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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.

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This is a rapid review and meta-analysis of available comparative studies on ivermectin showing that ivermectin will probably substantially reduce the risk of death in people with COVID-19 and that it will probably substantially reduce the risk of COVID-19 infection among health care workers and contacts.
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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.
Theresa 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
2
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
Data analysis and evidence quality assessment
3
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 13 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
4
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
5
Elgazzar
2020b
Egypt
OCT
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.
6
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 second analysis, which includes OCTs can be found in the Appendix at the end of this
document. Findings from the latter 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.
7
Analysis 1.2: Condition 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.
8
Analysis 1.3: Condition 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.
9
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) similarly require more data to
improve the certainty of this evidence.
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.
10
Analysis 1.5: Recovery time to a negative PCR test
Low certainty evidence from two studies among outpatients suggests that ivermectin may
reduce the time to a negative PCR test by about two days compared with no ivermectin
treatment (2 studies, 186 participants; MD -1.88, 95% CI -3.62 to -0.15). The evidence was
downgraded for imprecision and study design limitations.
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.
11
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.
12
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.
13
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
14
Table 2. Summary of findings
Review outcome
Effect estimate
(95% CI)
Effect certainty
Deaths
RR 0.17 (0.08 to 0.35)
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 to negative
PCR test
MD-1.09 days (-2.55 to
0.37)
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
15
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%. The only
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.
16
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.
17
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Appendix
Forest plot for the primary outcome (deaths) including RCTs and OCTs with accompanying
funnel plot.
21

Supplementary resource (1)

... Finally, Kow et al [13] evaluated 6 RCTs, 5 from Asia and none from Latin America. Other systematic reviews or narrative reviews of IVM effects have been disseminated only as preprints [14][15][16] or on Web sites [17][18][19]. We conducted a systematic review and metaanalysis to evaluate treatment effects of IVM on clinical outcomes and adverse events (AEs) in people with COVID-19. ...
... In consequence, they were subject to selection bias, which may explain the reported effects of IVM on mortality rates. Several Web sites published systematic reviews and metaanalyses about IVM in patients with COVID-19 with unclear or absent details on methods and reporting guidelines [17][18][19] (see Supplementary Table 2). These Web sites did not include protocol registration and have relevant omissions, such as inclusion criteria [19], searched databases [18,19], study quality assessment [17,19], meta-analysis methods [19], and the definition of heterogeneity [17,19]. ...
... Several Web sites published systematic reviews and metaanalyses about IVM in patients with COVID-19 with unclear or absent details on methods and reporting guidelines [17][18][19] (see Supplementary Table 2). These Web sites did not include protocol registration and have relevant omissions, such as inclusion criteria [19], searched databases [18,19], study quality assessment [17,19], meta-analysis methods [19], and the definition of heterogeneity [17,19]. Arbitrarily broad inclusion criteria (ie, studies submitted directly to the Web sites, more preprints than peer-reviewed studies) led to a high number of RCTs and participants. ...
Article
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Background We systematically assessed benefits and harms of the use of ivermectin (IVM) in COVID-19 patients. Methods Published and preprint randomized controlled trials (RCTs) assessing IVM effects on COVID-19 adult patients were searched until March 22, 2021 in five engines. Primary outcomes were all-cause mortality, length of stay (LOS), and adverse events (AE). Secondary outcomes included viral clearance and severe AEs. Risk of bias (RoB) was evaluated using Cochrane RoB 2·0 tool. Inverse variance random effect meta-analyses were performed. with quality of evidence (QoE) evaluated using GRADE methodology. Results Ten RCTs (n=1173) were included. Controls were standard of care [SOC] in five RCTs and placebo in five RCTs. COVID-19 disease severity was mild in 8 RCTs, moderate in one RCT, and mild and moderate in one RCT. IVM did not reduce all-cause mortality vs. controls (RR 0.37, 95%CI 0.12 to 1.13, very low QoE) or LOS vs. controls (MD 0.72 days, 95%CI −0.86 to 2.29, very low QoE). AEs, severe AE and viral clearance were similar between IVM and controls (all outcomes: low QoE). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality in three RCTs at high RoB was reduced with IVM. Conclusions In comparison to SOC or placebo, IVM did not reduce all-cause mortality, length of stay or viral clearance in RCTs in COVID-19 patients with mostly mild disease. IVM did not have an effect on AEs or severe AEs. IVM is not a viable option to treat COVID-19 patients.
... Ivermectin is currently approved by the Food and Drug Administration (FDA) to treat people with intestinal strongyloidiasis and onchocerciasis. The European Medicines Agency [7] 16] or only presented on websites [17][18][19]. ...
... Several websites published systematic reviews and meta-analyses about IVM in COVID-19 patients with unclear or absent methodology and reporting guidelines [17][18][19] ( Table S2). These websites did not include protocol registration and have relevant omissions such as inclusion criteria [19], databases searched [18,19], quality assessment of the included studies [17,19], methods of meta-analysis [19], and definition of heterogeneity [17,19]. ...
... Several websites published systematic reviews and meta-analyses about IVM in COVID-19 patients with unclear or absent methodology and reporting guidelines [17][18][19] ( Table S2). These websites did not include protocol registration and have relevant omissions such as inclusion criteria [19], databases searched [18,19], quality assessment of the included studies [17,19], methods of meta-analysis [19], and definition of heterogeneity [17,19]. ...
Preprint
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Background We systematically assessed benefits and harms of the use of ivermectin (IVM) in COVID-19 patients. Methods Published and preprint randomized controlled trials (RCTs) assessing IVM effects on COVID-19 adult patients were searched until March 15, 2021 in five engines. Primary outcomes were all-cause mortality, length of stay (LOS), and adverse events (AE). Secondary outcomes included viral clearance and severe AEs. We evaluated risk of bias (RoB) using the Cochrane RoB 2·0 tool. Inverse variance random effect meta-analyses were performed with quality of evidence (QoE) evaluated using GRADE methodology. Subgroup analyses by severity of disease and RoB, and sensitivity analyses by time of follow-up were conducted. Results Ten RCTs (n=1173) were included. Controls were standard of care [SOC] in five RCTs and placebo in five RCTs. RCTs sample size ranged from 24 to 398 patients, mean age from 26 to 56 years-old, and severity of COVID-19 disease was mild in 8 RCTs, moderate in one RCT, and mild and moderate in one RCT. IVM did not reduce all-cause mortality vs. controls (RR 0.37, 95%CI 0.12 to 1.13, very low QoE). IVM did not reduce LOS vs. controls (MD 0.72 days, 95%CI -0.86 to 2.29, very low QoE). AEs, severe AE and viral clearance were similar between IVM and controls (low QoE for these three outcomes). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality in three RCTs at high RoB was reduced with IVM. Sensitivity analyses excluding RCTs with follow up <21 days showed no difference in all-cause mortality. Conclusions In comparison to SOC or placebo, IVM did not reduce all-cause mortality, length of stay or viral clearance in RCTs in COVID-19 patients with mostly mild disease. IVM did not have effect on AEs or SAEs. IVM is not a viable option to treat COVID-19 patients.
... A weakness of this study is the lack of a concomitantly enrolled control arm. However, given the potential fatal outcomes Tess Lawrie et al. indicated [41] 'it is no longer ethical to approve the use of a control arm as so many profoundly ill patients in the control arm would die', as did our two subjects who declined treatment [42]. Hence our study has made use of the ECT or 'synthetic' control arm which has enabled us to make matched age and comorbidity comparisons. ...
... The copyright holder for this preprint this version posted July 7, 2021. ; synthetic arms and reject trials that include in a COVID-19 trial a control arm as published by Lawrie [41]. ...
Preprint
Ivermectin is a safe, inexpensive and effective early COVID-19 treatment validated in 20+ RCTs. Having developed combination therapies for Helicobacter pylori , we tested various COVID-19 combinations and describe the most effective. In 24 consecutive COVID-19 subjects with high risk features, hypoxia and untreated moderate-severe symptoms averaging 9 days, we trialed this novel combination comprising ivermectin, doxycycline, zinc, and Vitamins D and C. It was highly effective. All subjects resolved symptoms in 11 days on average, and oxygen saturation improved in 24hrs (87.4% to 93.1%, p =0.001). Hospitalizations and deaths were significantly fewer ( p <0.002 or 0.05, respectively) than in background-matched controls from the CDC database. Triple combination therapy is safe and effective even in moderate-severe patients with hypoxia treated in the outpatient setting. Trial Registration N/A, see methods.
... Kory introduced the concept of disinformation to describe the practices of, among others, the WHO. He noted the converging expert opinions from the UK (the BIRD group [222]; [15]), Japan [2], UNITAID/WHO [16] and Spain, in contrast to the opposing recommendations issued by agencies including the European Medicine Agency (EMA), SAHPRA and CADTH. He said the FLCCC had tried to pursue data-based arguments with these organizations but it had been futile. ...
... Syed described five mechanisms of action of ivermectin. Lawrie described the principles of assessment of research evidence, the role of systematic reviews, details of the meta-analyses carried out by the BIRD group [222]; [15] and issues with WHO's meta-analysis. Lawrie referred to the Hippocratic oath and the Helsinki Declaration as fundamental rights of clinicians, adding that BIRD membership was intended for doctors in need of peer support. ...
Preprint
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Second part of the timeline covering a period from April 2021 to June 2021 *** Topics: WHO's role and its funding, Gavi, COVAX, Trusted News Initiative, International Fact-Checking Network, the role of private philantrophy, Frontiers issue, comparison to the H1N1 pandemic, new treatment protocols, causal modeling. *** Other parts: *** Part 0: https://www.researchgate.net/publication/348077948 *** Part 1: https://doi.org/10.13140/RG.2.2.13705.36966 *** Part 3: https://doi.org/10.13140/RG.2.2.23081.72805 *** Part 4: https://doi.org/10.13140/RG.2.2.26000.53767 *** Part 5: https://doi.org/10.13140/RG.2.2.35015.16807 *** Additional notes (Feb-Apr 2022): https://doi.org/10.13140/RG.2.2.24356.55682 ***
... On January 3, Lawrie et al. published a preprint of a rapid review and meta-analysis of seven ivermectin trials, indicating a mortality relative risk RR 0.17 (0.18-0.35) and prophylaxis cases RR 0.12 (0.08-0.18) [234]; [235]. Also on January 3, Kaur et al. published a review including results of molecular dynamics simulations [236]. ...
Preprint
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First part part of the timeline covering a period from April 2020 to March 2021 (this is an extended version of an earlier preprint written on March 24, 2021. Changes: Abstract, Introduction, April 26, September 25, December 7, February 9, March 15, from March 22 to March 31, Discussion) *** Other parts: Part 0: https://www.researchgate.net/publication/348077948 *** *** Part 2: https://doi.org/10.13140/RG.2.2.16973.36326 *** Part 3: https://doi.org/10.13140/RG.2.2.23081.72805 *** Part 4: https://doi.org/10.13140/RG.2.2.26000.53767 *** Part 5: https://doi.org/10.13140/RG.2.2.35015.16807 *** Additional notes (Feb-Apr 2022): https://doi.org/10.13140/RG.2.2.24356.55682 ***
... [ [223][224][225] Lopinavir/ritonavir Inhibition of 3CL pro Probably ineffective [226] Ivermectin Inhibition of the IMP α/β receptor responsible for viral protein transmission into host cell nucleus Inhibition of LPS-induced inflammation Inconclusive [227][228][229][230][231][232][233][234] Ribavirin Inhibition of viral RNA synthesis / mRNA capping Unrealistic dosing requirement [235] Favipiravir Inhibition of RdRp Unrealistic dosing requirement [236][237][238] Umifenovir Impeding trimerization of SARS-CoV-2 S-protein Probably ineffective [239] Zinc Inhibition of RdRp Uncertain [240] Anticoagulants LMWH (e.g. Nadroparin) ...
Article
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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID-19 cases are characterised by a mild, self-limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi-organ failure (MOF). Progression of COVID-19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS-CoV-2 infection and contribute to organspecific tissue damage. In this respect, dissecting currently available knowledge of COVID-19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology, but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune-mediated pathways during SARS-CoV-2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID-19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence-based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID-19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID-19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID-19 and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines.
... Evidence for this framework is derived from E-BMC Ltd's rapid review and metaanalysis. (11) The rapid review included randomized controlled trials (RCTs) and controlled observational studies (OCTs) included in the FLCCC literature review, (10) but due to their higher risk of bias, excluded case-control studies and case series. ...
Technical Report
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This is the draft evidence to decision (EtD) framework on ivermectin to prevent and treat Covid-19 infection for the British online meeting of clinical experts and other stakeholders to be held on the 13th January 2021. The aim is to assess the evidence on effectiveness, resource use, equity, acceptability, and feasibility of using ivermectin for Covid-19 and develop a recommendation/s on its use. Feel free to use this framework in other country contexts.
Preprint
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Ivermectin reduces risk for COVID-19 with very high confidence for mortality, ventilation, ICU admission, hospitalization, progression, recovery, cases, viral clearance, and in pooled analysis. We show traditional outcome specific analyses and combined evidence from all studies, incorporating treatment delay, a primary confounding factor in COVID-19 studies. Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for 42 treatments. 83 ivermectin COVID-19 controlled studies, 34 RCTs 63% improvement for early treatment, R 0.37 (0.29-0.48] Probability results from ineffective treatment (since 25 Mar 2021): under 1 in 1 billion @ME: Licensing & copy-editing suggestions, RG u/l. @CA: Everything else.
Preprint
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This is an outdated version of the first part of the timeline. Please see current versions *** Part 0: https://www.researchgate.net/publication/348077948 *** Part 1: https://doi.org/10.13140/RG.2.2.13705.36966 *** Part 2: https://doi.org/10.13140/RG.2.2.16973.36326 *** Part 3: https://doi.org/10.13140/RG.2.2.23081.72805 *** Part 4: https://doi.org/10.13140/RG.2.2.26000.53767 *** Part 5: https://doi.org/10.13140/RG.2.2.35015.16807 *** Additional notes (Feb-Apr 2022): https://doi.org/10.13140/RG.2.2.24356.55682 ***
Article
The global number of deaths due to COVID-19 is almost at the two million mark, with over 35 000 deaths in South Africa. Although there are hopes of a safe and effective vaccination programme, the increasing number of COVID-19 cases in the country is putting a significant strain on the healthcare system. Ivermectin, an antiparasitic drug, has been widely published on social media platforms and news outlets as a so-called miracle drug for the treatment of COVID-19. Ivermectin is not registered in SA as a drug for human use, but rather as a veterinary and agricultural product. Currently, from a small number of randomised controlled trials (RCTs), there does seem to be a signal of evidence for the use of ivermectin in the management of COVID-19. Pharmacists must, however, remain cognisant of their ethical responsibilities as well as the applicable regulations that prohibit the procurement and dispensing of any unregistered medicine.
Article
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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.
Article
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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.
Article
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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.
Thesis
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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.
Article
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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.
Article
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.
Article
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.