya and other
alphaviruses, zyka virus, dengue virus and other simple-strain RNA viruses.
In the search for drugs with anti-SARS-CoV-2 activity, considering its effects on other
viruses, ivermectin was tested in a Vero-hSLAM cell model and demonstrated potent in vitro
action, by reducing viral load by 5000x after 48 hours of incubation. However, after initial
promising results, simultaneous pharmacokinetics simulations suggested that the minimum
effective concentrations would be unfeasible to be reached within safety range (EC-50 = 2
Micromol).
Although the theoretical minimum concentration required for antiviral action was apparently
at least 17 times higher than the lethal dose and up to 10,000 times the usually prescribed
doses for humans ( IC50 of 2.2 - 2.8 µM for monkeys), which would reduce the chances of
ivermectin efficacy for COVID-19, preliminary observational yet well-structured studies
demonstrated substantial synergistic action of ivermectin when added to "standard of care",
usually hydroxychloroquine with or without macrolides. In a specific study, the use of
ivermectin, even in low doses, reduced by 40% the absolute risk of death among patients more
severely affected by COVID-19.
Some randomized clinical trials (RCTs) demonstrated efficacy of ivermectin when combined with
hydroxychloroquine, doxycycline or azithromycin, in both mildly (and presumedly early) and
more severely affected subjects with COVID-19. Demonstrated benefits included lower disease
progression and reduced COVID-related mortality.
In comparative analyses, combinations between ivermectin and azithromycin, doxycycline or
hydroxychloroquine demonstrated superiority compared to combinations between
hydroxychloroquine and azithromycin or hydroxychloroquine alone.
The exact mechanisms of action remain nuclear. At least one study employing higher doses
(0.6mg/kg/day) demonstrated in vivo antiviral activity, but only when maximum concentration
reached serum levels above 160 ng/ml, which only occurred in 45% of subjects, even at higher
doses. The antiviral mechanisms include modification in the ACE-2 glycation patterns,
inhibition of the viral Helicase (NSP13) and disruption of the alpha-importin heterodimer.
In a recent systematic review and metanalysis, a dose-response correlation has also been
observed in terms of endpoints, reinforcing the role of ivermectin as actins as an
anti-SARS-CoV-2 action drug. However, even in lower doses ivermectin was able to demonstrate
clinical benefits, allowing the hypothesis that ivermectin also exerts anti-inflammatory
effects, which could include the blockage of STAT-1 migration to the nucleus, and could
justify its use even at later stages of the disease.
Collectively, higher yet safe ivermectin doses find stronger plausibility and preliminary
evidence to be tested in RCTs. In addition, approaches to increase ivermectin absorption and
bioavailability should be encouraged.
Based on the scientific rationale combined with preliminary evidence, ivermectin has
sufficient evidence to be tested at higher doses in a RCT for COVID-19. The investigators
propose to test ivermectin at high doses as a treatment for patients recently diagnosed with
COVID-19. This study is intended to explore the possible protective role of high-dose
ivermectin in SARS-CoV-2 infection in terms of reduction of clinic and virologic disease
duration, and prevention of oxygen use, hospitalization, mechanical ventilation, death, and
post-COVID persisting symptoms.
Drug: Ivermectin 0.6mg/kg/day
Use of ivermectin 0.6m/kg/day q.d.for 05 days
Drug: Ivermectin 1.0mg/kg/day
Ivermectin 1.0mg/kg/day q.d. for 05 days
Drug: Placebo
Placebo q.d.for 05 days
Drug: Hydroxychloroquine
Hydroxychloroquine 200mg/day q.d. for 05 days
Inclusion Criteria:
1. Laboratory or clinically confirmed positive SARS-CoV-2 rtPCR test (AndroCoV Clinical
Scoring for COVID-19 Diagnosis1) within 7 days prior to randomization
2. ≥18 years old
3. Laboratory confirmed positive SARS-CoV-2 rtPCR test within 7 days prior to
randomization
4. Clinical status on the COVID-19 Ordinal Scale (defined in Section 5.1) of 1 to 3
5. Subject (or legally authorized representative) gives written informed consent prior to
performing any study procedures
6. Subject (or legally authorized representative) agree that subject will not participate
in another COVID-19 trial while participating in this study
Exclusion Criteria:
1. Subject enrolled in a study to investigate a treatment for COVID-19
2. Require oxygen use, hospitalization or mechanical ventilation
3. Tachycardia (HR > 150 bpm) or hypotension (BP < 90/60 mmHg)
4. Patients who are allergic to the investigational product or similar drugs (or any
excipients);
5. Subjects with QTcF > 450 ms
6. Subjects with uncontrolled medical conditions that could compromise participation in
the study - uncontrolled hypertension (BP > 220/120 mmHg), uncontrolled hypothyroidism
(TSH > 10 iU/L), uncontrolled diabetes mellitus (HbA1c > 12%)
7. Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit
of normal.
8. Estimated glomerular filtration rate (eGFR) < 30 ml/min or requiring dialysis
9. Subject (or legally authorized representative) not willing or unable to provide
informed consent
Flavio A Cadegiani, MD, PhD
+55 61 99650.6111
flavio.cadegiani@gmail.com