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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
Ivermectin dose and
frequency*
Risk of bias
COVID-19 treatment studies
Ahmed
2020
Bangladesh
RCT
72
12mg x1 or x5 (3
arms)*
Low
Cepelowicz
Rajter 2020
USA
OCT
280
0.2mg/kg x 1 or 2
Low
Chaccour
2020
Spain
RCT
24
0.4mg/kg x 1
Low
Chachar
2020
Pakistan
RCT
50
12mg at 0, 12, and 24
hours
Moderate
Chowdhury
2020
Bangladesh
RCT
116
0.2mg/kg x1*
Moderate
Elgazzar
2020a
Egypt
RCT
200
0.4mg/kg daily x4
Moderate
Mahmud
2020
Bangladesh
RCT
363
12mg x 1*
Low
Podder
2020
Bangladesh
RCT
62
0.2mg/kg x1
High
Hashim
2020
Iran
RCT
140
0.2mg/kg x 2 days*
Some had a 3rd dose a
week later
Moderate
Khan 2020
Bangladesh
OCT
248
12mg x 1
Moderate
Niaee 2020
Iran
RCT
180
0.2mg/kg x 1 and
others (6 arms)
Low
Spoorthi
2020
India
OCT
100
0.2mg/kg x 1*
Moderate
COVID-19 prophylaxis studies
Alam 2020
Bangladesh
OCT
118
12mg tab monthly x4
Low
Carvallo
2020 pilot
Argentina
OCT
229
1 drop of 0.6mg/ml
solution x 5 daily
Moderate
Carvallo
2020
Argentina
OCT
1195
12mg tab weekly
High
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Elgazzar
2020b
Egypt
RCT
200
0.4mg/kg, weekly x 2
Moderate
Shouman
2020
Egypt
RCT
303
2 doses 72 hours
apart -15mg tab for
60-80 kg
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
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hearing. 8 December 2020. https://www.youtube.com/watch?v=Tq8SXOBy-4w
(Accessed 27 December 2020).
V1.2 6th January 2021
Appendix
Funnel plot for the primary outcome analysis 1.1.b. (Death) including RCTs and OCTs
