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Research Article
Hydroxychloroquine, nitazoxanide and ivermectin have similar effects in early COVID-19: a head-to-head comparison of the Pre-AndroCoV Trial.
Flavio A. Cadegiani
Corpometria Institute
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2699-4344
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that all necessary patient/participant consent or assent has been obtained and the appropriate institutional forms have been archived.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.
Background: COVID-19 pandemic requires urgent responses in terms of identification of effective and safe therapies to reduce hospitalization, death, and post-COVID symptoms, while vaccines are not extensively available. Repurposing already existing medications for COVID-19 should be preferred over the development of new drugs due to their inherent advantages of well-established safety profile, familiarity, and cost. Although antiandrogens have strong plausibility to be effective against COVID-19, hydroxychloroquine, nitazoxanide and ivermectin gained unquestionable popularity due to their in vitro and in vivo direct or indirect antiviral activity, and preliminary observations of efficacy against COVID-19. The objective of the present open-label prospective observational study (the pre-AndroCoV trial) was to make a head-to-head comparative analysis between hydroxychloroquine, nitazoxanide and ivermectin, in terms of potential efficacy for COVID-19, combined with early COVID-19 detection, aiming to choose one of these three drugs to include in the AndroCoV randomized clinical trial (RCT).
Materials and methods: Participants were recruited from social media and referred from other medical centers. Patients confirmed for COVID-19 with positive rtPCR-SARS-CoV-2 with fewer than seven days of symptoms and four days of treatment were included. Patients were actively questioned for age, sex, body mass index (BMI), presence of approximately 40 existing diseases and regular use of 30 drug classes, and COVID-19 symptomatology. Hydroxychloroquine 400mg/day for five days, nitazoxanide 500mg twice daily for six days, or ivermectin 0.2mg/kg/day for three consecutive days was given in a quasi-random manner, in association with azithromycin 500mg/day for five days, and optional addition of vitamin C, vitamin D and zinc, and glucocorticoids and anticoagulants in case of signs of lung injury or higher risk for thrombosis, respectively. Patients were followed up for 60 days, including active questions on disease course and symptoms on Days 0, 1, 2, 3, 7, 14 and 30, and virtual medical visits on Days 0 and 14, and whenever symptoms got worse on in the presence of severe adverse effects.
Results: In total, 585 participants, including 270 females and 305 males, were included. Of these, 159, 357, and 110 patients received hydroxychloroquine, nitazoxanide, and ivermectin, respectively, with similar baseline characteristics and time-to-treat between them. The three groups had similar duration of positive rtPCR-SARS-CoV-2, clinical disease duration and recovery speed. Of the 585 patients, none was hospitalized, needed mechanical ventilation, or died, and 1.5% persisted with symptoms after recovery.
Conclusion: Hydroxychloroquine, nitazoxanide and ivermectin seem to be similarly effective for overall clinical outcomes in COVID-19 when used before seven days of symptoms, and overwhelmingly superior compared to untreated COVID-19 population, even for those outcomes not influenced by placebo effect, at least when combined with azithromycin, and vitamin C, D and zinc in the majority of the cases. Between these drugs, nitazoxanide demonstrated the strongest broad spectrum antiviral activity, plausibility to act as an anti-COVID agent, and safety profile, at least at the time of the choice of the drug for the AndroCoV Trial.
Keywords
COVID-19, SARS-CoV-2, antiandrogen, hydroxychloroquine, ivermectin, nitazoxanide
Robert Brown
commented on 01 November, 2020
The BMJ Rapid Response: "Vitamin D Mitigates COVID-19, Say 40+ Patient Studies (listed below) – Yet BAME, Elderly, Care-homers, and Obese are still ‘D’ deficient, thus at greater COVID-19 risk - WHY? lists 40+ COVI19 positive patient studies all pointing to vitamin D mitigating COVID-19. (there are more studies since rapid response - link posted below) Vitamin D was given to 82.3% of patients in your study. Could you please provide more detail as to dosing, timing, etc please. Have you considered that the nutritional / vitamin D interventions may have accounted for many of the benefits you saw?
Robert Brown
commented on 01 November, 2020
Has this study focused on the boots (Hydroxychloroquine), helmet (nitazoxanide), and jacket (ivermectin) all of importance in combat, but omitted to consider it may be the parachutes, in the form of Vitamin D and Zinc, that actually saved patients from COVID-19 - the factor in question (jumping out of aircraft). A RCT on parachutes humorously makes the point study design can impact outcomes. Yeh R, Valsdottir L, Yeh M, Shen C, Kramer D, et al. PARACHUTE Investigators. (13th December 2018) Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial. BMJ. 2018 Dec 13;363:k5094. doi: 10.1136/bmj.k5094. Erratum in: BMJ. 2018 Dec 18;363:k5343. PMID: 30545967; PMCID: PMC6298200. Available at https://pubmed.ncbi.nlm.nih.gov/30545967/
Robert Brown
commented on 01 November, 2020
Link to Rapid Response above: Vitamin D Mitigates COVID-19, Say 40+ Patient Studies (listed below) – Yet BAME, Elderly, Care-homers, and Obese are still ‘D’ deficient, thus at greater COVID-19 risk - WHY? BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m3872 (Published 05 October 2020) Cite this as: BMJ 2020;371:m3872 Available at https://www.bmj.com/content/371/bmj.m3872/rr-5
Bruce Stewart
commented on 04 November, 2020
I find it very interesting that ivermectin has shown effectiveness in treating COVID-19 since many claim it to also be effective in treating some cancers.
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Research Article
Hydroxychloroquine, nitazoxanide and ivermectin have similar effects in early COVID-19: a head-to-head comparison of the Pre-AndroCoV Trial.
Flavio A. Cadegiani
Corpometria Institute
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2699-4344
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 29 Oct, 2020
Community comments: 4
Metrics
Comments: 4
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.
Background: COVID-19 pandemic requires urgent responses in terms of identification of effective and safe therapies to reduce hospitalization, death, and post-COVID symptoms, while vaccines are not extensively available. Repurposing already existing medications for COVID-19 should be preferred over the development of new drugs due to their inherent advantages of well-established safety profile, familiarity, and cost. Although antiandrogens have strong plausibility to be effective against COVID-19, hydroxychloroquine, nitazoxanide and ivermectin gained unquestionable popularity due to their in vitro and in vivo direct or indirect antiviral activity, and preliminary observations of efficacy against COVID-19. The objective of the present open-label prospective observational study (the pre-AndroCoV trial) was to make a head-to-head comparative analysis between hydroxychloroquine, nitazoxanide and ivermectin, in terms of potential efficacy for COVID-19, combined with early COVID-19 detection, aiming to choose one of these three drugs to include in the AndroCoV randomized clinical trial (RCT).
Materials and methods: Participants were recruited from social media and referred from other medical centers. Patients confirmed for COVID-19 with positive rtPCR-SARS-CoV-2 with fewer than seven days of symptoms and four days of treatment were included. Patients were actively questioned for age, sex, body mass index (BMI), presence of approximately 40 existing diseases and regular use of 30 drug classes, and COVID-19 symptomatology. Hydroxychloroquine 400mg/day for five days, nitazoxanide 500mg twice daily for six days, or ivermectin 0.2mg/kg/day for three consecutive days was given in a quasi-random manner, in association with azithromycin 500mg/day for five days, and optional addition of vitamin C, vitamin D and zinc, and glucocorticoids and anticoagulants in case of signs of lung injury or higher risk for thrombosis, respectively. Patients were followed up for 60 days, including active questions on disease course and symptoms on Days 0, 1, 2, 3, 7, 14 and 30, and virtual medical visits on Days 0 and 14, and whenever symptoms got worse on in the presence of severe adverse effects.
Results: In total, 585 participants, including 270 females and 305 males, were included. Of these, 159, 357, and 110 patients received hydroxychloroquine, nitazoxanide, and ivermectin, respectively, with similar baseline characteristics and time-to-treat between them. The three groups had similar duration of positive rtPCR-SARS-CoV-2, clinical disease duration and recovery speed. Of the 585 patients, none was hospitalized, needed mechanical ventilation, or died, and 1.5% persisted with symptoms after recovery.
Conclusion: Hydroxychloroquine, nitazoxanide and ivermectin seem to be similarly effective for overall clinical outcomes in COVID-19 when used before seven days of symptoms, and overwhelmingly superior compared to untreated COVID-19 population, even for those outcomes not influenced by placebo effect, at least when combined with azithromycin, and vitamin C, D and zinc in the majority of the cases. Between these drugs, nitazoxanide demonstrated the strongest broad spectrum antiviral activity, plausibility to act as an anti-COVID agent, and safety profile, at least at the time of the choice of the drug for the AndroCoV Trial.
Robert Brown
commented on 01 November, 2020
The BMJ Rapid Response: "Vitamin D Mitigates COVID-19, Say 40+ Patient Studies (listed below) – Yet BAME, Elderly, Care-homers, and Obese are still ‘D’ deficient, thus at greater COVID-19 risk - WHY? lists 40+ COVI19 positive patient studies all pointing to vitamin D mitigating COVID-19. (there are more studies since rapid response - link posted below) Vitamin D was given to 82.3% of patients in your study. Could you please provide more detail as to dosing, timing, etc please. Have you considered that the nutritional / vitamin D interventions may have accounted for many of the benefits you saw?
Robert Brown
commented on 01 November, 2020
Has this study focused on the boots (Hydroxychloroquine), helmet (nitazoxanide), and jacket (ivermectin) all of importance in combat, but omitted to consider it may be the parachutes, in the form of Vitamin D and Zinc, that actually saved patients from COVID-19 - the factor in question (jumping out of aircraft). A RCT on parachutes humorously makes the point study design can impact outcomes. Yeh R, Valsdottir L, Yeh M, Shen C, Kramer D, et al. PARACHUTE Investigators. (13th December 2018) Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial. BMJ. 2018 Dec 13;363:k5094. doi: 10.1136/bmj.k5094. Erratum in: BMJ. 2018 Dec 18;363:k5343. PMID: 30545967; PMCID: PMC6298200. Available at https://pubmed.ncbi.nlm.nih.gov/30545967/
Robert Brown
commented on 01 November, 2020
Link to Rapid Response above: Vitamin D Mitigates COVID-19, Say 40+ Patient Studies (listed below) – Yet BAME, Elderly, Care-homers, and Obese are still ‘D’ deficient, thus at greater COVID-19 risk - WHY? BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m3872 (Published 05 October 2020) Cite this as: BMJ 2020;371:m3872 Available at https://www.bmj.com/content/371/bmj.m3872/rr-5
Bruce Stewart
commented on 04 November, 2020
I find it very interesting that ivermectin has shown effectiveness in treating COVID-19 since many claim it to also be effective in treating some cancers.