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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
References
1. Kory P, Meduri GU, Iglesias J, et al. Review of the emerging evidence demonstrating
the efficacy of ivermectin in the prophylaxis and treatment of COVID-19. 18 Dec
2020.https://covid19criticalcare.com/wp-content/uploads/2020/11/FLCCC-
Ivermectin-in-the-prophylaxis-and-treatment-of-COVID-19.pdf.
2. Conterno LO, Turchi MD, Corrêa I, Monteiro de Barros Almeida RA. Anthelmintic
drugs for treating ascariasis. Cochrane Database of Systematic Reviews 2020, Issue 4.
Art. No.: CD010599. DOI: 10.1002/14651858.CD010599.pub2. Accessed 28
December 2020.
3. Barrow NJ, Campos RK, Powell ST, et al. A screen of FDA-approved drugs for
inhibitors of Zika virus infection. Cell Host & Microbe. 2016;20(2):259-270.
4. Kircik, LH, Del Rosso, JQ, Layton AM, Schauber J. Over 25 Years of Clinical Experience
With Ivermectin: An Overview of Safety for an Increasing Number of Indications. J
Drugs Derm 2016; 15:325-332.
5. World Health Organization. 21st Model List of Essential Medicines. Geneva,
Switzerland. 2019.
https://www.who.int/publications/i/item/WHOMVPEMPIAU2019.06. Accessed 29
December 2020.
6. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors).
Cochrane Handbook for Systematic Reviews of Interventions Version 6.0 [updated
July 2019]. Cochrane, 2019. Available from www.training.cochrane.org/handbook.
7. Sterne JA, Hernán MA, Reeves BS, Savovíc J, Berkman ND, Viswanathan V, et al.
ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
BMJ 2016;355:i4919.
8. Review Manager 5 (RevMan 5) [Computer program]. Version 5.4. Copenhagen:
Nordic Cochrane Centre, The Cochrane Collaboration, 2020.
9. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-
analyses. BMJ 2003;327(7414):557-60.
10. The GRADE Working Group. GRADE [website] 2020 [Available from:
www.gradeworkinggroup.org.
11. Alam MT, Murshed R, Gomes PF, Masud ZM, Saber S, Chaklader MA, Khanam F,
Hossain M, Momen ABIM, Yasmin N, Alam RF, Sultana A, Robin RC. Ivermectin as
Pre-exposure Prophylaxis for COVID-19 among Healthcare Providers in a Selected
Tertiary Hospital in Dhaka An Observational Study. EJMED [Internet]. 15Dec.2020
Available from: https://ejmed.org/index.php/ejmed/article/view/599. (Accessed
29Dec.2020)
12. Carvallo HE, Hircsh R, Alkis P and Contreras V. Study of the Efficacy and Safety of
Topical Ivermectin + IotaCarrageenan in the Prophylaxis against COVID-19 in Health
18
Personnel. J. Biomed. Res. [Internet] 19oct.2020. ISSN:2633-8653. ClinicalTrials.gov
registration number: NCT04425850. (Accessed 29Dec.2020)
13. Elgazzar A, Eltaweel A, Youssef SA, Hany B, Hafez M and Moussa H. Efficacy and
Safety of ivermectin for Treatment and prophylaxis of COVID-19 Pandemic. Res.
Square [Internet] 28Dec.2020. Available from:
https://www.researchsquare.com/article/rs-100956/v3 (Accessed 29 Dec.2020)
14. Shouman W. Use of Ivermectin as a Prophylactic Option in Asymptomatic Family
Close Contact for Patient with COVID-19. Clinical Trials.gov [Internet] 2020 Jun
registration number NCT04422561. (Accessed 29Dec.2020)
15. Mahmud R. Clinical Trial of Ivermectin Plus Doxycycline for the Treatment of
Confirmed Covid-19 Infection. ClinicalTrials.gov [Internet] 2020 Oct registration
number: NCT04523831. (Accessed 20Dec.2020)
16. Chowdhury, ATMM, Shahbaz, M, Karim, MR, Islam, J, Guo, D, and He, SA
Randomized Trial of Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin
therapy on COVID19 patients. Res. Square [Internet] 14Jul.2020. Available from:
https://www.researchsquare.com/article/rs-38896/v1. (Accessed 29Dec.2020.)
17. Podder CS, Chowdhury N, Mohim IS and Haque W. (2020). Outcome of ivermectin
treated mild to moderate COVID-19 cases: a single-centre, open-label, randomised
controlled study. IMC Journal of Medical Science. 14. Available from:
https://www.researchgate.net/publication/344240147_Outcome_of_ivermectin_tre
ated_mild_to_moderate_COVID-19_cases_a_single-centre_open-
label_randomised_controlled_study. (accessed 30Dec.2020)
18. Niaee MS, Gheibi N, Namdar P, Allami A, Zolghadr L, Javadi A, et al. Ivermectin as an
adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-
centre clinical trial. Res. Square [Internet] 24Nov.2020. Available from:
https://www.researchsquare.com/article/rs-109670/v1 (Accessed 29Dec.2020.)
19. Hashim HA, Maulood MF, Rasheed AM, Fatak DF, Kabah KK, Abdulami AS, et al.
Controlled randomized clinical trial on using Ivermectin with Doxycycline for treating
COVID-19 patients in Baghdad, Iraq. medRxiv [Internet] 2020.10.26.20219345.
Available from: https://doi.org/10.1101/2020.10.26.20219345 (Accessed
29Dec.2020)
20. Ahmed S, Karim MM, Ross AG, Hossain MS, Clemens JD, Sumiya MK, et al. A five day
course of ivermectin for the treatment of COVID-19 may reduce the duration of
illness. Int. J. Infect. Disease [Internet] 2Dec.2020. Available from:
https://www.ijidonline.com/article/S1201-9712(20)32506-6/fulltext (Accessed
29Dec.2020)
21. Chachar AZK, Khan KA, Asif M, Tanveer K, Khaqan A and Basri R. Effectiveness of
Ivermectin in SARS-CoV-2/COVID-19 Patients, Int. J. Sciences [Internet] Nov.2020:31-
19
35 Available from: https://www.ijsciences.com/pub/article/2378 (Accessed
29Dec.2020)
22. Cepelowicz Rajter J, Sherman MS, Fatteh N, Vogel F, Sacks J and Rajter JJ. Use of
Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With
Coronavirus Disease 2019. J. Chest [Internet] 27Oct.2020. Available from:
https://journal.chestnet.org/action/showPdf?pii=S0012-3692%2820%2934898-4 .
(Accessed 29Dec.2020)
23. Khan SI, Khan SI, Debnath CR, Nath PN, Al Mahtab M, Nabeka H, et al. [Ivermectin
Treatment May Improve the Prognosis of Patients With COVID-19.] Archivos de
Bronconeumología, 2020. Volume 56, Issue 12, Pages 828-830,ISSN 0300-
2896.Spain. Available from: https://doi.org/10.1016/j.arbres.2020.08.007.
24. Gorial FI, Mashhadani S, Sayaly HM, Dakhil BD, AlMashhadani MM, Aljabory AM, et
al. Effectiveness of Ivermectin as add-on Therapy in COVID-19 Management (Pilot
Trial).MedRxiv. 2020.07.07.20145979; Available from:
https://doi.org/10.1101/2020.07.07.20145979 (Accessed 29Dec.2020).
25. Spoorthi V, Sasank S. Utility of ivermectin and doxycycline combination for the
treatment of SARS-CoV-2. International Archives of Integrated Medicine. [Internet]
2020:7(10). Available from: https://www.iaimjournal.com/volume-7-issue-10-
october-2020/
26. “I can’t keep doing this.” Doctor pleads for review of data during COVID-19 Senate
hearing. 8 December 2020. https://www.youtube.com/watch?v=Tq8SXOBy-4w
(Accessed 27 December 2020).
Appendix
Forest plot for the primary outcome (deaths) including RCTs and OCTs with accompanying
funnel plot.
21

Supplementary resource (1)

... 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
Full-text available
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
Full-text available
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: 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.
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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.
Review of the emerging evidence demonstrating the efficacy of ivermectin in the prophylaxis and treatment of COVID-19
  • P Kory
  • G U Meduri
  • J Iglesias
Kory P, Meduri GU, Iglesias J, et al. Review of the emerging evidence demonstrating the efficacy of ivermectin in the prophylaxis and treatment of COVID-19. 18 Dec 2020.https://covid19criticalcare.com/wp-content/uploads/2020/11/FLCCC-Ivermectin-in-the-prophylaxis-and-treatment-of-COVID-19.pdf.
Anthelmintic drugs for treating ascariasis
  • L O Conterno
  • M D Turchi
  • I Corrêa
  • Monteiro De Barros Almeida
Conterno LO, Turchi MD, Corrêa I, Monteiro de Barros Almeida RA. Anthelmintic drugs for treating ascariasis. Cochrane Database of Systematic Reviews 2020, Issue 4. Art. No.: CD010599. DOI: 10.1002/14651858.CD010599.pub2. Accessed 28 December 2020.
Available from www.training.cochrane.org/handbook
  • Cochrane
Cochrane, 2019. Available from www.training.cochrane.org/handbook.
Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration
Review Manager 5 (RevMan 5) [Computer program]. Version 5.4. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2020.