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Systematic Review
Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection
Andrew Hill
University of Liverpool
Corresponding Author
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Declarations:
Declarations
- This study involved human subjects.
- The author confirmed that all appropriate ethical guidelines for the use of human subjects have been followed, any necessary IRB and/or ethics committee review has been obtained, and information about the IRB/ethics committee is included in the manuscript.
- The author has confirmed that all necessary patient/participant consent or assent has been obtained and the appropriate institutional forms have been archived. If the IRB/ethics committee waived the requirement for patient/participant consent or assent, an explanation for the waiver is included in the text.
- This study reports on a clinical trial.
- The author has confirmed that this trial has been registered with an ICMJE-approved registry, and the trial registration ID has been provided in the text. If the article reports on a study that was registered retrospectively, a statement explaining why the study was not registered in advance has been provided in the text.
- The author has confirmed that a statement listing potential conflicts of interest or lack thereof is included in the text.
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 Many studies included were not peer reviewed and meta-analyses are prone to confounding issues.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.
Keywords
ivermectin, COVID-19, SARS-CoV-2
Figure 1
Figure 2
Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the latest manuscript can be downloaded and accessed as a PDF.
View 2 replies
Irena Cosic
ORCiDcommented on 30 January, 2021
Fantastic research. We have recently published theoretical proof that ivermectin can work against SARS-CoV-2. Here is our recently published paper: . Cosic I, Cosic D, Loncarevic I: Analysis of Ivermectin as Potential Inhibitor of SARS-CoV-2 Using Resonant Recognition Model. International Journal of Sciences, 2021, 10(1), 1-6, doi: 10.18483/ijSci.2433.
View 1 reply
Yeison Harvey Carlosama
ORCiDreplied on 05 February, 2021
Dr Andrew Hill, Congratulation for this great contribution. I respectfully allow myself to make some suggestions, especially for the next version of his meta-analysis. 1. Include a funnel plot and test for publication bias assessment (Egger test or another) 2. Chloroquine was the control group in some studies such as Niaee and Elgazaar. Now, we know that chloroquine increases the risk of death. Because of that, the results in the meta-analysis may overestimate a beneficial effect of ivermectin treatment. It would be great if you perform subgroup analysis by separating studies with chloroquine and without chloroquine in the control group. 3. Finally, I hope that the data from the new studies allow you to suggest a recommendation according to the GRADE scale in a similar way that Theresa Lawrie. Go ahead and I’ll be waiting for your new results.
View 2 replies
Philip Machanick
ORCiDreplied on 07 February, 2021
Good points. I have just been perusing www.clinicaltrials.gov and 57 Covid-19 ivermectin trials are listed, most without results (and many of poor quality but that’s another whole issue), which points to a real risk of publication bias. Another correction for this: choose a list of trials in advance and follow them to conclusion. Dr Hill is doing this. Until that is done, I am not sure that we have solid evidence either way.
Daniel
replied on 08 February, 2021
How did you know that chloroquine increases the risk offre death? https://academic.oup.com/ofid/article/7/11/ofaa500/5930834
View 1 reply
Philip Machanick
ORCiDreplied on 20 February, 2021
The paper you cite says “We excluded individuals with contraindications to hydroxychloroquine.” The list of exclusions is quite extensive, a far cry from the early claims that this was a safe medication that everyone could take. And a lot more extensive than the list of known contraindications before anyone used if for this condition. A small fraction of covid-19 cases turn really serious but they overlap strongly with the rare complications of hydroxychloroquine. This is why proper studies designed to eliminate bias including safety are necessary. Harmful side-effects that are rare or unlikely otherwise could be triggered by the interaction with ivermectin and covid-19. We don’t know until we actually measure this.
Peter Yim
ORCiDcommented on 05 February, 2021
Dr. Hill discusses the NIH COVID-19 Treatment Guidelines recommendation at length. We have asked through FOIA and other channels if the recent NIH recommendation was put to a vote. The NIH has declined to answer that question. As such, we should not assume that there was a vote on the current ivermectin recommendation at the NIH. The recommendation it received may have been the result of a much more perfunctory process. The validity of these comments are obvious from the FOIA and other communications linked in this article: https://trialsitenews.com/the-ivermectin-recommendation-was-a-deception/
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This is a preprint. It has not completed peer review.
Systematic Review
Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection
Andrew Hill
University of Liverpool
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 19 Jan, 2021
Community comments: 11
Metrics
Comments: 11
PDF Downloads: ...
HTML Views: ...
Subject Areas
Infectious Diseases
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Declarations:
Declarations
- This study involved human subjects.
- The author confirmed that all appropriate ethical guidelines for the use of human subjects have been followed, any necessary IRB and/or ethics committee review has been obtained, and information about the IRB/ethics committee is included in the manuscript.
- The author has confirmed that all necessary patient/participant consent or assent has been obtained and the appropriate institutional forms have been archived. If the IRB/ethics committee waived the requirement for patient/participant consent or assent, an explanation for the waiver is included in the text.
- This study reports on a clinical trial.
- The author has confirmed that this trial has been registered with an ICMJE-approved registry, and the trial registration ID has been provided in the text. If the article reports on a study that was registered retrospectively, a statement explaining why the study was not registered in advance has been provided in the text.
- The author has confirmed that a statement listing potential conflicts of interest or lack thereof is included in the text.
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.
Figure 1
Figure 2
Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the latest manuscript can be downloaded and accessed as a PDF.
View 2 replies
Someone with eyes
replied on 26 January, 2021
The declaration is on the first page of the full-text PDF.
Andrew Hill
replied on 26 January, 2021
A declaration of interest statement was included on the cover page of this paper.
View 1 reply
Marco Camion
replied on 26 January, 2021
Yip, I see that now and I apologize to the author/s and Researchsquare. I guess I initially skipped past the intro and couldn't find it again in my anger at reading the conclusion: Why would a medication that scored 75% success against COVID death, which is so cheap and so safe need further testing before DEMANDING its implementation? 15 000 people die every day and the conclusion calls for more tests! What kind of doctor/s would recommend such a thing? The evidence suggests that at those odds and proven safety in that dosage range one should recommend immediate implementation. We don't have the privilege of time nor need large studies in order to start treatment. 1 year into this pandemic - it has now become unethical and immoral not to use ivermectin, or at least start to roll it out. In the unlikely event of ivermectin not working no one is harmed, if it does work hundreds of thousands of lives could be saved and the world's economy restored. And we do have enough good evidence to support its efficacy; the evidence in this review supports it (but strangely the conclusion denies it - what is going on?). Further studies can happen while we start to treat patients, protect health workers and get factories gearing up manufacturing capacity. I wonder if the author/s are familiar with the Helsinki Declaration (and the Geneva one for that matter) concerning physicians' authority to use unproven interventions on ill patients in the absence of proven interventions, with the patient's consent of course. Nowhere does it say regulators will decide what a physician will use. Stoopid is as stoopid does, as we say down here on the creek.
View 1 reply
HJK
replied on 27 January, 2021
I agree with you, and the FLCCC: there is sufficient evidence now, of satisfactory-enough quality, for regulators unequivocally to recommend the use of ivermectin for the treatment and prevention of Covid-19. What we have been witnessing, and are continuing to witness, is the utter failure of the health care regulators and the medical profession in the so-called advanced economies. Where I live, the US, the vast majority of doctors refuse to exercise their minds even one bit to look into potential treatments to help their patients. The vast majority of them are waiting for Fauci and NIH to tell them what to do for Covid-19. The vast majority of them would rather do nothing, and watch patients die, than to step outside of the box and try something, anything, that might help a patient survive Covid-19. A year into this, and the NIH's early outpatient treatment recommendation is to wait at home to get sick enough to go to the ER. So yes, regulators de facto do decide for the vast majority of doctors in the US what they will use to treat Covid-19 patients. The vast majority of doctors in the US have proven themselves not to be healers or thinkers at all, but merely followers of sanctioned protocols. And regulators in the US have proven that the health of the population is not their primary concern. If it were, they would have pursued all avenues to tackle Covid-19, including an all-out search for repurposed drugs to combat it. They have the technological tools to analyze on a molecular level every known drug and the structure of SARS-CoV-2, to see what might work. Instead, the regulators went all-in hand-in-hand with the pharmaceutical industry and put all their eggs in the magical vaccines and new, expensive treatments-only basket. History will not look favorably upon the health regulators and medical profession of the so-called advanced economies.
View 1 reply
Marco Camion
replied on 26 January, 2021
Jorge, I do apologize to the forum/site. Yes, there is a one-liner. I probably missed it because I was astounded at the discrepancy of the startling evidence that the meta-analysis produced and the bizarre conclusion expressed. I have seen authors exaggerate their findings, especially before peer-reviewing, but never have I seen an author undermine their own findings! A 75% success rate against death with a medication that is one of the safest known to man and that is very cheap, and conclude that we need more trials 'before it can be allowed to be used' while 15 000 people a day die of Covid! That is scientifically bizarre. We are in a world-crippling pandemic and regulators/health authorities fiddle while Rome burns! What was the author thinking? I'm not so sure there is no conflict of interest. Ivermectin should be licensed for human use in all countries that it's not and doctors should be allowed to treat their patients as they see fit, as per the Helsinki Declaration. And it is not just this study (that, unfortunately, is flawed) whose data confirms it but another recent, and more rigorous, meta-analysis as well. More RCTs at this point are unethical given the results of all the meta-analyses and the author should know this. However, as there seems to be an orchestrated push-back against ivermectin I do not want to weaken the cause with so-called ín-fighting'. But the way I see it the conclusion of this review is doing the naysayer's work for them by advising authorities not to license/use IVM. How many more people have to die before they wake up. If IVM doesn't work nobody is harmed, if it does hundreds and thousands of lives are saved and the global economy could be pulled back from the brink. And we have proof that it does work.
Irena Cosic
ORCiDcommented on 30 January, 2021
Fantastic research. We have recently published theoretical proof that ivermectin can work against SARS-CoV-2. Here is our recently published paper: . Cosic I, Cosic D, Loncarevic I: Analysis of Ivermectin as Potential Inhibitor of SARS-CoV-2 Using Resonant Recognition Model. International Journal of Sciences, 2021, 10(1), 1-6, doi: 10.18483/ijSci.2433.
View 1 reply
Yeison Harvey Carlosama
ORCiDreplied on 05 February, 2021
Dr Andrew Hill, Congratulation for this great contribution. I respectfully allow myself to make some suggestions, especially for the next version of his meta-analysis. 1. Include a funnel plot and test for publication bias assessment (Egger test or another) 2. Chloroquine was the control group in some studies such as Niaee and Elgazaar. Now, we know that chloroquine increases the risk of death. Because of that, the results in the meta-analysis may overestimate a beneficial effect of ivermectin treatment. It would be great if you perform subgroup analysis by separating studies with chloroquine and without chloroquine in the control group. 3. Finally, I hope that the data from the new studies allow you to suggest a recommendation according to the GRADE scale in a similar way that Theresa Lawrie. Go ahead and I’ll be waiting for your new results.
View 2 replies
Philip Machanick
ORCiDreplied on 07 February, 2021
Good points. I have just been perusing www.clinicaltrials.gov and 57 Covid-19 ivermectin trials are listed, most without results (and many of poor quality but that’s another whole issue), which points to a real risk of publication bias. Another correction for this: choose a list of trials in advance and follow them to conclusion. Dr Hill is doing this. Until that is done, I am not sure that we have solid evidence either way.
Daniel
replied on 08 February, 2021
How did you know that chloroquine increases the risk offre death? https://academic.oup.com/ofid/article/7/11/ofaa500/5930834
View 1 reply
Philip Machanick
ORCiDreplied on 20 February, 2021
The paper you cite says “We excluded individuals with contraindications to hydroxychloroquine.” The list of exclusions is quite extensive, a far cry from the early claims that this was a safe medication that everyone could take. And a lot more extensive than the list of known contraindications before anyone used if for this condition. A small fraction of covid-19 cases turn really serious but they overlap strongly with the rare complications of hydroxychloroquine. This is why proper studies designed to eliminate bias including safety are necessary. Harmful side-effects that are rare or unlikely otherwise could be triggered by the interaction with ivermectin and covid-19. We don’t know until we actually measure this.
Peter Yim
ORCiDcommented on 05 February, 2021
Dr. Hill discusses the NIH COVID-19 Treatment Guidelines recommendation at length. We have asked through FOIA and other channels if the recent NIH recommendation was put to a vote. The NIH has declined to answer that question. As such, we should not assume that there was a vote on the current ivermectin recommendation at the NIH. The recommendation it received may have been the result of a much more perfunctory process. The validity of these comments are obvious from the FOIA and other communications linked in this article: https://trialsitenews.com/the-ivermectin-recommendation-was-a-deception/
Someone with eyes
replied on 26 January, 2021
The declaration is on the first page of the full-text PDF.
Andrew Hill
replied on 26 January, 2021
A declaration of interest statement was included on the cover page of this paper.
View 1 reply
Marco Camion
replied on 26 January, 2021
Yip, I see that now and I apologize to the author/s and Researchsquare. I guess I initially skipped past the intro and couldn't find it again in my anger at reading the conclusion: Why would a medication that scored 75% success against COVID death, which is so cheap and so safe need further testing before DEMANDING its implementation? 15 000 people die every day and the conclusion calls for more tests! What kind of doctor/s would recommend such a thing? The evidence suggests that at those odds and proven safety in that dosage range one should recommend immediate implementation. We don't have the privilege of time nor need large studies in order to start treatment. 1 year into this pandemic - it has now become unethical and immoral not to use ivermectin, or at least start to roll it out. In the unlikely event of ivermectin not working no one is harmed, if it does work hundreds of thousands of lives could be saved and the world's economy restored. And we do have enough good evidence to support its efficacy; the evidence in this review supports it (but strangely the conclusion denies it - what is going on?). Further studies can happen while we start to treat patients, protect health workers and get factories gearing up manufacturing capacity. I wonder if the author/s are familiar with the Helsinki Declaration (and the Geneva one for that matter) concerning physicians' authority to use unproven interventions on ill patients in the absence of proven interventions, with the patient's consent of course. Nowhere does it say regulators will decide what a physician will use. Stoopid is as stoopid does, as we say down here on the creek.
View 1 reply
HJK
replied on 27 January, 2021
I agree with you, and the FLCCC: there is sufficient evidence now, of satisfactory-enough quality, for regulators unequivocally to recommend the use of ivermectin for the treatment and prevention of Covid-19. What we have been witnessing, and are continuing to witness, is the utter failure of the health care regulators and the medical profession in the so-called advanced economies. Where I live, the US, the vast majority of doctors refuse to exercise their minds even one bit to look into potential treatments to help their patients. The vast majority of them are waiting for Fauci and NIH to tell them what to do for Covid-19. The vast majority of them would rather do nothing, and watch patients die, than to step outside of the box and try something, anything, that might help a patient survive Covid-19. A year into this, and the NIH's early outpatient treatment recommendation is to wait at home to get sick enough to go to the ER. So yes, regulators de facto do decide for the vast majority of doctors in the US what they will use to treat Covid-19 patients. The vast majority of doctors in the US have proven themselves not to be healers or thinkers at all, but merely followers of sanctioned protocols. And regulators in the US have proven that the health of the population is not their primary concern. If it were, they would have pursued all avenues to tackle Covid-19, including an all-out search for repurposed drugs to combat it. They have the technological tools to analyze on a molecular level every known drug and the structure of SARS-CoV-2, to see what might work. Instead, the regulators went all-in hand-in-hand with the pharmaceutical industry and put all their eggs in the magical vaccines and new, expensive treatments-only basket. History will not look favorably upon the health regulators and medical profession of the so-called advanced economies.
View 1 reply
Marco Camion
replied on 26 January, 2021
Jorge, I do apologize to the forum/site. Yes, there is a one-liner. I probably missed it because I was astounded at the discrepancy of the startling evidence that the meta-analysis produced and the bizarre conclusion expressed. I have seen authors exaggerate their findings, especially before peer-reviewing, but never have I seen an author undermine their own findings! A 75% success rate against death with a medication that is one of the safest known to man and that is very cheap, and conclude that we need more trials 'before it can be allowed to be used' while 15 000 people a day die of Covid! That is scientifically bizarre. We are in a world-crippling pandemic and regulators/health authorities fiddle while Rome burns! What was the author thinking? I'm not so sure there is no conflict of interest. Ivermectin should be licensed for human use in all countries that it's not and doctors should be allowed to treat their patients as they see fit, as per the Helsinki Declaration. And it is not just this study (that, unfortunately, is flawed) whose data confirms it but another recent, and more rigorous, meta-analysis as well. More RCTs at this point are unethical given the results of all the meta-analyses and the author should know this. However, as there seems to be an orchestrated push-back against ivermectin I do not want to weaken the cause with so-called ín-fighting'. But the way I see it the conclusion of this review is doing the naysayer's work for them by advising authorities not to license/use IVM. How many more people have to die before they wake up. If IVM doesn't work nobody is harmed, if it does hundreds and thousands of lives are saved and the global economy could be pulled back from the brink. And we have proof that it does work.