Low-risk RCT in Thailand with zero mortality, reporting no significant differences with the addition of ivermectin to favipiravir treatment, however the study as reported does not make sense as detailed below.
All participants were suspected of having COVID-19 and authors assigned 536 PCR- at baseline to a “prevention” study where the only outcome tested was cases. However 62% of these patients were already symptomatic at baseline. Since PCR has a high false negative rate in the first few days, patients may already have COVID-19. It doesn’t make sense to study prevention of cases with already symptomatic patients - studying progression and clinical outcomes would make sense, however authors report only case results. The reported time to PCR+ is also not informative because patients were instructed to do an antigen test only if there were new symptoms (followed by a PCR test).
For both “prevention” and treatment, authors note:
“All participant without evaluable outcomes and drop-out participant were considered as having a poor outcome”, and “…assumed all participants who withdraw or do not take the study drug, and those in the prevention study who do not perform the second NP swab, have a poor outcome.”
This is not logical, participants that recover quickly are more likely to drop out.
Notably, 100% of the 4 ivermectin patients that did not receive the treatment (which may be because they dropped out) were reported as hospitalized (compared to 2% overall). Authors do not report how many patients dropped out or did not have evaluable outcomes.
We are unable to find protocol registration. The study protocol published with the paper unusually uses past tense in a few places, e.g., “290 patients … were needed”, “The ITT population comprised…”, and “applied a worst-case scenario”, as if it was written after the study. The study protocol file metadata indicates creation June 2022 by Pakpoom Phoompoung. The supplementary figure file shows creation April 2022 by Noppasit Musiwiraphat (not a listed author).
Treatment and placebo were labeled as A and B, meaning any indication of treatment assignment results in a total loss of blinding (e.g., if an investigator observes typical treatment side effects, blinding is lost).
The same hospital has an ivermectin vs. HCQ trial which was registered, was due for completion November 2021, but has not reported results
1.
Dyspnea was ~2x more prevalent in the ivermectin group (9.2% vs. 4.7%), suggesting incomparable groups for serious outcomes.
Studies show that favipiravir is effective, reducing the potential benefit of additional treatments.
Authors have not responded to a request for data.
Angkasekwinai et al., 12 Jun 2022, Double Blind Randomized Controlled Trial, placebo-controlled, Thailand, peer-reviewed, mean age 38.4, 9 authors, study period August 2021 - November 2021, dosage 400μg/kg days 1-3, 400-600µg/kg.
Contact: nasikarn@gmail.com (corresponding author), pinyo.rat@mahidol.ac.th, methee.cha@mahidol.ac.th, pakpoom.pho@mahidol.ac.th, pornpan.koo@mahidol.ac.th, walaiporn.wan@mahidol.ac.th, visanu.tha@mahidol.ac.th, sorawit.cha@mahidol.ac.th, varalak.sri@mahidol.ac.th, nasikarn.ang@mahidol.ac.th.
Safety and Efficacy of Ivermectin for the Prevention and Treatment of COVID-19: A Double-Blinded Randomized Placebo-Controlled Study
Nasikarn Angkasekwinai, Pinyo Rattanaumpawan, Methee Chayakulkeeree, Pakpoom Phoompoung, Pornpan Koomanachai, Sorawit Chantarasut, Walaiporn Wangchinda, Varalak Srinonprasert, Visanu Thamlikitkul
Antibiotics, doi:10.3390/antibiotics11060796
The safety and efficacy of ivermectin for the prevention and treatment of COVID-19 are still controversial topics. From August to November 2021, we conducted a double-blinded, randomized controlled trial at Siriraj Hospital, Thailand. Eligible participants were adults ≥ 18 years with suspected COVID-19 who underwent a SARS-CoV-2 RT-PCR test. After enrollment, the participants were randomized to receive either ivermectin (400-600 µg/kg/d) or placebo once daily for 3 days. Among 983 participants, 536 (54.5%) with a negative RT-PCR result were enrolled in the prevention study, and 447 (45.5%) with a positive RT-PCR result were enrolled in the treatment study. In the prevention study, the incidence of COVID-19 on Day 14 was similar between the ivermectin and the placebo group (4.7% vs. 5.2%; p = 0.844; ∆ = −0.4%; 95% CI; −4.3-3.5%). In the treatment study, there was no significant difference between the ivermectin and placebo group for any Day 14 treatment outcome: proportion with oxygen desaturation (2.7% vs. 1.9%; p = 0.75), change in WHO score from baseline (1 [−5, 1] vs. 1 [−5, 1]; p = 0.50), and symptom resolution (76% vs. 82.2%; p = 0.13). The ivermectin group had a significantly higher proportion of transient blurred vision (5.6% vs. 0.6%; p < 0.001). Our study failed to demonstrate the efficacy of a 3-day once daily of ivermectin for the prevention and treatment of COVID-19. The given regimen of ivermectin should not be used for either prevention or treatment of COVID-19 in populations with a high rate of COVID-19 vaccination.
Conflicts of Interest: The authors declare no conflict of interest.
References
Abd-Elsalam, Noor, Badawi, Khalaf, Esmail et al., Clinical study evaluating the efficacy of ivermectin in COVID-19 treatment: A randomized controlled study, J. Med. Virol,
doi:10.1002/jmv.27122Ahmed, Karim, Ross, Hossain, Clemens et al., A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2020.11.191Bartoletti, Azap, Barac, Bussini, Ergonul et al., ESCMID COVID-19 living guidelines: Drug treatment and clinical management, Clin. Microbiol. Infect,
doi:10.1016/j.cmi.2021.11.007Behera, Patro, Singh, Chandanshive, Ravikumar et al., Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study, PLoS ONE,
doi:10.1371/journal.pone.0247163Buonfrate, Chesini, Martini, Roncaglioni, Ojeda Fernandez et al., High-dose ivermectin for early treatment of COVID-19 (COVER study): A randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial, Int. J. Antimicrob. Agents,
doi:10.1016/j.ijantimicag.2021.106516Cavalcanti, Berwanger, Zampieri, Hydroxychloroquine with or without Azithromycin in Covid-19, N. Engl. J. Med
Guzzo, Furtek, Porras, Chen, Tipping et al., Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects, J. Clin. Pharmacol,
doi:10.1177/009127002401382731Hassanipour, Arab-Zozani, Amani, Heidarzad, Fathalipour et al., The efficacy and safety of Favipiravir in treatment of COVID-19: A systematic review and meta-analysis of clinical trials, Sci. Rep,
doi:10.1038/s41598-021-90551-6Hill, Ahmed, Asghar, Meta-Analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection
Hill, Mirchandani, Pilkington, Ivermectin for COVID-19: Addressing Potential Bias and Medical Fraud, Open Forum. Infect. Dis,
doi:10.1093/ofid/ofab645Krolewiecki, Lifschitz, Moragas, Travacio, Valentini et al., Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial, EClinicalMedicine,
doi:10.1016/j.eclinm.2021.100959Lopez-Medina, Lopez, Hurtado, Davalos, Ramirez et al., Effect of Ivermectin on Time to Resolution of Symptoms Among Adults with Mild COVID-19: A Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2021.3071Murray, Piot, The Potential Future of the COVID-19 Pandemic: Will SARS-CoV-2 Become a Recurrent Seasonal Infection?, JAMA,
doi:10.1001/jama.2021.2828Navarro, Camprubi, Requena-Mendez, Buonfrate, Giorli et al., Safety of high-dose ivermectin: A systematic review and meta-analysis, J. Antimicrob. Chemother
Ravikirti, None
Rayner, Dron, Park, Decloedt, Cotton et al., Accelerating Clinical Evaluation of Repurposed Combination Therapies for COVID-19, Am. J. Trop. Med. Hyg,
doi:10.4269/ajtmh.20-0995Reis, Silva, Silva, Thabane, Milagres et al., Effect of Early Treatment with Ivermectin among Patients with Covid-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2115869Roman, Burela, Pasupuleti, Piscoya, Vidal et al., Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials, Clin. Infect. Dis
Roy, Pattadar, Raj, Agarwal, Biswas et al., Evaluation of Ivermectin as a Potential Treatment for Mild to Moderate COVID-19: A Double-Blind Randomized Placebo Controlled Trial in Eastern India, J. Pharm. Pharm. Sci,
doi:10.18433/jpps32105Schmith, Zhou, Lohmer, The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19, Clin. Pharmacol. Ther,
doi:10.1002/cpt.1889Shoumann, Hegazy, Nafae, Ragab, Samra et al., Use of Ivermectin as a Potential Chemoprophylaxis for COVID-19 in Egypt: A Randomised Clinical Trial, J. Clin. Diagn. Res
Sirijatuphat, Suputtamongkol, Angkasekwinai, Horthongkham, Chayakulkeeree et al., Epidemiology, clinical characteristics, and treatment outcomes of patients with COVID-19 at Thailand's university-based referral hospital, BMC Infect. Dis,
doi:10.1186/s12879-021-06081-zSmit, Ochomo, Aljayyoussi, Kwambai, Abong'o et al., Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisininpiperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): A randomised, double-blind, placebo-controlled trial, Lancet Infect. Dis,
doi:10.1016/S1473-3099(18)30163-4Vallejos, Zoni, Bangher, Villamandos, Bobadilla et al., Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial, BMC Infect. Dis,
doi:10.1186/s12879-021-06348-5Zhang, Song, Ci, An, Ju et al., Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice, Inflamm. Res,
doi:10.1007/s00011-008-8007-8DOI record:
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