Ivermectin for COVID-19: real-time analysis of all 86 studies

Covid Analysis (Preprint) (meta analysis)

Ivermectin is effective for COVID-19: real-time meta analysis of 50 studies

• 98% of the 50 studies to date report positive effects (24 statistically significant in isolation). Random effects meta-analysis for early treatment and pooled effects shows an 81% reduction, RR 0.19 [0.09-0.38], and prophylactic use shows 88% improvement, RR 0.12 [0.07-0.22]. Mortality results show 76% lower mortality, RR 0.24 [0.14-0.42] for all treatment delays, and 84% lower, RR 0.16 [0.04-0.63] for early treatment.

• 96% of the 26 Randomized Controlled Trials (RCTs) report positive effects, with an estimated 66% improvement, RR 0.34 [0.22-0.51].

• The probability that an ineffective treatment generated results as positive as the 50 studies to date is estimated to be 1 in 22 trillion (p = 0.000000000000045).

• All data to reproduce this paper and the sources are in the appendix. See [Bryant, Hill, Kory, Lawrie, Nardelli] for other meta analyses, all with similar results confirming effectiveness.

	Improvement	Studies	Authors	Patients
Early treatment	81% [62‑91%]	18	175	1,942
Late treatment	43% [27‑56%]	20	143	6,831
Prophylaxis	88% [78‑93%]	12	77	7,011
Mortality	76% [58‑86%]	18	155	7,267
RCTs only	66% [49‑78%]	26	231	3,618
All studies	73% [64‑79%]	50	395	15,784

WHO ivermectin approval status
Indication	Studies	Patients	Effect size	Status
Scabies	6	613	35% [22‑46%]	Approved
COVID‑19	50	15,784	73% [64‑79%]	Pending

Turkia, M., Research Gate (Review) (Preprint)

A timeline of ivermectin-related events in the COVID-19 pandemic

An extensive timeline of ivermectin-related events from April 2020 to March 2021 including studies, news, health authority decisions, biased news coverage, and censorship.

The author concludes that in a broader historical perspective, the timeline depicts rather dysfunctional societies unable to properly communicate and organize themselves, leading to misallocation of resources and decisions that may have conflicted with elementary ethical considerations, with this behavior rationalized by claiming adherence to mental paradigms that may have poorly matched the situation.

Mourya et al., Int. J. Health and Clinical Research (Peer Reviewed)

Comparative Analytical Study of Two Different Drug Regimens in Treatment of Covid 19 Positive Patients in Index Medical College Hospital and Research Center, Indore, India

Retrospective 100 patients in India with 50 treated with ivermectin, and SOC for all patients including HCQ+AZ, showing much higher viral clearance with ivermectin. Baseline clinical status was worse in the control group. Time of testing after treatment initiation was longer in the control group (mean 7.24 days versus 5.22 days).

risk of no virological cure, 89.4% lower, RR 0.11, p < 0.001, treatment 5 of 50 (10.0%), control 47 of 50 (94.0%).

Chahla et al., medRxiv, doi:10.1101/2021.03.29.21254554 (Preprint)

Ivermectin reproposing for COVID-19 treatment outpatients in mild stage in primary health care centers

Cluster RCT outpatients in Argentina showing signficantly faster recovery with ivermectin. There were no deaths. Cluster RCT where outpatients in Tucumán were assigned to the ivermectin group and outpatients from San Miguel de Tucumán and Gran San Miguel de Tucumán were assigned to the control group. All comorbidities, percentage of male patients, and age were higher in the ivermectin group, favoring the control group. NCT04784481.

risk of no medical release, 89.1% lower, RR 0.11, p = 0.005, treatment 2 of 110 (1.8%), control 8 of 62 (12.9%), adjusted, OR converted to RR.

Kow et al., Pharmacological Reports, doi:10.1007/s43440-021-00245-z (Peer Reviewed)

The association between the use of ivermectin and mortality in patients with COVID-19: a meta-analysis

Small meta analysis of 6 RCTs showing mortality OR 0.21 [0.11-0.42]. Authors do not include two more recent RCTs with mortality results, 10 other studies with mortality results, and a total of 42 other studies including other outcomes. Authors do not distinguish between studies with very different treatment delays (earlier treatment is more successful).

Tanioka et al., medRxiv, doi:10.1101/2021.03.26.21254377 (Preprint)

Why COVID-19 is not so spread in Africa: How does Ivermectin affect it?

Retrospective study of the 31 onchocerciasis-endemic countries using the community-directed treatment with ivermectin (CDTI) and the 22 non-endemic countries in Africa, showing significantly lower mortality per capita in the countries using ivermectin.

risk of death, 88.2% lower, RR 0.12, p = 0.002, relative mean mortality per million.

Udofia et al., Network Modeling Analysis in Health Informatics and Bioinformatics, doi:10.1007/s13721-021-00299-2 (Peer Reviewed)

In silico studies of selected multi-drug targeting against 3CLpro and nsp12 RNA-dependent RNA-polymerase proteins of SARS-CoV-2 and SARS-CoV

In Silico analysis finding that ivermectin had the highest binding energy against the 3CLpro of SARS-CoV-2 and RdRps of both SARS-CoV and SARS-CoV-2.

Choudhury et al., Future Medicine, doi:10.2217/fvl-2020-0342 (Peer Reviewed)

Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach

In Silico analysis finding that ivermectin has high binding affinity for the SARS-CoV-2 viral spike protein, main protease, replicase, and human TMPRSS2 receptors.

Huvemek Press Release (Preprint)

Kovid-19 - Huvemek® Phase 2 clinical trial

Phase 2 results from a multicenter RCT of hospitalized patients in Bulgaria showing faster viral clearance, greater clinical improvement, and improved biomarkers with treatment. Ivermectin was taken on an empty stomach, potentially reducing lung tissue concentration by ~2.5x [1]. Limited data has been reported currently. No serious adverse events were observed. EudraCT 2020-002091-12.

[1] twitter.com/Covid19Crusher/status/1367854845340844039

risk of no improvement, 31.6% lower, RR 0.68, p = 0.28, treatment 13 of 50 (26.0%), control 19 of 50 (38.0%), day 7, patients with improvement on WHO scale.

risk of no improvement, 34.5% lower, RR 0.66, p = 0.07, treatment 19 of 50 (38.0%), control 29 of 50 (58.0%), day 4, patients with improvement on WHO scale.

Yagisawa et al., The Japanese Journal of Antibiotics, 74-1, Mar 2021 (Review) (Peer Reviewed)

Global trends in clinical studies of ivermectin in COVID-19

Review of ivermectin for COVID-19. Authors note that Kitasato University's project was expanded in response to the results of Caly et al. which had left questions regarding in vivo therapeutic levels, and the results of those studies were positive. Early in the pandemic, Kitasato University requested Merck to conduct clinical trials in Japan because they have priority for an expansion of ivermectin's indications, however Merck declined.

Since large companies have declined to study ivermectin for COVID-19, trials have been mostly doctor-initiated with relatively little funding. Authors discuss these, noting that the physicians involved are enthusiastic about avoiding bias, and strive to treat and prevent COVID-19 witn non-profit motives.

Authors discuss the trials, epidemiological data, and inaccurate statements made by certain authorities.

Authors note that regulations make it challenging for doctor-initiated trials to enroll many participants in a timely manner.

Authors conclude that ivermectin may turn out to be comparable to the benefits achieved from the discovery of penicillin - said to be one of the greatest discoveries of the twentieth century.

Authors include the nobel prize winning biochemist who discovered ivermectin, Satoshi Ōmura [1].

[1] en.wikipedia.org/wiki/Satoshi_%C5%8Cmura

Emmerich et al., Int. J. Environ. Res. Public Health, doi:10.3390/ijerph18073371 (Peer Reviewed)

Comparisons between the Neighboring States of Amazonas and Pará in Brazil in the Second Wave of COVID-19 Outbreak and a Possible Role of Early Ambulatory Treatment

Comparison between the two largest neighboring states in Brazil, Amazonas and Pará, showing more than 5 times lower mortality in Pará during the second wave when the Pará government supported early treatment and Amazonas did not, compared to similar results in the first wave when treatment protocols were similar.

Del Franco et al., Journal of Biomedical Research and Clinical Investigation, doi:10.31546/2633-8653.1008 (Peer Reviewed)

Ivermectin in Long-Covid Patients: A Retrospective Study

Retrospective 856 patients previously admitted to hospital for COVID-19 in Argentina, finding that ivermectin improved recovery from "long covid" symptoms.

Roy et al., medRxiv, doi:10.1101/2021.03.08.21252883 (Preprint)

Outcome of Different Therapeutic Interventions in Mild COVID-19 Patients in a Single OPD Clinic of West Bengal: A Retrospective study

Retrospective database analysis of 56 mild COVID-19 patients, all treated with vitamin C, vitamin D, and zinc, comparing ivermectin + doxycycline (n=14), AZ (n=13), HCQ (n=14), and SOC (n=15), finding that all groups recover quickly, and there was no significant difference between the groups. Subject to the usual limitation of a database study, very small size, and limited evaluation of patients.

relative time to clinical response of wellbeing, 5.6% lower, relative time 0.94, p = 0.87, treatment 14, control 15.

Nardelli et al., Signa Vitae, doi:10.22514/sv.2021.043 (Peer Reviewed)

Crying wolf in time of Corona: the strange case of ivermectin and hydroxychloroquine. Is the fear of failure withholding potential life-saving treatment from clinical use?

Meta analysis of RCT mortality results showing RR 0.19, p < 0.00001.

risk of death, 79.5% lower, RR 0.21, p < 0.001, treatment 14 of 703 (2.0%), control 57 of 620 (9.2%), OR converted to RR.

Scheim et al., OSF Preprints (Preprint)

Ivermectin sales in Valle del Cauca, Colombia, patterns of AEs, and other background re López-Medina et al. 2021

Analysis of several issues with López-Medina et al. including the atypical adverse effects in the control arm and population use of ivermectin.

Bryant et al., Research Square, doi:10.21203/rs.3.rs-317485/v1 (OSF preprints 3/11) (Preprint)

Ivermectin for prevention and treatment of COVID-19 infection: a systematic review and meta-analysis

Systematic review and meta analysis of 21 RCTs finding mortality RR 0.32 [0.14-0.72], and prophylaxis case RR 0.14 [0.09-0.21].

risk of death, 68.0% lower, RR 0.32, p = 0.006.

risk of COVID-19 case, 86.0% lower, RR 0.14, p < 0.001.

Scheim et al., OSF Preprints (Preprint)

Protocol violations in López-Medina et al.: 38 switched ivermectin (IVM) and placebo doses, failure of blinding, widespread IVM sales OTC in Cali, and nearly identical AEs for the IVM and control groups

Report on protocol violations in López-Medina et al.

Yesilbag et al., Virus Research, doi:10.1016/j.virusres.2021.198384 (Peer Reviewed) (In Vitro)

Ivermectin also inhibits the replication of bovine respiratory viruses (BRSV, BPIV-3, BoHV-1, BCoV and BVDV) in vitro

In Vitro study showing that ivermectin can inhibit infection of bovine respiratory disease viral agents BCoV, BPIV-3, BVDV, BRSV and BoHV-1 at the concentrations of 2.5 and 5 μM and in a dose-dependent manner.

Pott-Junior et al., Toxicology Reports, doi:10.1016/j.toxrep.2021.03.003 (Peer Reviewed)

Use of ivermectin in the treatment of Covid-19: a pilot trial

Small RCT with 4 control patients and 28 ivermectin patients split across 3 different dosage levels, showing lower (non-statistically significant) ICU admission with treatment. Authors suggest that ivermectin for SARS-CoV-2 is safe and reduces symptoms and viral load. They note that ivermectin’s antiviral effect appear to be dose-dependent. NCT04431466.

risk of ICU admission, 85.2% lower, RR 0.15, p = 0.25, treatment 1 of 27 (3.7%), control 1 of 4 (25.0%).

relative improvement in Ct value, 0.8% lower, RR 0.99, p = 1.00, treatment 27, control 3.

risk of no virological cure, 11.1% higher, RR 1.11, p = 1.00, treatment 10 of 27 (37.0%), control 1 of 3 (33.3%).

time to viral-, 16.7% lower, relative time 0.83, treatment 27, control 3.

Chamie-Quintero et al., OSF Preprints (Preprint)

Ivermectin for COVID-19 in Peru: 14-fold reduction in nationwide excess deaths, p=.002 for effect by state, then 13-fold increase after ivermectin use restricted

Analysis of ivermectin use in Peru concluding that ivermectin most likely caused 14 times reductions in excess deaths in Peru, prior to 13 times increase after reversal of ivermectin use. Authors conclude that the results strongly suggest that ivermectin can complement vaccination. They note that the potential mechanism of action, competitive binding with the SARS-CoV-2 spike protein, is likely to be non-epitope specific, possibly maintaining efficacy against emerging mutant strains.

Guzman et al., medRxiv, doi:10.1101/2021.03.04.21252084 (Preprint)

Factors associated with increased mortality in critically ill COVID-19 patients in a Mexican public hospital: the other faces of health system oversaturation

Retrospective 196 critically ill patients in Mexico. Patients overlap with the existing RCT by Beltran-Gonzalez (NCT04391127). This preprint shows a larger treated population and greater (non-statistically significant) improvement with ivermectin, RR 0.81 [0.53-1.24].

Galan et al., Pathogens and Global Health, doi:10.1080/20477724.2021.1890887 (Peer Reviewed)

Phase 2 randomized study on chloroquine, hydroxychloroquine or ivermectin in hospitalized patients with severe manifestations of SARS-CoV-2 infection

RCT 168 very late stage severe condition hospitalized patients comparing CQ, HCQ, and ivermectin not showing significant differences. Authors were unable to add a control arm due to ethical issues.

Authors claim that "the mortality rates of the three groups are very similar to historical reports of other studies that used placebo in hospitalized patients", without providing any reference. However [1] shows 43% hospital mortality in the northern region of Brazil, where the study was performed, from which we can estimate the mortality with ivermectin in this study is 47% lower, RR 0.53. Further, the study is restricted to more severe cases, hence the expected mortality may be higher.

[1] sciencedirect.com/science/article/pii/S2214109X20302850

Descotes, J., ImmunoSafe Consultance (Preprint)

Medical Safety of Ivermectin

Safety analysis of >350 articles showing that ivermectin has an excellent safety profile. The author notes that "no severe adverse event has been reported in dozens of completed or ongoing studies involving thousands of participants worldwide to evaluate the efficacy of ivermectin against COVID-19".

López-Medina et al., JAMA, doi:10.1001/jama.2021.3071 (Peer Reviewed)

Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial

Phone survey based RCT with low risk patients, 200 ivermectin and 198 control, showing lower mortality, lower disease progression, lower treatment escalation, and faster resolution of symptoms with treatment, without reaching statistical significance. Authors find the results of this trial alone do not support the use of ivermectin. However the effects are all positive, especially for serious outcomes which are unable to reach statistical significance with the very small number of events in the low risk population.

With the low risk patient population, there is little room for improvement with an effective treatment - 59/57% (IVM/control) recovered within the first 2 days to either "no symptoms" or "not hospitalized and no limitation of activities"; 73/69% within 5 days. Less than 3% of all patients ever deteriorated.

The primary outcome was changed mid-trial, it was originally clinical deterioration, which is more meaningful, and shows greater benefit. The new outcome of resolution of symptoms includes "not hospitalized and no limitation of activities" as a negative outcome and is not very meaningful in terms of assessing how much treatment reduces serious outcomes. Using this measure could completely invalidate results - for example a treatment that eliminates all COVID-19 symptoms but has a temporary minor adverse event could be seen as worse.

Authors state that "preliminary reports of other randomized trials of ivermectin as treatment for COVID-19 with positive results have not yet been published in peer-reviewed journals", however there were actually 8 peer-reviewed RCTs with positive effects published prior to this paper (and 19 total peer-reviewed studies with positive effects).

Authors advised taking ivermectin on an empty stomach, reducing lung tissue concentration by ~2.5x [1].

76 patients were excluded due to control patients receiving ivermectin. However, there was a similar percentage of adverse events like diarrhea, nausea, and abdominal pain in both treatment and control groups. These are potential non-serious side effects of treatment and suggest that it is possible that many more control patients received some kind of treatment.

Ivermectin was widely used in the population and available OTC at the time of the study. The study protocol only excluded patients with previous ivermectin use within 5 days, however other trials often monitor effects 10+ days after the last dose [2].

This study reportedly has an ethical issue whereby participants were told the study drug was "D11AX22" [3]. The editor-in-chief of JAMA initially offered to help with this issue, but later indicated that "JAMA does not review consent forms", however the lead author reportedly confirmed the issue. Therefore this paper may be retracted (JAMA has not indicated their response yet) [4, 5, 6].

The study protocol specifically allows "the use of other treatments outside of clinical trials". The paper provides no information on what other treatments were used, but other treatments were commonly used at the time, for example [7]. Additionally, the control group did about 5x better than anticipated for deterioration, also suggesting that the control patients used some kind of treatment. Patients which enroll in such a study may be more likely to learn about and use other treatments, especially since they do not know if they are receiving the study medication.

Most data was collected via surveys, without physical examination.

The trial protocol lists “the duration of supplemental oxygen” as an outcome but the results for this outcome are missing.

The study protocol was amended 4 times. Amendments 2-4 are provided but amendment 1 is missing. Amendment 2 increased the inclusion criteria to within 7 days of onset, including more later stage patients and reducing the expected effectiveness.

Grants and/or personal fees, including in some cases during the conduct of the study, were provided by Sanofi Pasteur, GlaxoSmithKline, Janssen, Merck, and Gilead.

Other issues can be found in the comments of the article [8].

87% medication adherence. NCT04405843.

[1] twitter.com/Covid19Crusher/status/1367854845340844039

[2] osf.io/6m3ch/

[3] trialsitenews.com/jama-ivermectin-study-deceived-participants-on-study-drug/

[4] trialsitenews.com/jama-unable-to-confirm-ivermectin-study-consent-form-used-ivermectin/

[5] trialsitenews.com/jama-ivermectin-study-deception-of-study-participants-is-publicly-confirmed/

[6] francesoir.fr/societe-sante/la-tromperie-de-letude-jama-sur-livermectine-des-participants-letude-e..

[7] hsj.gr/medicine/is-there-a-correlation-between-changesin-hydroxychloroquine-use-and-mortalityrates..

[8] jamanetwork.com/journals/jama/fullarticle/2777389

risk of death, 66.8% lower, RR 0.33, p = 0.50, treatment 0 of 200 (0.0%), control 1 of 198 (0.5%), continuity correction due to zero event.

risk of escalation of care, 60.8% lower, RR 0.39, p = 0.10, treatment 4 of 200 (2.0%), control 10 of 198 (5.1%), OR converted to RR.

risk of escalation of care with post-hoc <12h exclusion, 34.3% lower, RR 0.66, p = 0.51, treatment 4 of 200 (2.0%), control 6 of 198 (3.0%), OR converted to RR.

risk of deterioration by >= 2 points on an 8-point scale, 43.1% lower, RR 0.57, p = 0.35, treatment 4 of 200 (2.0%), control 7 of 198 (3.5%), OR converted to RR.

risk of fever post randomization, 24.8% lower, RR 0.75, p = 0.33, treatment 16 of 200 (8.0%), control 21 of 198 (10.6%), OR converted to RR.

risk of unresolved symptoms at day 21, 15.3% lower, RR 0.85, p = 0.53, treatment 36 of 200 (18.0%), control 42 of 198 (21.2%), OR converted to RR, Cox proportional-hazard model.

hazard ratio for lack of resolution of symptoms, 6.5% lower, RR 0.93, p = 0.53, treatment 200, control 198.

relative median time to resolution of symptoms, 16.7% lower, relative time 0.83, treatment 200, control 198.

Saha et al., Research Square, doi:10.21203/rs.3.rs-160254/v1 (Preprint)

The Binding mechanism of Ivermectin and levosalbutamol with spike protein of SARS-CoV-2

In SIlico analysis predicting that ivermectin has a large binding affinity for the SARS-CoV-2 spike protein. Three different computer modeling techniques show that ivermectin can inhibit SARS-CoV-2 entrance via hACE2.

Beltran-Gonzalez et al., medRxiv, doi:10.1101/2021.02.18.21252037 (Peer Reviewed)

Efficacy and safety of Ivermectin and Hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial

RCT late stage severe condition (93% SOFA ≥ 2, 96% APACHE ≥ 8) high comorbidity hospitalized patients in Mexico with 36 low dose ivermectin and 37 control patients not finding significant differences. NCT04391127

risk of death, 14.4% lower, RR 0.86, p = 1.00, treatment 5 of 36 (13.9%), control 6 of 37 (16.2%).

risk of respiratory deterioration or death, 8.6% lower, RR 0.91, p = 1.00, treatment 8 of 36 (22.2%), control 9 of 37 (24.3%).

risk of no hospital discharge, 37.0% higher, RR 1.37, p = 0.71, treatment 4 of 36 (11.1%), control 3 of 37 (8.1%).

BIRD Meeting 20th February 2021 (News)

BIRD Meeting 20th February 2021

The British Ivermectin Recommendation Development (BIRD) panel, with dozens of multi-national scientists & doctors, issued sweeping recommendations for the immediate global use of ivermectin.

Elalfy et al., J. Med. Virol., doi:10.1002/jmv.26880 (Peer Reviewed)

Effect of a combination of Nitazoxanide, Ribavirin and Ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-1

Non-randomized controlled trial with 62 mild and early moderate patients with home treatment with ivermectin + nitazoxanide + ribavirin + zinc, showing significantly faster viral clearance.

risk of no virological cure, 86.9% lower, RR 0.13, p < 0.001, treatment 7 of 62 (11.3%), control 44 of 51 (86.3%), day 15.

risk of no virological cure, 58.1% lower, RR 0.42, p < 0.001, treatment 26 of 62 (41.9%), control 51 of 51 (100.0%), day 7.

Behera et al., Research Square, doi:10.21203/rs.3.rs-208785/v1 (Preprint)

Prophylactic role of ivermectin in SARS-CoV-2 infection among healthcare workers

Prospective prophylaxis study with 3,532 healthcare workers, 2,199 receiving two-dose ivermectin prophylaxis, showing adjusted relative risk of confirmed COVID-19 with treatment 0.17 [0.12-0.23] p<0.001.

186 patients took only the first dose, and no significant difference was observed for this group. The same group published an earlier small study with 115 ivermectin patients.

risk of COVID-19 case, 83.0% lower, RR 0.17, p < 0.001, treatment 45 of 2199 (2.0%), control 133 of 1147 (11.6%), two doses.

risk of COVID-19 case, 4.0% higher, RR 1.04, p = 0.85, treatment 23 of 186 (12.4%), control 133 of 1147 (11.6%), patients only receiving the first dose.

Schwartz, E., Sheba Ivermectin Project (Preprint)

Ivermectin vs. placebo treatment in non-hospitalized patients with COVID-19 - A double blind, randomized controlled trial

Double blind RCT for mild-moderate COVID-19 outpatients in Israel showing significantly faster reduction in viral load with treatment, and zero hospitalizations with treatment compared with 2 for the control group.

There were no safety issues. Sheba IRB-7156/20. NCT04429711.

risk of hospitalization, 80.7% lower, RR 0.19, p = 0.23, treatment 0 of 49 (0.0%), control 2 of 45 (4.4%), continuity correction due to zero event.

risk of no virological cure, 51.4% lower, RR 0.49, p = 0.01, treatment 16 of 49 (32.7%), control 25 of 45 (55.6%), adjusted, OR converted to RR, multivariable logistic regression, day 6, Ct>30.

risk of no virological cure, 54.1% lower, RR 0.46, p = 0.02, treatment 9 of 49 (18.4%), control 18 of 45 (40.0%), day 10, Ct>30.

risk of no virological cure, 54.1% lower, RR 0.46, p = 0.02, treatment 10 of 49 (20.4%), control 20 of 45 (44.4%), day 8, Ct>30.

risk of no virological cure, 41.2% lower, RR 0.59, p = 0.04, treatment 16 of 49 (32.7%), control 25 of 45 (55.6%), day 6, Ct>30.

risk of no virological cure, 37.9% lower, RR 0.62, p = 0.09, treatment 11 of 26 (42.3%), control 15 of 22 (68.2%), day 4, Ct>30.

Lima-Morales (Peer Reviewed)

Effectiveness of a multidrug therapy consisting of ivermectin, azithromycin, montelukast and acetylsalicylic acid to prevent hospitalization and death among ambulatory COVID-19 cases in Tlaxcala, Mexico

Prospective trial of 768 COVID-19 outpatients in Mexico, 481 treated with ivermectin, AZ, montelukast, and aspirin, and 287 control patients with various treatments, showing significantly lower mortality and hospitalization, and significantly higher recovery at 14 days with treatment.

risk of death, 77.7% lower, RR 0.22, p < 0.001, treatment 15 of 481 (3.1%), control 52 of 287 (18.1%), adjusted, OR converted to RR, multivariate.

risk of hospitalization, 67.4% lower, RR 0.33, p < 0.001, treatment 44 of 481 (9.1%), control 89 of 287 (31.0%), adjusted, OR converted to RR, multivariate.

risk of no recovery, 58.6% lower, RR 0.41, p < 0.001, treatment 75 of 481 (15.6%), control 118 of 287 (41.1%), adjusted, OR converted to RR, recovery at day 14 after symptoms, multivariate.

Mohan et al., Research Square, doi:10.21203/rs.3.rs-191648/v1 (Preprint)

Ivermectin in mild and moderate COVID-19 (RIVET-COV): a randomized, placebo-controlled trial

RCT in India with low risk patients, comparing 24mg ivermectin, 12mg ivermectin, and placebo showing non-statistically significant improvements in recovery and PCR+ status (day 5 both arms, day 7 24mg only) with treatment, and showing greater improvement for the higher dose arm. Viral load decline was similar in all arms. There were no deaths or use of mechanical ventilation. There were no safety concerns. We note that our pre-specified protocol prioritizes clinical outcome results over PCR results.

risk of no discharge at day 14, 62.5% lower, RR 0.38, p = 0.27, treatment 2 of 40 (5.0%), control 6 of 45 (13.3%), ivermectin 24mg.

risk of no discharge at day 14, 43.8% lower, RR 0.56, p = 0.49, treatment 3 of 40 (7.5%), control 6 of 45 (13.3%), ivermectin 12mg.

risk of no virological cure, 10.3% lower, RR 0.90, p = 0.65, treatment 20 of 36 (55.6%), control 26 of 42 (61.9%), ivermectin 24mg, day 7.

risk of no virological cure, 3.2% higher, RR 1.03, p = 1.00, treatment 23 of 36 (63.9%), control 26 of 42 (61.9%), ivermectin 12mg, day 7.

risk of no virological cure, 23.8% lower, RR 0.76, p = 0.18, treatment 21 of 40 (52.5%), control 31 of 45 (68.9%), ivermectin 24mg, day 5.

risk of no virological cure, 5.6% lower, RR 0.94, p = 0.82, treatment 26 of 40 (65.0%), control 31 of 45 (68.9%), ivermectin 12mg, day 5.

Castaneda-Sabogal et al., medRxiv, doi:10.1101/2021.01.26.21250420 (Preprint) (meta analysis)

Outcomes of Ivermectin in the treatment of COVID-19: a systematic review and meta-analysis

Student-written meta analysis of a very small subset of studies exhibiting very high bias and significant flaws. Some of the problems:

- As of the publication date, there are 35 studies, authors include only 4. (They list 5, but two are the same study, preprint and published version).

- From the 17 RCTs, authors include 0.

- Authors include only late treatment studies, excluding all 10 early treatment studies and all 10 prophylaxis studies.

- Authors did not locate 13 studies, despite this being trivial from existing meta analyses.

- There is no logic in the exclusion reasons. For example, they include the most biased study to date, Soto-Becerra, and assign the highest weight to it.

- Authors randomly exclude letters but include preprints (excluding letters to help avoid positive results, including preprints to include Soto-Becerra).

- Soto-Becerra has clear evidence of extreme bias. The study presents 30 day results and extended KM curves up to day 43 for ivermectin. At 30 days the result is negative but reverts (as do all treatments in the study) and becomes positive before day 43. Authors of this meta analysis ignore the extended followup. Soto-Becerra is a database analysis that includes anyone with ICD-10 COVID-19 codes which includes asymptomatic PCR+ patients, therefore many patients in the control group are likely asymptomatic with regards to SARS-CoV-2, but in the hospital for another reason. For those that had symptomatic COVID-19, there is also likely significant confounding by indication. In this study all medications show higher mortality at day 30, which is consistent with asymptomatic (for COVID-19) or mild condition patients being more common in the control group. For ivermectin they show 30 day mortality aHR = 1.39 [0.88 - 2.22]. KM curves show that the treatment groups were in more serious condition, and also that after about day 35 survival became better with ivermectin. More than the total excess mortality happened on the first day. This is consistent with treated patients being in more serious condition, and with many of the control group patients being in hospital for something unrelated to COVID-19. Authors use a machine learning based propensity scoring system that appears over-parameterized and likely to result in significant overfitting and inaccurate results. Essentially they test for all interactions between two and three covariates. The nature and large number of covariates means many random correlations may be found. COVID-19 severity is not used. In summary, this is the lowest quality ivermectin study to date. This study also does not compare treatments with a control group not receiving the treatment - authors put patients receiving treatments after 48 hours in the control group. Authors also state that outcomes within 24 hours were excluded, however KM curves show significant mortality at day 1 (only for the treatment groups).

- We checked the reported results for the mortality outcome and found they do not appear to match the actual papers.

- Rajter: authors list mortality as 13/85 (treatment), 24/74 (control), the paper shows (for the matched cohort) 13/98 (treatment), 24/98 (control). The adjusted result in the paper is OR 0.27 [0.09-0.80] (multivariate) or OR 0.47 [0.22-0.99] (PSM). These correspond to RR 0.33 and 0.54 respectively, or logRR -1.1 and -0.62. However authors here show logRR 0.54 and 0.85 - they include the study twice (preprint and published). The preprint and published papers have the same multivariate result, the PSM result was added in the published paper. Neither of the two results the authors use match the actual results.

- Khan: the paper shows RR 0.13, logRR -2.0. Authors show logRR 0.13.

- Soto-Becerra at day 30 shows wHR 1.39 [0.88-2.22], and day 43 weighted KM 0.82 [0.76-0.88]. These correspond to logRR 0.33 and -0.19. Authors show logRR 1.75.

- Gorial: there is zero mortality with treatment in this paper. Using the typical continuity correction, the paper shows RR 0.29 when accounting for the different group sizes, or 0.86 when using naive continuity correction that does not account for the very different group sizes. These correspond to logRR -1.24 or -0.15. Authors show logRR 0.60.

- Authors did not locate and reference the existing widely known meta-analyses from well-known researchers - Kory et al., Hill et al., Lawrie et al.

For more issues see: [1, 2]

Authors on Twitter: [3, 4, 5, 6]

[1] twitter.com/Covid19Crusher/status/1354463260599328778

[2] twitter.com/joshuanbarbozam/status/1354471295690403840

[3] twitter.com/DiegoMichilot

[4] twitter.com/carlostoro_29

[5] twitter.com/christiansr96

[6] twitter.com/joshuanbarbozam

Eweas et al., Frontiers in Microbiology, doi:10.3389/fmicb.2020.592908 (Peer Reviewed)

Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2

Molecular docking analysis showing that ivermectin efficiently binds to the viral S protein as well as the human cell surface receptors ACE-2 and TMPRSS2; therefore, it might be involved in inhibiting the entry of the virus into the host cell. It also binds to Mpro and PLpro of SARS-CoV-2; therefore, it might play a role in preventing the post-translational processing of viral polyproteins. The highly efficient binding of ivermectin to the viral N phosphoprotein and nsp14 is suggestive of its role in inhibiting viral replication and assembly.

Errecalde et al., Journal of Pharmaceutical Sciences, doi:10.1016/j.xphs.2021.01.017 (Peer Reviewed)

Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model

Animal study of a novel spray formulation of ivermectin, showing an advantage of the spray formulation in terms of fast attainment of high and
persistent ivermectin concentrations in nasopharyngeal tissue.

Chamie-Quintero et al., Preprint, doi:10.2139/ssrn.3765018 (Preprint)

Sharp Reductions in COVID-19 Case Fatalities and Excess Deaths in Peru in Close Time Conjunction, State-By-State, with Ivermectin Treatments

Analysis of ivermectin usage within states in Peru showing sharp reductions in COVID-19 deaths corresponding to the usage of ivermectin treatment.

Mody et al., Communications Biology, doi:10.1038/s42003-020-01577-x (Peer Reviewed) (In Vitro)

Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

Computational molecular modeling screening and in vitro analysis for inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme, showing that ivermectin blocked more than 85% of 3CLpro activity of SARS-CoV-2. Antiviral activity of ivermectin mediated through the blocking of α/β1 importin has been previously established, this analysis suggests an additional antiviral mechanism of ivermectin for SARS-CoV-2 via inhibitory effects on 3CLpro.

Rezai et al., IRCT20111224008507N3 (Preprint)

Effectiveness of Ivermectin in the Treatment of Coronavirus Infection in Patients admitted to Educational Hospitals of Mazandaran in 2020

RCT in Iran showing shorter time to clinical recovery with Ivermectin.

Results are from: [1]
Trial details: [2] (double blind according to the trial registration)

[1] c19ivermectin.com/hill.html

[2] en.irct.ir/trial/49174

recovery time, 21.2% lower, relative time 0.79, p = 0.02, treatment 51, control 52.

hospitalization time, 17.9% lower, relative time 0.82, p = 0.01, treatment 51, control 52.

Hill et al., Research Square, doi:10.21203/rs.3.rs-148845/v1 (Preprint) (meta analysis)

Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection

Meta analysis of 18 ivermectin RCTs with 2,282 patients showing faster viral clearance (dose and duration dependent), improved clinical recovery, and lower hospitalization and mortality. In six RCTs of moderate or severe infection, there was a 75% reduction in mortality, RR 0.25 [0.12-0.52], p = 0.0002.

A sponsor reportedly required the conclusion of this paper to be changed against the wishes of the authors (to suggest that more trials should be done as opposed to the existing evidence being sufficient) [1, 2, 3].

[1] francesoir.fr/videos-les-debriefings/le-scandale-de-livermectine-tess-lawrie-le-retour

[2] youtube.com/watch?v=y2FWPQm6sxw&t=3s

[3] reddit.com/r/ivermectin/comments/m5kr7b/dr_tess_lawrie_discusses_her_ivermectin/

risk of death, 75.0% lower, RR 0.25, p < 0.001.

Raad et al., ChiCTR2000033627 (Preprint)

In vivo use of ivermectin (IVR) for treatment for corona virus infected patients (COVID-19): a randomized controlled trial

RCT in Lebanon showing significantly lower viral load at day 3, and lower hospitalization.

Results are from: [1]

[1] c19ivermectin.com/hill.html

risk of hospitalization, 85.7% lower, RR 0.14, p = 0.24, treatment 0 of 50 (0.0%), control 3 of 50 (6.0%), continuity correction due to zero event.

risk of viral load, 59.0% lower, RR 0.41, p = 0.01, treatment 50, control 50, percentage relative improvement in Ct value with treatment at day 3.

Bukhari et al., medRxiv, doi:10.1101/2021.02.02.21250840 (results 1/16) (Preprint)

Efficacy of Ivermectin in COVID-19 Patients with Mild to Moderate Disease

RCT of relatively low risk hospitalized patients with 50 ivermectin and 50 control patients showing significantly faster viral clearance with treatment. 9 patients in the treatment arm were lost to followup compared with 5 in the control arm, which could be in part due to faster recovery with treatment. There were no safety concerns. No mortality was reported. The numbers in Table 3 are the number of patients that became negative on that day, i.e., non-cumulative. NCT04392713.

risk of no virological cure, 82.4% lower, RR 0.18, p < 0.001, treatment 4 of 41 (9.8%), control 25 of 45 (55.6%), day 7.

risk of no virological cure, 38.7% lower, RR 0.61, p < 0.001, treatment 24 of 41 (58.5%), control 43 of 45 (95.6%), day 3.

Kory et al., Frontiers in Pharmacology, doi:10.3389/fphar.2021.643369 (Review) (Peer Reviewed)

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

Meta analysis of ivermectin clinical studies and natural experiments where ivermectin has been widely used, showing efficacy of ivermectin in prophylaxis and treatment of COVID-19. This paper was censored by the journal after acceptance [1].

[1] the-scientist.com/news-opinion/frontiers-removes-controversial-ivermectin-paper-pre-publication-68..

Okumuş et al., NCT04646109 (Preprint)

Evaluation of the Effectiveness and Safety of Adding Ivermectin to Treatment in Severe COVID-19 Patients

Small RCT for severe COVID-19 comparing the addition of ivermectin to SOC (low dose HCQ+AZ+favipiravir), with 30 treatment and 30 control patients in Turkey, showing lower mortality and faster clinical recovery. Authors also investigate the presence of gene mutations that alter ivermectin metabolism, predicting that ivermectin can be used safely without serious side effects in patients without MDR-1/ABCB1 and/or CYP3A4 gene mutation, and recommending monitoring and appropriate treatment if necessary when sequencing is unavailable.

risk of death, 33.3% lower, RR 0.67, p = 0.55, treatment 6 of 30 (20.0%), control 9 of 30 (30.0%).

risk of no improvement at day 10, 42.9% lower, RR 0.57, p = 0.18, treatment 8 of 30 (26.7%), control 14 of 30 (46.7%).

risk of no improvement at day 5, 15.8% lower, RR 0.84, p = 0.60, treatment 16 of 30 (53.3%), control 19 of 30 (63.3%).

risk of no virological cure, 80.0% lower, RR 0.20, p = 0.02, treatment 2 of 16 (12.5%), control 5 of 8 (62.5%), day 10.

Chahla et al., medRxiv, doi:10.1101/2021.03.26.21254398 (Preprint)

A randomized trial - intensive treatment based in ivermectin and iota-carrageenan as pre-exposure prophylaxis for COVID-19 in healthcare agents

Prophylaxis RCT for ivermectin and iota-carrageenan in Argentina, 117 healthcare workers treated with ivermectin and iota-carrageenan, and 117 controls, showing significantly lower cases with treatment. There were no moderate/severe cases with treatment vs. 10 in the control group. There were 4 cases with treatment (all mild) vs. 25 for the control group. NCT04701710.

risk of COVID-19 case, 95.2% lower, RR 0.05, p = 0.002, treatment 0 of 117 (0.0%), control 10 of 117 (8.5%), continuity correction due to zero event, moderate/severe COVID-19.

risk of COVID-19 case, 84.0% lower, RR 0.16, p < 0.001, treatment 4 of 117 (3.4%), control 25 of 117 (21.4%), adjusted, OR converted to RR, all cases.

risk of COVID-19 case, 84.0% lower, RR 0.16, p < 0.001, treatment 4 of 117 (3.4%), control 25 of 117 (21.4%), all cases.

Bousquet-Melou et al., Preprint, doi:10.22541/au.161047848.80388481/v1 (Preprint)

Large Impact of obesity on the disposition of ivermectin, moxidectin and eprinomectin in a canine model: relevance for COVID-19 patients

Animal dosing study with an obese dog model concluding that ivermectin maintenance doses should be based on lean body weight and not the total body weight in obese subjects, while the loading dose should be based on the total body weight.

Formiga et al., J. Control Release, doi:10.1016/j.jconrel.2020.10.009 (Review) (Peer Reviewed)

Ivermectin: an award-winning drug with expected antiviral activity against COVID-19

Review hypothesizing that micro- and nanotechnology-based formulations of ivermectin for the pulmonary delivery of ivermectin may be beneficial for use with COVID-19.

Kirti et al., medRxiv, doi:10.1101/2021.01.05.21249310 (Preprint)

Ivermectin as a potential treatment for mild to moderate COVID-19: A double blind randomized placebo-controlled trial

RCT with 112 mild and moderate COVID-19 patients in India, showing lower mortality, ventilation, and ICU admission, although not statistically significant due to the small number of events. There was no mortality in the treatment arm (55 patients) versus 7% (4 of 57) in the control arm. The PCR result is subject to confounding by biased loss of followup, with 23 lost in the treatment group and 13 in the control group, and 8 more people in the treatment group discharged before day 6.

risk of death, 88.7% lower, RR 0.11, p = 0.12, treatment 0 of 55 (0.0%), control 4 of 57 (7.0%), continuity correction due to zero event.

risk of mechanical ventilation, 79.3% lower, RR 0.21, p = 0.09, treatment 1 of 55 (1.8%), control 5 of 57 (8.8%).

risk of ICU admission, 13.6% lower, RR 0.86, p = 0.80, treatment 5 of 55 (9.1%), control 6 of 57 (10.5%).

risk of no virological cure, 11.6% higher, RR 1.12, p = 0.35, treatment 42 of 55 (76.4%), control 39 of 57 (68.4%).

Chamie, J. (News)

COVID-19 in Mexico

Comparison of COVID-19 death rates in Mexico showing that the only state using ivermectin has a dramatically lower rate.

Babalola et al., QJM: An International Journal of Medicine, doi:10.1093/qjmed/hcab035 (preprint 1/6) (Peer Reviewed)

Ivermectin shows clinical benefits in mild to moderate COVID19: A randomised controlled double-blind, dose-response study in Lagos

Small RCT comparing ivermectin 6mg & 12mg q84hr with lopinavir/ritonavir, showing a statistically significant and dose dependent effect of ivermectin on reducing the time to PCR-.

adjusted risk of viral+ at day 5, 63.9% lower, RR 0.36, p = 0.11, treatment 40, control 20, adjusted.

risk of no virological cure, 58.0% lower, RR 0.42, p = 0.01, treatment 20, control 20, 12mg - Cox proportional hazard model.

risk of no virological cure, 40.5% lower, RR 0.60, p = 0.12, treatment 20, control 20, 6mg - Cox proportional hazard model.

time to viral-, 49.2% lower, relative time 0.51, treatment 20, control 20, 12mg.

time to viral-, 34.4% lower, relative time 0.66, treatment 20, control 20, 6mg.

Hirsch et al., Microbiology & Infectious Diseases (Peer Reviewed)

Ivermectin as Prophylaxis Against COVID-19 Retrospective Cases Evaluation

Report on ivermectin prophylaxis for healthcare workers in a hospital in Argentina, showing 0 cases in the 162 participants. Dosage was 0.2mg/kg weekly for eight weeks, followed by 4 months rest.

Lawrie et al., Preprint (Preprint) (meta analysis)

Ivermectin reduces the risk of death from COVID-19 – a rapid review and meta-analysis in support of the recommendation of the Front Line COVID-19 Critical Care Alliance

Meta analysis confirming the effectiveness of ivermectin for COVID-19, showing ivermectin treatment mortality relative risk RR 0.17 [0.18-0.35] and prophylaxis cases RR 0.12 [0.08-0.18].

risk of death, 83.0% lower, RR 0.17, p < 0.001, treatment 8 of 585 (1.4%), control 44 of 522 (8.4%).

Wijaya et al., Cermin Dunia Kedokteran, 47:7 (Peer Reviewed)

Ivermectin as a Potential Therapeutic Agent for COVID-19 – case studies

Case report on 3 confirmed cases of COVID-19 with significant clinical and radiological improvement after a single dose of ivermectin.

Madrid et al., Heliyon, doi:10.1016/j.heliyon.2020.e05820 (Peer Reviewed)

Safety of oral administration of high doses of ivermectin by means of biocompatible polyelectrolytes formulation

In vivo analysis of the safety of high dose ivermectin with a Corydoras fish animal model.

McCullough et al., Reviews in Cardiovascular Medicine, doi:10.31083/j.rcm.2020.04.264 (Review) (Peer Reviewed)

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19)

Review urging early treatment of COVID-19 with sequential multidrug treatment that has been shown to be safe and effective. Proposed treatment includes zinc, vitamin D & C, quercetin, and depending on age, comorbidities, and symptoms may include >=2 of HCQ, ivermectin, favipiravir; AZM/DOXY; corticosteroids; colchicine; bamlanivimab; aspirin; LMWH; and supplemental oxygen.

Procter et al., Reviews in Cardiovascular Medicine, doi:10.31083/j.rcm.2020.04.260 (Peer Reviewed)

Clinical outcomes after early ambulatory multidrug therapy for high-risk SARS-CoV-2 (COVID-19) infection

Retrospective 922 outpatients, with 320 treated early due to age>50 or comorbidities, showing 2.2% hospitalization and 0.3% death, which authors note is considerably lower than reported in other studies in their region.

At least two of zinc, HCQ, and ivermectin were used, along with one antibiotic, and budesonide and/or dexamethasone.

Hill, A., Preprint (Preprint) (meta analysis)

Meta-analysis of clinical trials of ivermectin to treat COVID-19 infection

WHO-funded meta analysis showing ivermectin treatment mortality relative risk RR 0.17 [0.08-0.35] for RCTs and RR 0.28 [0.13-0.62] for RCTs and observational studies, and confirming a dose-response effect.