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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. (Latest version v1.2 - 6 Jan 2021)

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Abstract and Figures

This is version 1.2 of the ivermectin report dated 6 Jan 2021
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Research for Impact
03 January 2021
URGENT COVID-19 information:
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.
Tess Lawrie MBBCh, PhD;
E-BMC Ltd, Office 305, Northgate House, Upper Borough Walls, Bath, United Kingdom
Email: info@e-bmc.co.uk
Website: www.e-bmc.co.uk:
ORCID iD 0000-0002-5500-8590
https://www.researchgate.net/profile/Theresa_Lawrie
Background to this rapid review
Recently a group of expert critical care physicians, called the Front Line COVID-19 Critical
Care Alliance (FLCCC), reviewed the evidence on the effects of ivermectin on SARS-CoV-2
virus and COVID-19 infections.1 They concluded that the evidence on ivermectin
“demonstrates a strong signal of therapeutic efficacy” and recommended that ivermectin is
adopted globally and systematically for the prophylaxis and treatment of COVID-19.1
Ivermectin is an anti-parasitic medication widely used in low- and middle-income countries
to treat parasitic worm infections in adults and children.1,2 Having been used for decades for
this purpose, it is considered extremely safe and effective2,3 and has an increasing list of
indications due to its antiviral and anti-inflammatory properties.4 On the WHO’s Model List
of Essential Medicines it is retained in the form of a 3 mg tablet.5 For parasitic infections in
adults, ivermectin is commonly administered as a single 12 mg oral dose (0.2mg/kg).
The FLCCC review summarizes the findings of 27 studies evaluating ivermectin for
prophylaxis and treatment of COVID-19 infection; however, it does not include meta-
analyses for the majority of outcomes. The FLCCC has called upon national and international
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health care agencies to devote the necessary resources to checking and confirming this
groundbreaking evidence.
Given the urgency of the situation, I undertook this rapid systematic review and meta-
analysis of studies included in the FLCCC paper to validate the FLCCC’s conclusions.
Target audience
This report is aimed primarily at health professionals and policymakers.
Methodology
Study selection, data extraction and outcome measures
I downloaded the available texts of the 27 studies included in the FLCCC summary tables. 1
From this list, I included randomized controlled trials (RCTs) and controlled observational
studies (OCTs), excluding case-control studies and case series due to their higher risk of bias.
I extracted data on the characteristics of the studies, risk of bias and important COVID-19
health outcomes (see Box 1), which I compiled with reference to the FLCCC review tables.
Risk of study bias was assessed using the Cochrane Handbook for Systematic Reviews of
Interventions and the ROBINS-I tools for RCTs and OCTs, respectively.6,7
Box 1. COVID-19 outcome measures
A: Ivermectin treatment versus control
1. Death (primary outcome)
2. Condition improvement, as measured by the study authors
3. Condition deterioration, as measured by the study authors
4. Recovery time, in days
5. Length of hospital stay, in days
6. Admission to hospital (for outpatient treatment)
7. Admission to ICU or requiring ventilation
8. Serious adverse events
B. Ivermectin prophylaxis versus control
1. COVID-19 infection, defined as a positive COVID-19 test with or without
symptoms (primary outcome)
2. Serious adverse events
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Data analysis and evidence quality assessment
I used Review Manager (RevMan) software version 5.4 for meta-analysis.8 For dichotomous
outcomes (most outcomes), I calculated the effect size as a risk ratio (RR) with its 95%
confidence intervals (CIs); for continuous outcomes (i.e. recovery time and length of
hospital stay), I calculated the mean difference (MD) between treatment groups with 95%
CIs. I used the random effects model for all meta-analyses because I anticipated that there
would be clinical heterogeneity in the participant characteristics, control interventions and
the ivermectin dose, frequency and accompanying medicines. I subgrouped studies
according to the severity of COVID-19 in the sample. For the primary outcome (deaths), I
performed two analyses, one with only RCT data, the other with both RCT and OCT data. For
all other outcomes I used both RCT and OCT data because there was generally less RCT data
for these outcomes.
Statistical heterogeneity was assessed by visual inspection of forest plots and by use of the
I2 statistic,9 and I defined substantial statistical heterogeneity as I2 ≥ 60%. Where
heterogeneity was found, I conducted sensitivity analysis by excluding studies assessed as
having a high risk of bias from the analysis. I graded the evidence from meta-analysis based
on a set of established criteria (study design limitations, inconsistency, imprecision,
indirectness and publication bias) using the GRADE approach to judging the quality
(certainty) of the evidence.10 Data extraction, including risk of bias decisions, and grading
were checked by a colleague at the Evidence-based Medicine Consultancy Ltd (see
acknowledgements).
Review findings
Description of studies
Fifteen study reports were included, nine of RCTs and six of OCTs. One RCT (Elgazzar 2020)
reported findings of a prophylaxis study and a treatment study within the same paper and
these were regarded as separate studies. Similarly, one OCT (Carvallo 2020) reported
findings of a pilot study and a further multicentre study and these were treated separately.
Eleven studies were excluded with reasons (see supplementary file). Five of the included
studies involving 2045 participants were of COVID-19 prophylaxis among health care
workers and patient contacts; the remaining 12 involving 1835 participants were of COVID-
19 treatment. Study sample sizes ranged from 24 to 1195 participants and studies were
conducted in Argentina (2), Bangladesh (6), Egypt (3) India (1), Iran (2), Pakistan (1), Spain
(1), and the USA (1) (Table 1). Fifteen studies were at low or moderate risk of bias and two
studies were at high risk of bias. Eight were registered on clinical trial registries; most
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appeared to be self-funded, undertaken by clinicians working in the field not by dedicated
research teams. There were no apparent conflicts of interest.
Table 1. Included study characteristics
Study ID
(refs 12-27)
Country
Design
Sample
size
Risk of bias
COVID-19 treatment studies
Ahmed
2020
Bangladesh
RCT
72
Low
Cepelowicz
Rajter 2020
USA
OCT
280
Low
Chaccour
2020
Spain
RCT
24
Low
Chachar
2020
Pakistan
RCT
50
Moderate
Chowdhury
2020
Bangladesh
RCT
116
Moderate
Elgazzar
2020a
Egypt
RCT
200
Moderate
Mahmud
2020
Bangladesh
RCT
363
Low
Podder
2020
Bangladesh
RCT
62
High
Hashim
2020
Iran
RCT
140
Moderate
Khan 2020
Bangladesh
OCT
248
Moderate
Niaee 2020
Iran
RCT
180
Low
Spoorthi
2020
India
OCT
100
Moderate
COVID-19 prophylaxis studies
Alam 2020
Bangladesh
OCT
118
Low
Carvallo
2020 pilot
Argentina
OCT
229
Moderate
Carvallo
2020
Argentina
OCT
1195
High
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Elgazzar
2020b
Egypt
RCT
200
Moderate
Shouman
2020
Egypt
RCT
303
Moderate
OCT, observational controlled trial; RCT, randomised controlled trial
*Also administered doxycycline.
Note: 0.2 mg/kg is equivalent to giving 12 mg and 0.4 mg/kg is equivalent to giving 24 mg
for a 60 kg person.
Study participant characteristics
The mean age of study participants was between 30 and 40 years old for six studies, 40 and
50 years old for four studies, and 50 to 60 years old for five studies; two studies reported a
median age of participants of 26 and 35 years old, respectively; one study did not report
participant age.
People with co-morbidities (e.g. diabetes mellitus, hypertension, cardiovascular disease,
asthma, obesity) were excluded from three studies and were included in eight studies in
which they occurred at a cumulative frequency ranging from 28% to the vast majority of
participants; co-morbidities were not reported in seven studies. Four studies reported the
proportion of smokers, which ranged from 13% to 30%. In most studies pregnant and
lactating women were excluded from participation, and several studies excluded people
with chronic liver or kidney disease.
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Comparison 1: Ivermectin treatment versus control
Analysis 1.1: Death
Moderate certainty evidence indicates that ivermectin probably reduces deaths by an
average 83% (95% CI, 65% to 92%) compared with no ivermectin treatment (5 RCTs, 1107
participants; RR 0.17, 95% 0.08 to 0.35; risk of death 1.4% versus 8.4% among participants in
this analysis).
Forest plot 1.1.a. RCTs only
A second analysis, which includes RCTs and OCTs can be found below. Findings from this
analysis which included nine studies and 1735 participants are consistent with the above
analysis and suggest a probable reduction in deaths of about 69% on average (RR 0.31, 95%
CI 0.16 to 0.61; risk of death was 3.9% vs 9.9 %), a slightly more modest effect estimate than
the analysis above that includes RCTs only.
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Forest plot 1.1.b. RCTs and OCTs
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Analysis 1.2: Improvement
Data for ‘mild to moderate COVID-19’ and ‘severe’ COVID-19’ subgroups were not pooled
for this outcome because the statistical test for subgroup differences indicates that the
effect size is not the same for these subgroups. Moderate certainty evidence suggests that
ivermectin probably increases the likelihood of people with mild to moderate COVID-19
improving by about 34% (22% to 48%) (5 studies, 743 participants; RR 1.34, 95% CI 1.22 to
1.48; evidence certainty downgraded for study design limitations) compared with no
ivermectin treatment.
For those with severe COVID-19 infection, low certainty evidence suggests that it may
increase the likelihood of improvement by a greater extent than for mild to moderate
infections (1 study, 200 participants, RR 1.88, 95% CI 1.54 to 2.30). This evidence was
downgraded to low certainty because of study design limitations and because it was derived
from a single small study.
Forest plot 1.2.
Note: Ahmed 2020 is a 3 arm study, therefore the control group has been split between its two study comparisons in this analysis.
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Analysis 1.3: Deterioration
Moderate certainty evidence suggests that ivermectin probably reduces the risk of a
person’s condition deteriorating by about 53% (95% CI 23% to 71%) compared with no
ivermectin treatment (5 studies, 1175 participants; RR 0.47, 95% CI 0.29 to 0.77).
Forest plot 1.3.
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Analysis 1.4: Recovery time (clinical), as measured by study authors
For the subgroup of studies evaluating ivermectin as an outpatient treatment for COVID-19
infection, low certainty evidence suggests that ivermectin may reduce recovery time
compared with no ivermectin treatment by about a day (2 studies, 176 participants; MD -
1.06, 95% CI -1.63 to -0.49). Although the effect is consistent across the two studies in this
subgroup, the evidence was downgraded for imprecision
1
and study design limitations.
Evidence on the effect of ivermectin on recovery time among people treated in hospital
(subgroup analysis 1.4.2 and 1.4.3 in the forest plot below) require more data to improve
the certainty of this evidence. One study (subgroup analysis 1.4.3) showed a large treatment
effect favouring the ivermectin group. However, this evidence was graded as very low
certainty as all people with critical illness were allocated to the ivermectin group for ethical
reasons.
Forest plot 1.4.
1
According to the World Health Organization’s standard operating procedure for grading evidence for
guidelines, the total cumulative study population needs to be more than 300 participants for continuous data
when evaluating imprecision.
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Analysis 1.5: Recovery time to a negative PCR test
Evidence for this outcome was graded as very low certainty (2 studies, 186 participants; MD
-1.12, 95% CI -2.58 to 0.35); downgrading was performed twice for imprecision and also
because most of the data were derived from a study only available as pre-print at the time
of writing.
Forest plot 1.5.
Note: Ahmed 2020 is a 3 arm study, therefore the control group has been split between its two study comparisons in this analysis.
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Analysis 1.6: Length of hospital stay
The evidence presented here is based on a sensitivity analysis whereby study data at high
risk of bias (Elgazzar 2020) were excluded pending author query. The resulting low certainty
evidence suggests that ivermectin may reduce the length of hospital stay by about a day in
people with mild to moderate COVID-19 infection (2 studies, participants; MD -1.03, 95% CI
-1.82 to -0.23; downgraded for study design limitations and imprecision).
Forest plot 1.6.
Additional data for this outcome were reported in one randomized (Niaee 2020) and three
observational studies (Cepelowicz Rajter 2020, Khan 2020, Spoorthi 2020). However, these
data were not presented as means and standard deviations, therefore, could not be
included in this meta-analysis. Three of the studies (Khan 2020, Niaee 2020 and Spoorthi
2020) as well as the excluded Elgazzar 2020 data demonstrated reduced hospital stays with
ivermectin, whereas Cepelowicz Rajter 2020 showed no difference.
Outcome 1.7: Admission to hospital (for treated outpatients)
There were no data for this outcome.
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Outcome 1.8. Admission to ICU or requiring ventilation
Low certainty evidence from a single OCT suggests that ivermectin may lead to potentially
large reductions in the number of people with COVID-19 infections requiring ICU admission
(248 participants; RR 0.11, 95% CI 0.01 to 0.80). The evidence for this outcome was
downgraded due to design limitations and imprecision.
Forest plot 1.8
Outcome 1.9: Severe adverse events
These findings are of very low certainty. It is not possible to determine whether the two
adverse events in the Mahmud 2020 study were due to ivermectin or doxycycline; however,
esophagitis (the adverse event reported) is a known adverse effect associated with
doxycycline. Non-severe adverse events were reported in a few studies but these data were
not extracted.
Forest plot 1.9.
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Comparison 2. Ivermectin prophylaxis versus control
Outcome 2.1: COVID-19 infection
The evidence presented here is based on a sensitivity analysis whereby study data at high
risk of bias from one study were excluded
2
. Moderate certainty evidence suggests that
ivermectin prophylaxis among health care workers and COVID-19 contacts probably reduces
the risk of COVID-19 infection by about 88% (4 studies, 851 participants; RR 0.12, 95% CI
0.08 to 0.18; 4.3% vs 34.5% contracted COVID-19). The certainty of this evidence was
downgraded to moderate due to study design limitations (the Shouman 2020 results,
reported on the clinicaltrials.gov website on 27 August 2020, were based on symptoms
rather than a positive COVID-19 test).
Forest plot 2.1
2
The multicentre data from Carvallo 2020 were excluded; pilot study data from Carvallo 2020 are included
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Table 2. Summary of findings
Review outcome
Effect estimate
(95% CI)
Effect certainty
Deaths (RCTs only)
RR 0.17 (0.08 to 0.35)
MODERATE
Deaths (RCTs and OCTs)
RR 0.31 (0.16 to 0.61)
MODERATE
Condition improvement
(mild to moderate COVID-
19)
RR 1.34 (1.22 to 1.48)
MODERATE
Condition improvement
(severe COVID-19)
RR 1.88 (1.54 to 2.30)
LOW
Condition deterioration
RR 0.47 (0.29 to 0.77)
MODERATE
Recovery time (outpatients)
MD -1.06 days (-1.63 to -
0.49 days)
LOW
Recovery time (in-patients
with mild to moderate
COVID-19)
MD -0.99 days (-1.89 to -
0.09)
LOW
Recovery time (in-patients
with mild to critical COVID-
19)
MD -7.29 days (-9.31 to -
5.27)
LOW
Recovery time to negative
PCR test
MD-1.12 days (-2.58 to
0.35)
VERY LOW
Length of hospital stay (mild
to moderate COVID-19)
MD -1.03 days (-1.82 to -
0.23)
LOW
Admission to ICU
RR 0.11 (0.01 to 0.80)
LOW
Prophylaxis outcome
COVID-19 infection
RR 0.12 (0.08 to 0.18)
MODERATE
RR = relative risk; CI = confidence interval; MD = mean difference; ICU = intensive care unit
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Discussion
This review and meta-analysis confirms that ivermectin substantially reduces the risk of a
person dying from COVID-19 by probably somewhere in the region of 65% to 92% according
to RCT data. The uncertainty in the evidence relates to the precise extent of the reduction,
not in the effectiveness of ivermectin itself. Similarly, when ivermectin is used as
prophylaxis among health care workers and contacts, it is clear that ivermectin substantially
reduces COVID-19 infections, probably somewhere in the region of 88% (82% to 92%). Data
from numerous currently active RCTs will help to determine the precise extent of its
protective effect in these at risk groups.
Despite the FLCCC’s strong recommendation that ivermectin should be implemented
globally to save lives from COVID-19, most governments and health professionals still
appear to be unaware of this profoundly effective COVID-19 treatment. Not only is
ivermectin a safe, effective and well-known medicine, at an estimated cost of less than 10
pence per person treated with a 12 mg tablet, it does indeed seem like a miracle drug in the
context of the current global COVID-19 situation.26 Guidance and protocols on using
ivermectin for COVID-19 can be found on the FLCCC website
https://covid19criticalcare.com.
Conclusions
Ivermectin is an essential drug to reduce morbidity and mortality from COVID-19
infection.
Placebo-controlled trials of ivermectin treatment among people with COVID-19
infection are no longer ethical and active placebo-controlled trials should be closed.
Declaration of interests
I am the Director of the Evidence-based Medicine Consultancy Ltd and have no conflicts of
interests to declare. The business of E-BMC Ltd is to conduct independent medical evidence
synthesis to inform clinical practice guidelines.
Funding
Neither I nor E-BMC Ltd have received funding for this work.
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Author statement
I take full responsibility for the scientific integrity of this urgent evidence synthesis. The
evidence derived from the studies included in the FLCCC review is sufficient to support a
strong recommendation on ivermectin for the treatment of COVID-19.
Due to the urgency and imperative to communicate this critical information to health
professionals, and in the context of the probable effect size of ivermectin on COVID-19
deaths revealed by this meta-analysis, additional exploratory analyses (for example looking
at the effect of co-administration of doxycycline) have not been conducted. Neither have I
sought unpublished data from the numerous ongoing trials of ivermectin on clinical trial
registries.
It is my hope that both health professionals and policy makers now respond to this
information with the required urgency, so that critical time in saving lives is not wasted.
Acknowledgements
Many thanks go to the FLCCC for bringing this critical evidence to the attention of health
professionals and authorities, to the individual study investigators and clinicians, and to the
people who have participated in the studies for the greater good of humanity. We all owe
you a debt of gratitude.
With regard to this report, I gratefully acknowledge the assistance of Dr Therese Dowswell,
Dr Ewelina Rogozinska, Mark Lawrie and Vicky Powell in its preparation. Dr Dowswell
checked the data extraction and evidence grading, Dr Rogozinska commented on the draft
manuscript, Mark Lawrie provided administrative support and Vicky Powell proof read the
manuscript.
Versions
v1.0
Urgent preliminary report
03/01/2021
v1.1
Typo corrections
04/01/2021
v1.2
Feedback incorporated Forest 1.5 SD for Chowdhury
corrected; edits to summary of findings table; second forest
plot for death (RCT’s and OCT’s) moved from appendix to page
7.
06/01/2021
V1.2 6th January 2021
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Appendix
Funnel plot for the primary outcome analysis 1.1.b. (Death) including RCTs and OCTs
... The incubation period is usually around 15 days, but the reported range is 0-24 days (Bai et al., 2020). Cytokine storm is associated with severity and mortality in patients with COVID-19 (Hu et al., 2021;Kim et al., 2021). It can be argued that loss of smell and taste can predict COVID-19 disease, as it is one of the effects that the coronavirus causes in the body [4]. ...
... Ivermectin decreases morbidity and mortality from COVID-19 infection [25]. Ivermectin may be a useful model for additional therapy against coronavirus disease, leading to reduced MHV viral load and disease in mice [26]. ...
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Purpose: Ivermectin is a broad-spectrum antiparasitic and an effective drug to treat COVID-19. In this article, we looked at the effects of ivermectin on coronavirus and its patients in three ways. We have discussed and organized other previously discovered potential therapies and reviewed them in Table 2 and in the last section. Methods: We searched for articles on MedRxiv, PubMed, Google Scholar, MEDLINE, EMBASE uses the appropriate search terms. ClinicalTrials.gov was searched for available clinical trials evaluating the effectiveness of ivermectin. We also use EU clinical trial registry data and ANZ registry data for clinical trials. Also, we performed our methods in 4 stages: Identifying studies, Selection of Studies, Collating Studies, Reporting results. Results: Results are variable. Some studies have shown the effectiveness of ivermectin, others have not. Furthermore, some studies show that a combination of ivermectin with other drugs is useful. Conclusion: Overall, we believe the reason ivermectin is useful is that it goes back to its origin, which is soil. Our theory and hypothesis is that if the coronavirus, created by man or by nature, can generally be treated with nature, that is, the soil. The interesting thing is that today we know that ivermectin is effective in the fight against the coronavirus. In fact, other drugs like teicoplanin, cyclosporine and rapamycin that are effective against the coronavirus have come from the soil. We hope that this article has been able to take a step in finding a corona drug, InshaAllah.
... The incubation period is usually around 15 days, but the reported range is 0-24 days (Bai et al., 2020). Cytokine storm is associated with severity and mortality in patients with COVID-19 (Hu et al., 2021;Kim et al., 2021). It can be argued that loss of smell and taste can predict COVID-19 disease, as it is one of the effects that the coronavirus causes in the body [4]. ...
... Ivermectin decreases morbidity and mortality from COVID-19 infection [25]. Ivermectin may be a useful model for additional therapy against coronavirus disease, leading to reduced MHV viral load and disease in mice [26]. ...
Full-text available
Preprint
Purpose: Ivermectin is a broad-spectrum antiparasitic and an effective drug to treat COVID-19. In this article, we looked at the effects of ivermectin on coronavirus and its patients in three ways. We have discussed and organized other previously discovered potential therapies and reviewed them in Table 2 and in the last section. Methods: We searched for articles on MedRxiv, PubMed, Google Scholar, MEDLINE, EMBASE uses the appropriate search terms. ClinicalTrials.gov was searched for available clinical trials evaluating the effectiveness of ivermectin. We also use EU clinical trial registry data and ANZ registry data for clinical trials. Also, we performed our methods in 4 stages: Identifying studies, Selection of Studies, Collating Studies, Reporting results.Results: Results are variable. Some studies have shown the effectiveness of ivermectin, others have not. Furthermore, some studies show that a combination of ivermectin with other drugs is useful. Conclusion: Overall, we believe the reason ivermectin is useful is that it goes back to its origin, which is soil. Our theory and hypothesis is that if the coronavirus, created by man or by nature, can generally be treated with nature, that is, the soil. The interesting thing is that today we know that ivermectin is effective in the fight against the coronavirus. In fact, other drugs like teicoplanin, cyclosporine and rapamycin that are effective against the coronavirus have come from the soil. We hope that this article has been able to take a step in finding a corona drug, InshaAllah.
... The incubation period is usually around 15 days, but the reported range is 0-24 days (Bai et al., 2020). Cytokine storm is associated with severity and mortality in patients with COVID-19 (Hu et al., 2021;Kim et al., 2021). It can be argued that loss of smell and taste can predict COVID-19 disease, as it is one of the effects that the coronavirus causes in the body [4]. ...
... Ivermectin decreases morbidity and mortality from COVID-19 infection [25]. Ivermectin may be a useful model for additional therapy against coronavirus disease, leading to reduced MHV viral load and disease in mice [26]. ...
Full-text available
Preprint
Purpose: Ivermectin is a broad-spectrum antiparasitic and an effective drug to treat COVID-19. In this article, we looked at the effects of ivermectin on coronavirus and its patients in three ways. We have discussed and organized other previously discovered potential therapies and reviewed them in Table 2 and in the last section. Methods: We searched for articles on MedRxiv, PubMed, Google Scholar, MEDLINE, EMBASE uses the appropriate search terms. ClinicalTrials.gov was searched for available clinical trials evaluating the effectiveness of ivermectin. We also use EU clinical trial registry data and ANZ registry data for clinical trials. Also, we performed our methods in 4 stages: Identifying studies, Selection of Studies, Collating Studies, Reporting results.Results: Results are variable. Some studies have shown the effectiveness of ivermectin, others have not. Furthermore, some studies show that a combination of ivermectin with other drugs is useful. Conclusion: Overall, we believe the reason ivermectin is useful is that it goes back to its origin, which is soil. Our theory and hypothesis is that if the coronavirus, created by man or by nature, can generally be treated with nature, that is, the soil. The interesting thing is that today we know that ivermectin is effective in the fight against the coronavirus. In fact, other drugs like teicoplanin, cyclosporine and rapamycin that are effective against the coronavirus have come from the soil. We hope that this article has been able to take a step in finding a corona drug, InshaAllah.
... The incubation period is usually around 15 days, but the reported range is 0-24 days (Bai et al., 2020). Cytokine storm is associated with severity and mortality in patients with COVID-19 (Hu et al., 2021;Kim et al., 2021). It can be argued that loss of smell and taste can predict COVID-19 disease, as it is one of the effects that the coronavirus causes in the body [4]. ...
... Ivermectin decreases morbidity and mortality from COVID-19 infection [25]. Ivermectin may be a useful model for additional therapy against coronavirus disease, leading to reduced MHV viral load and disease in mice [26]. ...
Full-text available
Preprint
Purpose: Ivermectin is a broad-spectrum antiparasitic and an effective drug to treat COVID-19. In this article, we looked at the effects of ivermectin on coronavirus and its patients in three ways. We have discussed and organized other previously discovered potential therapies and reviewed them in Table 2 and in the last section. Methods: We searched for articles on MedRxiv, PubMed, Google Scholar, MEDLINE, EMBASE uses the appropriate search terms. ClinicalTrials.gov was searched for available clinical trials evaluating the effectiveness of ivermectin. We also use EU clinical trial registry data and ANZ registry data for clinical trials. Also, we performed our methods in 4 stages: Identifying studies, Selection of Studies, Collating Studies, Reporting results.Results: Results are variable. Some studies have shown the effectiveness of ivermectin, others have not. Furthermore, some studies show that a combination of ivermectin with other drugs is useful. Conclusion: Overall, we believe the reason ivermectin is useful is that it goes back to its origin, which is soil. Our theory and hypothesis is that if the coronavirus, created by man or by nature, can generally be treated with nature, that is, the soil. The interesting thing is that today we know that ivermectin is effective in the fight against the coronavirus. In fact, other drugs like teicoplanin, cyclosporine and rapamycin that are effective against the coronavirus have come from the soil. We hope that this article has been able to take a step in finding a corona drug, InshaAllah.
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Article
Highlights • Ivermectin, an FDA-approved anti-parasitic agent, was found to be an inhibitor of SARS-CoV-2 replication in the laboratory. • Ivermectin may be effective for the treatment of early-onset mild Covid-19 in adult patients. Early viral clearance of SARS-CoV-2 was observed in treated patients. J o u r n a l P r e-p r o o f • Remission of fever, cough and sore throat did not differ between those treated with or without ivermectin. No severe adverse event observed with the longer duration of ivermectin use. • Larger trials will be needed to confirm these preliminary findings. Abstract Ivermectin, an FDA-approved anti-parasitic agent, was found in vitro to inhibit SARS-CoV-2 replication. To determine the rapidity of viral clearance and safety of ivermectin among adult SARS-CoV-2 patients we conducted a randomized, double-blind, placebo-controlled trial of oral ivermectin alone (12mg once daily for 5 days) or in combination with doxycycline (12mg ivermectin single dose and 200mg stat doxycycline day-1 followed by 100mg 12hrly for next 4 days) compared with placebo among 72 hospitalized patients in Dhaka, Bangladesh. Clinical symptoms of fever, cough and sore throat were comparable among the three treatment arms. Virological clearance was earlier in the 5-day ivermectin treatment arm versus the placebo group (9.7 days vs. 12.7 days; P =0.02); but not with the ivermectin + doxycycline arm (11.5 days; P=0.27). There were no severe adverse drug events recorded in the study. A 5-day course of ivermectin was found to be safe and effective in treating mild COVID-19 adult patients. Larger trials will be needed to confirm these preliminary findings.
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Objectives COVID-19 patients suffer from the lack of curative therapy. Hence, there is an urgent need to try repurposed old drugs on COVID-19. Methods Randomized controlled study on 70 COVID-19 patients (48 mild-moderate, 11 severe, and 11 critical patients) treated with 200ug/kg PO of Ivermectin per day for 2-3 days along with 100mg PO doxycycline twice per day for 5-10 days plus standard therapy; the second arm is 70 COVID-19 patients (48 mild-moderate and 22 severe and zero critical patients) on standard therapy. The time to recovery, the progression of the disease, and the mortality rate were the outcome-assessing parameters. Results among all patients and among severe patients, 3/70 (4.28%) and 1/11 (9%), respectively progressed to a more advanced stage of the disease in the Ivermectin-Doxycycline group versus 7/70 (10%) and 7/22 (31.81%), respectively in the control group (P>0.05). The mortality rate was 0/48 (0%), 0/11 (0%), and 2/11 (18.2%) in mild-moderate, severe, and critical COVID-19 patients, respectively in Ivermectin-Doxycycline group versus 0/48 (0%), and 6/22 (27.27%) in mild-moderate and severe COVID-19 patients, respectively in standard therapy group (p=0.052). Moreover, the mean time to recovery was 6.34, 20.27, and 24.13 days in mild-moderate, severe, and critical COVID-19 patients, respectively in Ivermectin-Doxycycline group versus 13.66 and 24.25 days in mild-moderate and severe COVID-19 patients, respectively in standard therapy group (P<0.01). Conclusions Ivermectin with doxycycline reduced the time to recovery and the percentage of patients who progress to more advanced stage of disease; in addition, Ivermectin with doxycycline reduced mortality rate in severe patients from 22.72% to 0%; however, 18.2% of critically ill patients died with Ivermectin and doxycycline therapy. Taken together, the earlier administered Ivermectin with doxycycline, the higher rate of successful therapy.
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Background Ivermectin was shown to inhibit severe acute respiratory syndrome coronavirus 2 replication in vitro, which has led to off-label use, but clinical efficacy has not been described previously. Research Question Does ivermectin benefit hospitalized coronavirus disease 2019 (COVID-19) patients? Study Design and Methods Charts of consecutive patients hospitalized at four Broward Health hospitals in Florida with confirmed COVID-19 between March 15 and May 11, 2020, treated with or without ivermectin were reviewed. Hospital ivermectin dosing guidelines were provided, but treatment decisions were at the treating physician’s discretion. The primary outcome was all-cause in-hospital mortality. Secondary outcomes included mortality in patients with severe pulmonary involvement, extubation rates for mechanically ventilated patients, and length of stay. Severe pulmonary involvement was defined as need for Fio2 ≥ 50%, noninvasive ventilation, or invasive ventilation at study entry. Logistic regression and propensity score matching were used to adjust for confounders. Results Two hundred eighty patients, 173 treated with ivermectin and 107 without ivermectin, were reviewed. Most patients in both groups also received hydroxychloroquine, azithromycin, or both. Univariate analysis showed lower mortality in the ivermectin group (15.0% vs 25.2%; OR, 0.52; 95% CI, 0.29-0.96; P = .03). Mortality also was lower among ivermectin-treated patients with severe pulmonary involvement (38.8% vs 80.7%; OR, 0.15; 95% CI, 0.05-0.47; P = .001). No significant differences were found in extubation rates (36.1% vs 15.4%; OR, 3.11; 95% CI, 0.88-11.00; P = .07) or length of stay. After multivariate adjustment for confounders and mortality risks, the mortality difference remained significant (OR, 0.27; 95% CI, 0.09-0.80; P = .03). One hundred ninety-six patients were included in the propensity-matched cohort. Mortality was significantly lower in the ivermectin group (13.3% vs 24.5%; OR, 0.47; 95% CI, 0.22-0.99; P < .05), an 11.2% (95% CI, 0.38%-22.1%) absolute risk reduction, with a number needed to treat of 8.9 (95% CI, 4.5-263). Interpretation Ivermectin treatment was associated with lower mortality during treatment of COVID-19, especially in patients with severe pulmonary involvement. Randomized controlled trials are needed to confirm these findings.
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Article
Background and objectives: Various existing non-antiviral drugs are being used to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based mostly on existing data from previous coronavirus outbreaks. Ivermectin is one of such agents being widely used to treat early-stage of COVID-19. This study evaluated the outcome of ivermectin treated mild to moderate COVID-19 cases compared to usual care. Methods: This open-label randomised controlled study was conducted at a sub-district (Upazila) health complex from 1st May 2020 to the end of July 2020. Consecutive RT-PCR positive eligible COVID-19 patients were randomised into control and intervention arms. In the intervention arm, ivermectin 200 micrograms/kg single dose was administered orally in addition to usual care and was followed up till recovery. Repeat RT-PCR was done on day ten since the first positive result. The end point with regard to treatment outcome was time required for the resolution of symptoms from the onset of the symptoms and following enrollement in the study. Results: A total of 62 mild to moderate COVID-19 patients were enrolled in the study. There were 30 patients in the control arm and 32 patients in the intervention arm. Total recovery time from the onset of symptoms to complete resolution of symptoms of the patients in the intervention arm was 10.09 ± 3.236 days, compared to 11.50 ± 5.32 days in the control arm (95% CI -0.860,3.627, p>. 05) and was not significantly different. The mean recovery time after enrolment in the intervention arm was 5.31 ± 2.48 days, which also did not differ significantly from the control arm of 6.33 ± 4.23 days (95% CI – 0.766, 2.808, p> 0.05). Results of negative repeat RT- PCR were not significantly different between control and intervention arms (control 90% vs intervention 95%, p>.05). Conclusion: Ivermectin had no beneficial effect on the disease course over usual care in mild to moderate COVID-19 cases.
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Background: To date no effective therapy has been demonstrated for COVID-19. In vitro, studies indicated that ivermectin (IVM) has antiviral effect. Objectives: To assess the effectiveness of ivermectin (IVM) as add-on therapy to hydroxychloroquine (HCQ) and azithromycin (AZT) in treatment of COVID-19. Methods: This Pilot clinical trial conducted on hospitalized adult patients with mild to moderate COVID-19 diagnosed according to WHO interim guidance. Sixteen Patients received a single dose of IVM 200Mcg /kg on admission day as add on therapy to hydroxychloroquine ( HCQ)and Azithromycin (AZT) and were compared with 71 controls received HCQ and AZT matched in age, gender, clinical features, and comorbidities. The primary outcome was percentage of cured patients, defined as symptoms free to be discharged from the hospital and 2 consecutive negative PCR test from nasopharyngeal swabs at least 24 hours apart. The secondary outcomes were time to cure in both groups and evaluated by measuring time from admission of the patient to the hospital till discharge. Results: Of 87 patients included in the study,t he mean age ± SD (range) of patients in the IVM group was similar to controls [44.87 ± 10.64 (28-60) vs 45.23 ± 18.47 (8-80) years, p=0.78] Majority of patients in both groups were male but statistically not significant [11(69%) versus 52 (73%), with male: female ratio 2.21 versus 2.7-, p=0.72) All the patients of IVM group were cured compared with the controls [ 16 (100 %) vs 69 (97.2 %)]. Two patients died in the controls. The mean time to stay in the hospital was significantly lower in IVM group compared with the controls (7.62 ±2.75 versus 13.22 ±.90 days, p=0.00005, effect size= 0.82). No adverse events were observed Conclusions : Add-on use of IVM to HCQ and AZT had better effectiveness, shorter hospital stay, and relatively safe compared with controls. however, a larger prospective study with longer follow up may be needed to validate these results.
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Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I ("Risk Of Bias In Non-randomised Studies-of Interventions"), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.
Article
Objective: To evaluate different doses of ivermectin in adult patients with mild COVID-19 and to evaluate the effect of ivermectin on mortality and clinical consequences. Methods: A randomized, double-blind, placebo-controlled, multicenter clinical trial was performed at five hospitals. A total of 180 mild hospitalized patients with COVID-19 confirmed by PCR or chest image tests were enrolled and allocated to six arms including hydroxychloroquine 200 mg twice per day, placebo plus hydroxychloroquine 200 mg twice per day, single dose ivermectin (200 μg/kg), three low interval doses of ivermectin (200, 200, 200 μg/kg), single dose ivermectin (400 μg/kg), and three high interval doses of ivermectin (400, 200, 200 μg/kg). The primary endpoint of this trial was all-cause of mortality or clinical recovery. The radiographic findings, hospitalization and low O2 saturation duration, and hematological variables of blood samples were analyzed. Results: A total of 16.7% (5/30) and 20.0% (6/30) patients died in arms treated with hydroxychloroquine 200 mg twice per day and placebo plus hydroxychloroquine 200 mg twice per day, respectively, and a reduction in mortality rate in patients receiving ivermectin treatment to 0%, 10%, 0% and 3.3% for arms 1-4 were observed. Risk of mortality was also decreased about 15% in the ivermectin treated arms. Conclusions: Ivermectin as an adjunct reduces the rate of mortality, time of low O2 saturation, and duration of hospitalization in adult COVID-19 patients. The improvement of other clinical parameters shows that ivermectin, with a wide margin of safety, had a high therapeutic effect on COVID-19.
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Although the broad-spectrum anti-parasitic effects of the avermectin derivative ivermectin are well documented, its anti-inflammatory activity has only recently been demonstrated. For over 25 years, ivermectin has been used to treat parasitic infections in mammals, with a good safety profile that may be attributed to its high affinity to invertebrate neuronal ion channels and its inability to cross the blood-brain barrier in humans and other mammals. Numerous studies report low rates of adverse events, as an oral treatment for parasitic infections, scabies and head lice. Ivermectin has been used off-label to treat diseases associated with Demodex mites, such as blepharitis and demodicidosis. New evidence has linked Demodex mites to rosacea, a chronic inflammatory disease. Ivermectin has recently received FDA and EU approval for the treatment of adult patients with inflammatory lesions of rosacea, a disease in which this agent has been shown to be well tolerated. After more than 25 years of use, ivermectin continues to provide a high margin of safety for a growing number of indications based on its anti-parasitic and anti-inflammatory activities.
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Currently there are no approved vaccines or specific therapies to prevent or treat Zika virus (ZIKV) infection. We interrogated a library of FDA-approved drugs for their ability to block infection of human HuH-7 cells by a newly isolated ZIKV strain (ZIKV MEX_I_7). More than 20 out of 774 tested compounds decreased ZIKV infection in our in vitro screening assay. Selected compounds were further validated for inhibition of ZIKV infection in human cervical, placental, and neural stem cell lines, as well as primary human amnion cells. Established anti-flaviviral drugs (e.g., bortezomib and mycophenolic acid) and others that had no previously known antiviral activity (e.g., daptomycin) were identified as inhibitors of ZIKV infection. Several drugs reduced ZIKV infection across multiple cell types. This study identifies drugs that could be tested in clinical studies of ZIKV infection and provides a resource of small molecules to study ZIKV pathogenesis.