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

Abstract

Ivermectin is an antiparasitic drug being investigated for repurposing to SARS-CoV-2. In-vitro, ivermectin showed limited antiviral activity and a COVID-19 animal model demonstrated pathological benefits but no effect on viral RNA. This meta-analysis investigated ivermectin in 18 randomized clinical trials (2282 patients) identified through systematic searches of PUBMED, EMBASE, MedRxiv and trial registries. Ivermectin was associated with reduced inflammatory markers (C-Reactive Protein, d-dimer and ferritin) and faster viral clearance by PCR. Viral clearance was treatment dose- and duration-dependent. In six randomized trials of moderate or severe infection, there was a 75% reduction in mortality (Relative Risk=0.25 [95%CI 0.12-0.52]; p=0.0002); 14/650 (2.1%) deaths on ivermectin; 57/597 (9.5%) deaths in controls) with favorable clinical recovery and reduced hospitalization. Many studies included were not peer reviewed and meta-analyses are prone to confounding issues. Ivermectin should be validated in larger, appropriately controlled randomized trials before the results are sufficient for review by regulatory authorities.

Full text

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Preliminary meta-analysis of randomized trials of ivermectin to treat SARS-
CoV-2 infection
Authors: Andrew Hill on behalf of the International Ivermectin Project Team*
International Ivermectin Project Team
Ahmed S. Abdulamir1, Sabeena Ahmed2, Asma Asghar3, Olufemi Emmanuel
Babalola4, Rabia Basri5, , Aijaz Zeeshan Khan Chachar5, Abu Taiub Mohammed
Mohiuddin Chowdhury7, Ahmed Elgazzar8, Leah Ellis9, Jonathan Falconer10, Anna
Garratt11, Basma M Hany8, Hashim A. Hashim12, Wasim Md Mohosin Ul Haque13,
Arshad Hayat3, Shuixiang He7, Ramin Jamshidian14, Wasif Ali Khan2, Ravi Kirti15,
Alejandro Krolewiecki16, Carlos Lanusse17, Jacob Levi18, Reaz Mahmud19, Sermand
Ahmed Mangat3, Kaitlyn McCann9, Anant Mohan20, Morteza Shakhsi Niaee21,
Nurullah Okumuş22, Victoria Pilkington23, Chinmay Saha Podder24, Ambar Qavi9,
Houssam Raad25, Ali Samaha25, Hussein Mouawia25, Mohammad Sadegh Rezai26,
Surapaneni Sasank27, Veerapaneni Spoorthi28, Tejas Suri20, Junzheng Wang9,
Hannah Wentzel9 , Andrew Hill29
1. College of Medicine, Alnahrain University, Alkadymia, Baghdad, Iraq
2. International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
3. Department of Medicine, Combined Military Hospital, Lahore, Pakistan
4. Bingham University/Lagos University, Nigeria
5. Fatima Memorial Hospital, Lahore, Pakistan
6. Barcelona Institute for Global Health, Clinica Universidad de Navarra,
Universidad de Navarra, Spain
7. Xi'an Jiaotong University Medical College First Affiliated Hospital, Shaanxi,
China
8. Faculty of Medicine, Benha University, Banha, Egypt
9. Faculty of Medicine, Imperial College London, UK
10. Department of Infectious Diseases, Chelsea and Westminster Hospital,
Imperial NHS Trust, London, UK
11. Department of Infectious Diseases, University Hospital of Wales, Cardiff and
Vale University Health Board, UK
12. Alkarkh Hospital, Alatefiya, Baghdad, Iraq
13. Department of Nephrology, BIRDEM General Hospital, Dhaka, Bangladesh
14. Jundishapur University of Medical Sciences, Ahvaz, Iran
15. Department of General Medicine, All India Institute of Medical Sciences,
Patna, India
16. Instituto de Investigaciones de Enfermedades Tropicales (IIET-CONICET),
Sede Regional Orán, Universidad Nacional de Salta, Argentina
17. Laboratorio de Farmacología, Centro de Investigación Veterinaria de Tandil
(CIVETAN), CONICET-CICPBA-UNCPBA, Facultad de Ciencias Veterinarias,
Universidad Nacional del Centro de la Provincia de Buenos Aires, Tandil,
Argentina
18. Department of Intensive Care, University College London Hospital, ULCH
NHS Trust, London, UK

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19. Department of Neurology, Dhaka Medical College, Dhaka, Bangladesh
20. Department of Pulmonary Critical Care & Sleep Medicine, All India Institute of
Medical Sciences, New Delhi, India
21. Qazvin Science & Technology Park, Qazvin, Iran
22. Department of Neonatology, Afyonkarahisar Health Sciences University,
Afyonkarahisar, Turkey
23. Oxford University Clinical Academic Graduate School, University of Oxford, UK
24. Debidwar Upazila Health Complex, Debidwar, Comilla, Bangladesh
25. Biotherapies de Maldies Genetiques et Cancer, Universite Bordeaux Segalen,
Bordeaux, France
26. Pediatric Infectious Diseases Research Center, Communicable Diseases
Institute, Mazandaran University of Medical Sciences, Sari, Iran
27. Gandhi Hospital, Andhra Pradesh, India
28. Apollo Medical College, Hyderabad, India
29. Department of Pharmacology and Therapeutics, University of Liverpool,
Liverpool, L7 3NY, UK
Funding: Unitaid
Conflicts of Interest: None of the authors has declared a conflict of interest
Corresponding author:
Dr Andrew Hill PhD
Department of Pharmacology and Therapeutics
University of Liverpool,
70 Pembroke Place
Liverpool L69 3GF, UK
Email: microhaart@aol.com

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Abstract
Introduction: Ivermectin is a well-established antiparasitic drug licensed since 1981,
more recently approved for its anti-inflammatory effects against rosacea. It is being
investigated for repurposing against SARS-CoV-2. In-vitro, ivermectin showed some
antiviral activity but at higher concentrations than achieved in human plasma after
normal oral dosing. An animal model demonstrated pathological benefits in COVID-
19 but no effect on viral RNA. We aimed to assess the available global data from
randomized controlled trials (RCTs) of ivermectin in COVID-19.
Methods: We conducted a systematic search of PUBMED, EMBASE, MedRxiv and
trial registries. We excluded prevention studies and non-randomized or case-
controlled studies. We identified and included 18 RCTs. Data were combined from
2282 patients into a systematic review and meta-analysis.
Results: Ivermectin was associated with reduced inflammatory markers (C-Reactive
Protein, d-dimer and ferritin) and faster viral clearance by PCR. Viral clearance was
treatment dose- and duration-dependent. Ivermectin showed significantly shorter
duration of hospitalization compared to control. In six RCTs of moderate or severe
infection, there was a 75% reduction in mortality (Relative Risk=0.25 [95%CI 0.12-
0.52]; p=0.0002); 14/650 (2.1%) deaths on ivermectin; 57/597 (9.5%) deaths in
controls) with favorable clinical recovery and reduced hospitalization.
Discussion: Many studies that were included were not yet published or peer-
reviewed and meta-analyses are prone to confounding issues. Furthermore, there
was a wide variation in standards of care across trials, and ivermectin dose and
duration of treatment was heterogeneous. Ivermectin should be validated in larger,
appropriately controlled randomized trials before the results are sufficient for review
by regulatory authorities.
Keywords: SARS-CoV2, COVID-19, Ivermectin, repurposed

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Introduction
The pandemic of SARS-CoV-2 continues to grow, with 650,000 new infections and
over 11,000 deaths recorded worldwide daily in January 2021 [1]. Protective
vaccines have been developed, but current supplies are too low to cover worldwide
demand in the coming months [2]. Researchers worldwide are urgently looking for
interventions to prevent new infections, or prevent disease progression, and lessen
disease severity for those already infected.
While research on new therapeutic agents for COVID-19 is key, there is also great
interest on evaluating the potential use against COVID-19 of already existing
medicines, and many clinical trials are in progress to ‘re-purpose’ drugs normally
indicated for other diseases. The known safety profiles, shortened development
timelines, and well-established markets (with low price points and higher capacity to
deliver at scale) for most of already existing compounds proposed for COVID-19 are
particularly advantageous compared to new drug discovery in a pandemic situation.
Three re-purposed anti-inflammatory drugs have shown significant survival benefits
to date: the corticosteroid dexamethasone in the UK RECOVERY trial [3], and the
Interleukin-6 (IL-6) receptor antagonist drugs, tocilizumab and sarilumab, in the
REMAP-CAP trial [4]. Other re-purposed antimicrobials such as,
hydroxychloroquine, lopinavir/ritonavir, remdesivir and interferon-beta, have shown
no significant survival benefit in two large, randomized trials [3, 5] despite initial
reports of efficacy, underscoring the need for caution when interpreting early clinical
trial data.
Dexamethasone is recommended for use by the WHO and has proven survival
benefits for oxygen-dependent patients with COVID-19, while tocilizumab and
sarilumab improves survival for patients in intensive care [3, 4]. However, there are
no approved treatments for patients with mild SARS-CoV-2 infection, either to
prevent disease progression or reduce viral transmission. Treatments increasing
viral clearance rate, may lower risk of onward transmission but this requires
empirical demonstration.

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Ivermectin is a well-established anti-parasitic drug used worldwide for a broad
number of parasites and also for topical use against rosacea. Antiviral activity of
ivermectin has been demonstrated for SARS-CoV-2 in Vero/hSLAM cells [IB6].
However, concentrations required to inhibit viral replication in vitro (EC50=2.8M;
EC90=4.4M) are not achieved systemically after oral administration of the drug to
humans [6, 7]. The drug is estimated to accumulate in lung tissues (2.67 times that
of plasma) [8], but this is also unlikely to be sufficient to maintain target
concentrations for pulmonary antiviral activity [7, 9]. Current data suggest that the
dosages of ivermectin used in human trials are unlikely to provide systemic or
pulmonary concentrations necessary to exert meaningful direct antiviral activity.
Notwithstanding, ivermectin is usually present as a mixture of two agents and
although mainly excreted unchanged in humans, has two major metabolites [10].
Current data are insufficient to determine whether the minor form or a circulating
metabolite has higher direct potency against SARS-CoV-2, but it seems likely that it
would need to be profoundly more potent than the reported values.
Ivermectin has also demonstrated immunomodulatory and anti-inflammatory
mechanisms of action in preclinical models of several other indications. In-vitro
studies have demonstrated that ivermectin suppresses production of the
inflammatory mediators nitric oxide and prostaglandin E2 [11]. Furthermore,
avermectin (from which ivermectin is derived) significantly impairs pro-inflammatory
cytokine secretion (IL-1β and TNF-α) and increases secretion of the
immunoregulatory cytokine IL-10 [12]. Ivermectin also reduced TNF-α, IL-1, and IL-6,
and improved survival in mice given a lethal dose of lipopolysaccharide [13].
Preclinical evidence to support these immunomodulatory and anti-inflammatory
mechanisms of action have also been generated in murine models of atopic
dermatitis and allergic asthma [14, 15]. Finally, in Syrian golden hamsters infected
with SARS-CoV-2, subcutaneous ivermectin demonstrated a reduction in the IL-6/IL-
10 ratio in lung tissues and prevented pathological deterioration [16]. The impact of
ivermectin in this model appeared to be gender specific, appearing more active in
females than in males. Irrespective of gender, no impact of ivermectin on viral titers
in lung or nasal turbinate was observed in this model, supporting a mechanism of
action not relating to direct antiviral activity.

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In pharmacokinetic studies, the Area Under the Curve (AUC) and maximum
concentration (Cmax) of ivermectin are generally dose proportional, and
bioavailability of ivermectin increases 2.57-fold in the fed state [8]. Increasing the
frequency or dose of ivermectin does increase the Cmax and AUC of total drug, but
not sufficiently to reach the published EC50 against SARS-CoV-2 in monkey
Vero/hSLAM cells [8]. Ivermectin has approximately twice the systemic availability
when given as an oral solution compared to solid forms (tablets or capsules) [10].
At standard doses, of 0.2-0.4mg/kg for 1-2 days, ivermectin has a good safety profile
and has been distributed to billions of patients worldwide in mass drug administration
programs. A recent meta-analysis found no significant difference in adverse events
in those given higher doses of ivermectin, of up to 2mg/kg, and those receiving
longer courses, of up to 4 days, compared to those receiving standard doses [17].
Ivermectin is not licensed for pregnant or breast-feeding women, or children <15kg.
The objective of this systematic review and meta-analysis was to combine available
results from published or unpublished randomized trials of ivermectin in SARS-CoV-
2 infection.Limitations of current analysis is important as it is being performed with
secondary data from a wide variety of different trials in many different parts of the
world with designs that were not originally meant to be compatible. Further refined
analysis, including direct data examination, are warranted.

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Methods
The systematic review and meta-analysis was conducted according to PRISMA
guidelines. A systematic search of PUBMED and EMBASE was conducted to
identify randomized control trials (RCT) evaluating treatment with ivermectin for
SARS-CoV-2 infected patients. Clinical trials with no control arm, or those
evaluating prevention of infection were excluded alongside non-randomized trials
and case-control studies. Key data extracted included baseline characteristics (age,
sex, weight, oxygen saturation, stage of infection), changes in inflammatory markers,
viral suppression after treatment, clinical recovery, hospitalization and survival. Data
were extracted and cross-checked by two independent reviewers (HW and LE).
Search strategy and selection criteria
RCTs were eligible for inclusion if they compared an ivermectin-based regimen with
a comparator or standard of care (SOC) for the treatment of COVID-
19. Clinicaltrials.gov [18] was searched on 14th December 2020 using key words
COVID, SARS-CoV-2 and ivermectin to identify studies. The WHO International
Clinical Trials Registry Platform (ICTRP) was accessed via the COVID-NMA
Initiative’s mapping tool, updated to 9th December 2020, [19] and Stamford
University’s Coronavirus Antiviral Research Database (CoV-RDB), updated to 15th
December 2020, [20] to identify additional trials listed on other national, and
international registries.
Additionally, literature searches via PubMed, and the preprint server MedRxiv were
conducted to identify published studies not prospectively or retrospectively registered
in a trial registry. Duplicate registrations, non-controlled studies and prevention
studies were excluded following discussion between the authors.
In a third stage of data collection, the research teams conducting unpublished clinical
trials were contacted and requested to join regular international team meetings in
December 2020 and January 2021. All results available from unpublished studies
were also included in this systematic review.

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All of the clinical trials included in this meta-analysis were approved by local ethics
committees and all patients signed informed consent.
The primary outcome was all-cause mortality from randomization to the end of
follow-up. Changes in inflammatory markers, viral suppression, clinical recovery and
hospitalization were measured in different ways between trials and were summarized
for individual clinical trials where endpoints could not be combined.
Data analysis
Statistical analyses for all-cause mortality were conducted with summary published
data, on the intention-to-treat population, including all randomized patients. Clinical
trials with at least two deaths reported were included in this analysis. Treatment
effects were expressed as risk ratios (RR) for binary outcomes. For each outcome
we pooled the individual trial statistics using the random-effects inverse-variance
model; a continuity correction of 0.5 was applied to treatment arms with no deaths.
Heterogeneity was evaluated by I2. The significance threshold was set at 5% (two-
sided) and all analyses were conducted using Revman 5.3.
All studies included in this analysis were assessed for risk of bias using the
Cochrane Collaboration risk of bias standardized assessment tool [21] and the
outcome of this assessment is given in supplementary table 1.

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Results
In this meta-analysis, 18 RCTs involving a total of 2282 participants were included.
The sample sizes of each trial ranged from 24 to 400 participants. Of the 18 included
studies, five were published papers, six were available as pre-prints, six were
unpublished results shared for this analysis; one reported results via a trial registry
website.
Overall, nine trials investigated ivermectin as a single dose (Table 1A), nine trials
investigated multi-day dosing up to seven days (Table 1B), of which three trials were
dose-ranging. In this meta-analysis, ivermectin was largely investigated in
mild/moderate participants (11 trials). Overall, 12 trials were either single or double-
blinded and six were open-label.
Effects on Inflammatory Markers
Five trials provided results of the effect of ivermectin on inflammatory markers
including C-reactive protein (CRP), ferritin and d-dimer (Table 2). Four of these trials
demonstrated significant reductions in CRP compared to control. Furthermore, in the
Elgazzar trial [22], ivermectin significantly reduced ferritin levels compared to control
in the severe patient population while no significant difference was demonstrated in
the mild/moderate population. The Okumus trial [23] showed significantly greater
reductions in in ferritin on day 10 of follow-up for ivermectin versus control. The
Chaccour [24] and Ahmed [25] trials showed no significant difference in ferritin count
between ivermectin and control. Elgazzar [22] showed significant differences in d-
dimer between ivermectin and control in both the mild/moderate and severe
populations. Okumus [23] showed significant differences in d-dimer on day 5 whilst
Chaccour [24] found no differences between ivermectin and control, but with a
smaller sample size.

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Effects on Viral Clearance
Three different endpoints were used to analyze viral clearance: the percentage of
patients undetectable on a set day (Table 3A), the number of days from
randomization to negativity (Table 3B), and other measures such as cycle time (Ct)
values and dose-response correlations (Table 3C). The Kirti [26] and Okumus [23]
trials included viral load analysis only in a subset of patients. The effects of
ivermectin on viral clearance were generally smaller when dosed on only one day.
Several studies showed no statistically significant effect of ivermectin on viral
clearance [27, 28, 29].
The three studies randomizing patients to different doses or durations of ivermectin
showed apparent dose-dependent effects on viral clearance. Firstly, in the Babalola
trial [30], the 0.4mg/kg dose showed trends for faster viral clearance than the
0.2mg/kg dose. Secondly, in the Mohan trial [28], the 0.4 mg/kg dose of ivermectin
led to a numerically higher percentage of patients with viral clearance by day five
than the 0.2mg/kg dose. Thirdly, in the Ahmed trial [25], ivermectin treatment for five
days led to a higher percentage of patients with viral clearance at day 13 compared
with one day of treatment. Finally, in Krolewiecki [31], PK/PD correlations showed
significantly faster viral clearance for patients with PK exposures above 160ng/mL.
The effect of ivermectin on viral clearance was most pronounced in the randomized
trials evaluating doses of up to five days of ivermectin treatment, using doses of
0.4mg/kg (Figure 1). At these doses, there were statistically significant effects on
viral clearance in all four randomized trials.
Effects on Clinical Recovery and Duration of Hospitalization
Definitions of clinical recovery varied across trials, as shown in Table 4. In Table 4A,
four of the six trials showed significantly faster time to clinical recovery on ivermectin
compared to control. In five trials, ivermectin showed significantly shorter duration of
hospitalization compared to control (Table 4B).
Effects on Survival

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Six randomized trials reported that at least two people had died post-randomization
and were included in the analysis (Table 5). Across these six trials in 1255 patients,
there were 14/658 (2.1%) deaths in the ivermectin arms, versus 57/597 (9.5%)
deaths in the control arms. In a combined analysis using inverse variance weighting
ivermectin showed a 75% improvement in survival (RR 0.25 [95%CI 0.12-0.52];
p=0.0002, Figure 2). Heterogeneity was moderate, I2 = 34%.
Evaluation of Studies.
An evaluation of the quality of the studies included in this meta-analysis was
conducted according to the Cochrane Collaboration tool to assess the risk of bias. Of
the 18 trials, 11 were of poor quality and seven of fair or high quality. Further
evaluation with access to original data from the trials is warranted to increase quality
of evidence. [Supplementary table 1]

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Discussion
This systematic review of 18 RCTs (n = 2282) showed ivermectin treatment reduces
inflammatory markers, achieves viral clearance more quickly and improves survival
compared with SOC. The effects of ivermectin on viral clearance were stronger for
higher doses and longer durations of treatment. These effects were seen across a
wide range of RCTs conducted in several different countries. However, the data
should be interpreted carefully in the context that meta-analyses are highly prone to
confounding bias, and current viral PCR assays have several important limitations.
Many of the studies assessed have not been peer-reviewed. Larger, appropriately
controlled randomized trials are needed before rigorous evaluation of the clinical
benefits of ivermectin can be undertaken.
The results from this analysis have emerged from the International Ivermectin
Project Team meetings in December 2020 and January 2021. Independent research
teams were conducting the trials across 12 countries and agreed to share their data,
which was often unpublished, to accelerate the speed of reporting and to ensure
their fragmented research, widespread across the world, could contribute to global
learning. Viral clearance was evaluated by Polymerase Chain Reaction (PCR)
assays in all the studies. We have only included randomized clinical trials in this
meta-analysis. The 18 RCTs included were designed and conducted independently,
with results combined in December 2020.
Limitations
Key limitations to this meta-analysis include the comparability of the data, with
studies differing in dosage, treatment duration, and inclusion criteria. Furthermore,
the SOC used in the background treatment differed between different
trials. Additionally, ivermectin was often given in combination with doxycycline or
other antimicrobials. Individual trials may not have power to detect treatment effects
on rare endpoints such as survival. Outcome measures were not standardized; viral
clearance was measured in most trials, but at different time points and with different
PCR cycle thresholds. The reliability of PCR tests for quantification purposes has
been the subject of substantive debate. Most studies were conducted in populations

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with only mild/moderate infection and some trials excluded patients with multiple co-
morbidities.
For open label studies, there is a risk of bias in the evaluation of subjective endpoints
such as clinical recovery and hospital discharge. However, the risk is lower for
objective endpoints such as viral clearance and survival. We have attempted to
control for publication bias by contacting each research team conducting the trials
directly. This has generated more results than would be apparent from a survey of
published clinical trials only but means that many of the included trials have not been
peer-reviewed. Review and publication of RCTs generally takes three to six months.
It has become common practice for clinical trials of key COVID-19 treatments to be
evaluated from pre-prints, such as for the WHO SOLIDARITY, RECOVERY and
REMAP-CAP trials [3, 4, 5].
These RCTs have been conducted in a wide range of countries, often in low-
resource conditions and overburdened healthcare systems. The evidence from this
first set of studies will require validation in larger RCTs evaluating fixed dosing
schedules, preferably using higher doses for between 3-5 days. Larger RCTs are
currently underway in Mexico, South America and Egypt, with results expected in
February and March 2021.
Despite limitations, this analysis suggests a dose and duration-dependent impact of
ivermectin on rate of viral clearance. These trials evaluated a wide range of
ivermectin dosing, from 0.2mg/kg for 1 day to 0.6mg/kg for 5 days. This wide range
of doses allowed an estimation of dose-dependency on viral clearance but reduces
the number of patients included that were consistently administered the same dose
for the same duration. The maximum effective dose of ivermectin is not yet clear and
new clinical trials are evaluating higher doses, up to 1.2mg/kg for 5 days.
The 75% survival benefit seen in this meta-analysis is based only on 71 deaths, in
six different clinical trials. This is a smaller total number of deaths than in either the
RECOVERY or REMAP-CAP trials, which led to the approval of dexamethasone,
tocilizumab and sarilumab. However, the observed survival benefit of 75% is
stronger than for the other re-purposed drugs. Emerging mortality results from larger

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studies of ivermectin will require careful evaluation and may change the conclusions
from the current analysis.
Secondary endpoints for some RCTs included biomarkers of disease severity. Some
of these provide evidence for an anti-inflammatory mechanism of action of ivermectin
in SARS-CoV-2 infected patients. Previous meta-analyses have demonstrated that
high levels of CRP, ferritin, d-dimer and lymphocytopenia are related to COVID-19
severity and hyper-inflammation [32, 33]. Studies of IL-6 receptor antagonists have
been shown to reduce CRP and d-dimer levels in patients with COVID-19 [4].
Across three studies, in a cumulative 683 patients, we found a slight increase in
lymphocyte counts [22, 34, 35] following ivermectin administration. CRP, a marker of
infection and inflammation, were reduced following ivermectin administration across
four trials [22, 23, 25, 34]. D-dimer is a fibrin degradation product, often raised in
severe COVID-19 due to thrombus formation. Ferritin can also be raised in severe
COVID-19 due to the cytokine storm and hyperinflammation. Levels of both d-dimer
and ferritin following one week of ivermectin treatment in severe COVID-19 cases
were reduced to levels less than half of those receiving SOC [22]. These reductions
in D-dimer and ferritin were more significant in patients with severe disease
compared to those with mild/moderate disease at baseline. Furthermore, erythrocyte
sedimentation rate and lactate dehydrogenase, non-specific markers of inflammation
and tissue damage, respectively, were both reduced slightly following ivermectin
administration in two separate studies of patients with COVID-19 [34, 36].
A key component of SARS-CoV-2 pathogenesis is its pro-thrombotic effect, leading
to blood clots in the kidneys, brain and pulmonary emboli in the lungs. By reducing
hyper-inflammation, the risk of clots may be reduced. One histopathology study in
dogs with Dirofilaria immitis (heartworm) showed that ivermectin plus doxycycline
reduced lung tissue perivascular inflammation and endothelial proliferation leading to
fewer arterial lesions and virtually removed the risk of thrombi [37]. However, the
relevance of these findings to SARS-CoV-2 infection are unclear.

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Ivermectin may also have a role in short-term prevention of SARS-CoV-2 infection,
suggested by pilot studies [38, 39]. This potential benefit also needs to be validated
in larger randomized trials.
At the time of writing, knowledge gaps prevent a robust conclusion about the
mechanism of action, but current in vitro data do not support a direct antiviral activity
of the drug. Interestingly, ivermectin has been demonstrated to induce autophagy as
part of a proposed mechanism of action in cancer [40, 41] with autophagy providing
an innate defense against virus infection [42]. Furthermore, other viruses such as
cytomegalovirus have mechanisms to activate cyclooxygenase 2 and prostaglandin
E2 promoting the inflammatory response, which supports their replication [43] and it
is also possible that a pro-inflammatory phenotype may aid SARS-CoV-2 replication
[44]. However, immunological mechanisms of action are usually highly complex and
require careful empirical evaluation to understand the plausibility, which is currently
absent for ivermectin use in COVID-19.
Conclusion
This meta-analysis of 18 RCTs in 2282 patients showed a 75% improvement in
survival, faster time to clinical recovery and signs of a dose-dependent effect of viral
clearance for patients given ivermectin versus control treatment.
Despite the encouraging trend this existing data base demonstrates, it is not yet a
sufficiently robust evidence base to justify the use or regulatory approval of
ivermectin. However, the current paucity of high-quality evidence only highlights the
clear need for additional, higher-quality and larger-scale clinical trials, warranted to
investigate the use of ivermectin further.
The maximum effective dose of ivermectin needs to be clarified and new clinical
trials should use a consistent multi-day dosing regime, with at least 0.4mg/kg/day.
The appropriate dose and schedule of ivermectin still requires evaluation and the
current randomized clinical trials of ivermectin need to be continued until ready for
rigorous review by regulatory agencies.

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Acknowledgements
We would like to thank all the clinical staff, the research teams and the patients who
participated in these studies.

17
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21
List of Tables and figures
Table 1: Trial Summaries
A: Ivermectin trials with Dosing on day 1 only
B: Ivermectin trials with multi-day dosing
Table 2: Changes in Inflammatory Markers
Table 3: Effects of ivermectin on viral clearance
A: Effects of ivermectin on viral clearance (binary)
B: Effects of ivermectin on time to viral clearance
C: Effects of ivermectin on other measures of viral clearance
Table 4: Effects on of ivermectin on clinical recovery and hospitalization
A: Time to clinical recovery
B: Effects of ivermectin on duration of hospitalization
C: Number of Participants with clinical recovery by Day 7 to 10 post-randomization
Table 5: Effects of ivermectin on survival
Figure 1: Time to viral clearance
Figure 2: Forest plot of survival

22
Table 1: Trial Summaries
Table 1: Trial Summaries
Table 1A: Ivermectin trials with Dosing on day 1 only
Study
Country
Sample Size
Daily dose
Duration
Patients
Intervention
Arm
Comparator Arm
Mahmud et a l
[45]
Bangladesh
363
12 mg
1 day (DB)
Mild/ moderate
Ivermectin +
Doxycycline + SOC
SOC
Mohan et al
[28]
India
157
0.2-0.4 mg/kg
(elixir)
1 day (DB)
Mild / moderate
Ivermectin + SOC
Placebo + SOC
Chowdhury
[29]
Bangladesh
116
0.2 mg/kg
1 day (DB)
PCR positive
Ivermectin +
Doxycycline
HCQ + Azithromycin
Rezai et al
[35]
Iran
103
0.2 mg/kg
1 day (DB)
Moderate / severe
Ivermectin + SOC
SOC
Spoorthi et al
[46]
India
100
0.2 mg/kg
1 day (DB)
Mild to moderate
Ivermectin +
Doxycycline
Placebo
Raad et al
[47]
Lebanon
100
0.2 mg/kg
1 day (SB)
Mild
Ivermectin + SOC
SOC
Asghar et al
[48]
Pakistan
100
0.2 mg/kg
1 day (OL)
Mild / moderate
Ivermectin + SOC
SOC
Podder et al
[27]
Bangladesh
62
0.2 mg/kg
1 day (OL)
Mild
Ivermectin + SOC
SOC
SAINT
[24]
Spain
24
0.4 mg/kg
1 day (DB)
Moderate
Ivermectin
Placebo

23
SOC = Standard of care; OL= open label; SB= single-blind; DB= double-blind
Table 1B: Ivermectin trials with multi-day dosing
Study
Country
Sample Size
Daily dose
Duration
Patients
Intervention
Arm
Comparator Arm
Elgazzar et al
[22]
Egypt
400
0.4 mg/kg
5 days (OL)
Mild to severe
Ivermectin + SOC
HCQ + SOC
Niaee et al
[34]
Iran
180
0.2 - 0.4
mg/kg
1-3 days (DB)
Mild / moderate
Ivermectin + SOC
SOC + Placebo
Hashim et al
[36]
Iraq
140
0.2 mg/kg
2-3 days (SB)
Symptomatic
Ivermectin +
Doxycycline + SOC
SOC
Kirti et al [26]
India
112
12 mg
2 days (DB)
Mild / moderate
Ivermectin + SOC
SOC + Placebo
Ahmed et al
[25]
Bangladesh
72
0.2 mg/kg
5 days (DB)
Mild
Ivermectin + SOC
SOC + Placebo
Okomus et al
[23]
Turkey
60
0.2 mg/kg
5 days (DB)
Severe
Ivermectin + SOC
FAVI/HQ/AZI (SOC)
Babaloa et a
[30]
Nigeria
60
0.1-0.2
mg/kg
2 / week (DB)
Mild
Ivermectin + SOC
Placebo + LPV/r
(SOC)
Chachar et al
[49]
Pakistan
50
0.2 mg/kg
2 days (OL)
Mild
Ivermectin + SOC
SOC
Krolewiecki et
al
[31]
Argentina
45
0.6 mg/kg
5 days (OL)
Mild to moderate
Ivermectin + SOC
SOC
SOC = Standard of care

24
Table 2: Changes in Inflammatory Markers
CRP (mg/L)
Ferritin (μg/L)
D-dimer (mg/L)
Ivermectin
Control
p value
Ivermectin
Control
p value
Ivermectin
Control
p value
Elgazzar, Egypt (n=200, mild/moderate COVID-19)
Baseline
48.4
50.6
168
172
4.8
5.4
Day 7
4.8
8.3
p<0.001
95
98
n.s
0.5
0.7
p<0.001
Elgazzar, Egypt (n=200, severe COVID-19)
Baseline
64.8
68.2
420
334
8.2
8.6
Day 7
28.6
58.6
p<0.001
104
294
p<0.001
0.7
1.9
p<0.001
Okomus, Turkey (n=60)
Baseline
340.3
215.0
683
747
1.3
1.3
Day 5
51.8
194.3
p<0.01
875
1028
n.s
5.9
3.6
n.s
Day 10
36.1
92.4
p<0.05
495
1207
p<0.01
0.7
1.5
p<0.05
Chaccour, Spain (n=24)*
Baseline
3.5
3.0
165
156
0.3
0.3
Day 7
1.0
1.1
n.s
125
199
n.s
0.3
0.3
n.s
Day 14
0.8
0.6
n.s
152
145
n.s
0.3
0.3
n.s
Ahmed, Bangladesh (n=45, Ivermectin 5 days)
Baseline
22.0
29.0
269
222
-
-
Day 7
3.0
14.0
p<0.05+
211
218
n.s+
-
-
Ahmed, Bangladesh (n= 46, Ivermectin 1 day)
Baseline
26.0
29.0
259
222
-
-
Day 7
11.0
14.0
n.s+
213
218
n.s+
-
-
Iran Niaee (n=60, Ivermectin- 0.2 mg)*
Baseline
200.0
270.0
-
-
-
-
Day 5
85.0
245.0
p<0.001++
-
-
-
-
Iran Niaee (n=60, Ivermectin- 0.2, 0.2, 0.2 mg)*
Baseline
390.0
270.0
-
-
-
-
Day 5
200.0
245.0
p<0.001++
-
-
-
-
Iran Niaee (n=60, Ivermectin- 0.4 mg)*
Baseline
250.0
270.0
-
-
-
-
Day 5
80.0
245.0
p<0.001++
-
-
-
-
Iran Niaee (n=60, Ivermectin- 0.4, 0.2, 0.2 mg)*
Baseline
340.0
270.0
-
-
-
-

25
Day 5
170.0
245.0
p<0.001++
-
-
-
-
*Median presented, all other data mean.
+p value compares within group changes from baseline to end point of ivermectin group. ++p value shows significance of total changes from baseline. All other p values compare ivermectin vs.
control
Normal ranges: CRP(<10mg/L), Ferritin(11-336μg/L) D-dimer(<0.5mg/L).

26
Table 3: Effects of ivermectin on viral clearance
Table 3A:
Study
Country (n)
Daily dose
Duration
Viral load
endpoint
Result
IVA vs Control
P value
Number Detectable or Undetectable (%)
Mahmud et al
Bangladesh,
n=363
12 mg
1 day (DB)
Undetectable
Day 14
92% vs 80%
p < 0.001
Asghar et al
Pakistan,
n=103
0.2 mg/kg
1 day
Undetectable
Day 7
90% vs 44%
p < 0.001
Mohan et al
India,
n=157
0.2mg/kg
Elixir
1 day
Undetectable
Day 5
35% vs 31%
p = n.s.
Mohan et al
India,
n=157
0.4mg/kg
Elixir
1 day
Undetectable
Day 5
48% vs 31%
p = n.s.
Kirti et al
India,
n=112
12 mg
2 days
Undetectable
Day 6
24% vs. 32%
p = n.s.
Podder et al
Bangladesh,
n=62
0.2 mg/kg
1 day (OL)
Day 10 PCR neg
90% vs 95%
p = n.s.
Okomus et al
Turkey,
n=60
0.2 mg/kg
5 days (DB)
Day 10 PCR
Neg
88% vs 38%
p = 0.01

27
Table 3B: Effects of Ivermectin on Time to Viral Clearance
Study
Country (n)
Daily dose
Duration
Viral load
endpoint
Result
IVA vs Control
P value
Time to Viral Clearance (Days)
Chowdhury
Bangladesh,
n=112
0.2 mg/kg
1 day (DB)
Time to PCR neg
9 vs 9.3 days
p = n.s.
Elgazzar et al
Mild/Moderate
Egypt,
n=200
0.4 mg/kg
5 days (OL)
Days detectable
5 vs 10 days
p < 0.001
Elgazzar et al
Severe
Egypt,
n=200
0.4 mg/kg
5 days (OL)
Days detectable
6 vs 12 days
p < 0.001
Babaloa et al
*
Nigeria,
n=60
0.1 mg/kg
2 / week (DB)
Time to PCR neg
6 vs 9 days
p = 0.003
Babaloa et al
*
Nigeria,
n=60
0.2 mg/kg
2 / week (DB)
Time to PCR neg
4.7 vs. 9 days
p = 0.003
Ahmed et al *
Bangladesh, n=72
0.2 mg/kg
5 days (DB)
Time to PCR neg
10 vs 13 days
p = 0.02
Ahmed et al *
Bangladesh, n=72
0.2 mg/kg
1 days (DB)
Time to PCR neg
11.5 vs. 13 days
p = n.s

28
Table 3C: Effect of ivermectin on other measures of viral clearance.
Study
Country (n)
Daily dose
Duration
Viral load
endpoint
Result
IVA vs Control
P value
Other Measures of Viral clearance
Raad et al
Lebanon,
n=100
0.2 mg/kg
1 day
Day 3
Ct values
30.1 ± 6.22
vs. 18.96 ± 3.26
p = 0.01
Krolewiecki et
al*
Argentina,
n=45
0.6 mg/kg
5 days
PK/PD
Dose-related
p = 0.02
*Dose-response effect seen

29
Table 4: Effects on of ivermectin on clinical recovery and hospitalization
Table 4A: Time to clinical recovery
Study
Country
Daily dose
Duration
Endpoint
Results
IVS vs control
P value
Time to clinical recovery
Mohan et al
India
n=157
0.2 mg/kg
Elixir
1 day (SB)
Time to clinical
recovery
4.8 vs 4.6 days
p = n.s.
Mohan et al
India
n=157
0.4 mg/kg
Elixir
1 day (SB)
Time to clinical
recovery
4.3 vs 4.6 days
p = n.s.
Hashim et al
Iraq
n=140
0.2 mg/kg
2-3 days (SB)
Time to clinical
recovery
10.6 vs 17.9 days
p < 0.001
Chowdhury et al
Bangladesh
n=116
0.2 mg/kg
1 day (DB)
Time to clinical
recovery
5.9 vs 6.9 days
p = 0.071
Podder et al
Bangladesh
n=62
0.2 mg/kg
1 day (OL)
Time to clinical
recovery
5.3 vs 6.3 days
p = n.s.
Rezai et al
Iran
n=103
0.2 mg/kg
1 days (OL)
Time to clinical
recovery
4.1 vs 5.2 days
p = 0.018
Spoorthi et al
India
n=100
0.2 mg/kg
1 day (SB)
Time to clinical
recovery
3.7 vs 4.7 days
p=0.03

30
Table 4B: Effect of Ivermectin on duration of hospitalization
Study
Country
Daily dose
Duration
Endpoint
Results
IVS vs control
P value
Duration of hospitalization
Rezai et al
Iran
n=103
0.2 mg/kg
1 days (OL)
Days in hospital
6.9 vs 8.4 days
p = 0.01
Raad et al
Lebanon
n=100
0.2 mg/kg
1 day (OL)
Hospitalization
0% vs 6%
p = 0.00
Spoorthi et al
India
n=100
0.2 mg/kg
1 day (SB)
Time in hospital
6.7 vs 7.9 days
p=0.01
Niaee et al
Iran
n=165
0.2 - 0.4 mg/kg
1-3 days (DB)
Days in hospital
6.5 vs 7.5 days
p = 0.006
Elgazzar et al
Mild/moderate
Egypt
n=200
0.4 mg/kg
5 days (OL)
Days in hospital
5 vs 15 days
p < 0.001
Elgazzar et al
Severe
Egypt
n=200
0.4 mg/kg
5 days (OL)
Days in hospital
6 vs 18 days
p < 0.001

31
Table 4C: Number of Participants with clinical recovery by Day 7 to 10 post-randomization
Study
Country
Daily dose
Duration
Endpoint
Results
IVS vs control
P value
Number of Participants Recovered (%)
Chachar et al
Pakistan
n=50
0.2 mg/kg
2 days (OL)
Day 7 Clinical
recovery
64% vs 60%
p = n.s.
Okomus et al
Turkey
n=60
0.2 mg/kg
5 days (DB)
Day 10 Clinical
improvement
73% vs 53%
p = 0.10
Mahmud et al
Bangladesh
n=400
12 mg
1 day (DB)
Day 7 Clinical
Recovery
61% vs 44%
p <0.03

32
Table 5: Effects of ivermectin on survival
Trial
Country
Dosing
Ivermectin
Control
Mahmud et al
Bangladesh
0.2 mg/kg, 1 day
0/183
3/180
Niaee et al
Iran
0.2 mg/kg 1-3 days
4/120
11/60
Hashim et al
Iraq
0.2-0.4 mg/kg 2-3 days
2/70
6/70
Elgazzar et al
Egypt
0.4 mg/kg 5 days
2/200
24/200
Okomus et al
Turkey
0.2 mg/kg, 5 days
6/30
9/30
Kirti et al
India
12 mg, 5 days
0/55
4/57
Total
14/658 (2.1%)
57/597 (9.5%)

33
Figure 1: Effects of ivermectin on time to viral clearance
56
9.7
6
10
12 12.7
9
0
2
4
6
8
10
12
14
Egypt Elgazzar et al
Moderate Egypt Elgazzar et al Severe Bangladesh Ahmed et al Nigeria Babalola et al
Time to Viral Clearance (days)
p < 0.001
p < 0.001
p = 0.005
p = 0.003
Ivermectin
Control

34
Figure 2: Forest plot of survival.

35
Supplementary table 1. Assessment of Risk of Bias
Graded low, high or unclear risk of bias on the bases of the prespecified criteria set out in the Cochrane Risk of Bias Tool
Study
Random
Sequence
Generation
Allocation
Concealment
Blinding of
Participants and
Personnel
Blinding of
Outcome
Assessment
Incomplete
Outcome Data
Selective
Reporting
Overall Quality
of Evidence
Mahmud et a
l [R2]
Low
Low
Low
Low
High
(21% of patients
randomized not included
in the analysis)
Unclear
Limited
Mohan et al
[R14]
Unclear
Unclear
Low
(Unblinded but objective
outcome measure (PCR
and viral load)
Unclear
Unclear
Low
Limited
Chowdhury
[R15]
High
(Odd/Even
randomization
based on
registration
numbers)
Unclear
Unclear
Unclear
Low
Low
Limited
Rezai et al
[R13]
Low
Low
Low
Low
Low
Unclear
Fair
Spoorthi et al
[R10]
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Limited
Raad et al
[R11]
Unclear
Unclear
Low
Low
Unclear
Unclear
Limited
Asghar et al
Unclear
Unclear
Unclear
Low
High
(5% (control) vs 18%
(ivermectin) attrition rate
between arms)
Low
Limited
Podder et al
[R6]
High
(Odd/Even
randomization
based on
registration
Unclear
High
(Open Label + primary
endpoint symptoms
resolution (subjective
element))
High
(Open Label +
primary endpoint
symptoms
resolution
Unclear
Unclear
Limited

36
numbers)
(subjective
element))
SAINT
[R9]
Low
Low
Low
Low
Low
Low
Good
Elgazzar et
al
[R1]
Unclear
Unclear
Low
(Unblinded but primary
endpoint based on PCR
and laboratory markers)
High
(Investigators
interpreting and
collating results
were unblinded)
Unclear
Unclear
Limited
Niaee et al
[R3]
Low
Low
Low
(Unblinded - but objective
outcome measures used
(lab markers)
Unclear
Low
Low
Fair
Hashim et al
[R4]
High
(Randomization
based on date of
enrollment)
High
(Randomization
based on date of
enrollment)
High
(Unblinded and outcome
dependent on reporting of
symptoms)
High
(Unblinded -
outcome
dependent on
subjective
judgement of
disease
progression)
Unclear
Low
Limited
Ahmed et al
[R5]
Unclear
Unclear
Low
Low
Low
Low
Fair
Okomus et al
[R16]
Unclear
Unclear
Low
Objective measures
(Lab/PCR/FiO2/Mortality)
Unclear
Unclear
Unclear
Limited
Babaloa et a
[R17]
Unclear
Unclear
Low
Low
Low
Low
Fair
Chachar et al
[R7]
Low
Low
High
Open Label + primary
endpoint symptoms
resolution (subjective
element)
High
Open Label +
primary endpoint
symptoms
resolution
(subjective
element)
Low
Unclear
Limited
Krolewiecki
et al
[R8]
Unclear
Unclear
Low
(Low Risk Bias - Objective
measures
Unclear
Unclear
Unclear
Limited

37
(Lab/PCR/FiO2/Mortality))
Kirti et al
[R18]
Low
Low
Low
Low
Low
Low
Good