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Efficacy and safety of single-dose ivermectin in mild-to-moderate COVID-19: the double-blind, randomized, placebo-controlled CORVETTE-01 trial

Wada et al., Frontiers in Medicine, doi:10.3389/fmed.2023.1139046, NCT04703205

May 2023

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Ivermectin for COVID-19

4th treatment shown to reduce risk in August 2020

^*, now known with p < 0.00000000001 from 102 studies, recognized in 22 countries.

Lower risk for mortality, ventilation, ICU admission, hospitalization, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine complementary and synergistic treatments. ^* >10% efficacy in meta analysis with ≥3 clinical studies.

4,100+ studies for 60+ treatments. c19ivm.org

Late treatment (6.6 days after onset/PCR+) RCT with 221 low risk (no deaths) COVID-19 patients in Japan, showing no significant difference in viral clearance with a single dose of ivermectin under fasting. Authors note that a single 200 μg/kg dose under fasting was used as approved in Japan, and that the low dose, single day dosing, and fasting administration (~2.5 times lower plasma concentration according to Guzzo) limit applicability, and that studies with more favorable outcomes generally used a higher dose or multiday dosing. Details of PCR testing are not provided but the very slow clearance within the low risk population suggests a very high Ct value that may not accurately represent any reduction in replication-competent viral load.

An erratum notes a conflict of interest for a reviewer that was a Merck employee: frontiersin.org

Viral load measured by PCR may not accurately reflect infectious virus measured by viral culture. Porter show that viral load early in infection was correlated with infectious virus, but viral load late in infection could be high even with low or undetectable infectious virus. Assessing viral load later in infection may underestimate reductions in infectious virus with treatment.

This is the 47th of 49 COVID-19 RCTs for ivermectin, which collectively show efficacy with p=0.00000038.

This is the 99th of 102 COVID-19 controlled studies for ivermectin, which collectively show efficacy with p<0.0000000001 (1 in 560 quintillion).

1. frontiersin.org, www.frontiersin.org/articles/10.3389/fmed.2023.1289307/full.www.frontiersin.org/articles/10.3389/fmed.2023.1289307/full.

2. Guzzo et al., Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects, J. Clinical Pharmacology, doi:10.1177/009127002237994.wiley.com, doi.org.

3. Porter et al., The ratio between SARS-CoV-2 RNA viral load and culturable viral titer differs depending on stage of infection, medRxiv, doi:10.1101/2023.07.06.23292300.medrxiv.org, doi.org.

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risk of progression, 19.0% lower, RR 0.81, p = 0.46, treatment 19 of 106 (17.9%), control 23 of 106 (21.7%), NNT 26, adjusted per study, odds ratio converted to relative risk.

risk of progression, 27.1% lower, RR 0.73, p = 0.47, treatment 7 of 28 (25.0%), control 9 of 29 (31.0%), NNT 17, adjusted per study, odds ratio converted to relative risk, pneumonia for patients w/o pneumonia at baseline.

risk of oxygen therapy, 14.3% higher, RR 1.14, p = 0.46, treatment 22 of 106 (20.8%), control 19 of 106 (17.9%), adjusted per study, odds ratio converted to relative risk.

improvement, 23.5% worse, OR 1.23, p = 0.61, treatment 106, control 106, adjusted per study, inverted to make OR<1 favor treatment, RR approximated with OR.

risk of no recovery, 60.0% lower, RR 0.40, p = 0.17, treatment 4 of 107 (3.7%), control 10 of 107 (9.3%), NNT 18, day 15, dyspnea.

risk of no recovery, 20.0% lower, RR 0.80, p = 1.00, treatment 4 of 107 (3.7%), control 5 of 107 (4.7%), NNT 107, day 15, headache.

risk of no recovery, no change, RR 1.00, p = 1.00, treatment 7 of 107 (6.5%), control 7 of 107 (6.5%), day 15, sore throat.

risk of no recovery, 18.2% lower, RR 0.82, p = 0.81, treatment 9 of 107 (8.4%), control 11 of 107 (10.3%), NNT 53, day 15, nasal discharge.

risk of no recovery, 3.8% higher, RR 1.04, p = 1.00, treatment 27 of 107 (25.2%), control 26 of 107 (24.3%), day 15, cough.

risk of no recovery, no change, RR 1.00, p = 1.00, treatment 18 of 107 (16.8%), control 18 of 107 (16.8%), day 15, sputum.

risk of no recovery, 20.0% lower, RR 0.80, p = 1.00, treatment 4 of 107 (3.7%), control 5 of 107 (4.7%), NNT 107, day 15, diarhhea.

risk of no recovery, 66.7% higher, RR 1.67, p = 0.72, treatment 5 of 107 (4.7%), control 3 of 107 (2.8%), day 15, myalgia.

risk of no recovery, 1000.0% higher, RR 11.00, p = 0.06, treatment 5 of 107 (4.7%), control 0 of 107 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), day 15, arthralgia.

risk of no viral clearance, 4.2% higher, HR 1.04, p = 0.79, treatment 106, control 106, inverted to make HR<1 favor treatment, Kaplan–Meier, primary outcome.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Wada et al., 22 May 2023, Double Blind Randomized Controlled Trial, placebo-controlled, Japan, peer-reviewed, 26 authors, study period August 2020 - October 2021, average treatment delay 6.6 days, dosage 200μg/kg single dose, trial NCT04703205 (history). Contact: yamaoka@med.kitasato-u.ac.jp.

This Paper Ivermectin All

Efficacy and safety of single-dose ivermectin in mild-to-moderate COVID-19: the double-blind, randomized, placebo-controlled CORVETTE-01 trial

Tatsuhiko Wada, Makoto Hibino, Hiromi Aono, Shunsuke Kyoda, Yosuke Iwadate, Eri Shishido, Keisuke Ikeda, Nana Kinoshita, Yasuki Matsuda, Sakiko Otani, Ryo Kameda, Kenta Matoba, Miwa Nonaka, Mika Maeda, Yuji Kumagai, Junya Ako, Masayoshi Shichiri, Katsuhiko Naoki, Masato Katagiri, Masashi Takaso, Masatsugu Iwamura, Kazuhiko Katayama, Takeshi Miyatsuka, Yasushi Orihashi, Kunihiro Yamaoka

Frontiers in Medicine, doi:10.3389/fmed.2023.1139046

Background: To investigate whether ivermectin inhibits SARS-CoV-2 proliferation in patients with mild-to-moderate COVID-19 using time to a negative COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) test. Methods: CORVETTE-01 was a double-blind, randomized, placebo-controlled study (August 2020-October 2021) conducted in Japan. Overall, 248 patients diagnosed with COVID-19 using RT-PCR were assessed for eligibility. A single oral dose of ivermectin (200 μg/kg) or placebo was administered under fasting. The primary outcome was time to a negative COVID-19 RT-PCR test result for SARS-CoV-2 nucleic acid, assessed using stratified log-rank test and Cox regression models. Results: Overall, 112 and 109 patients were randomized to ivermectin and placebo, respectively; 106 patients from each group were included in the full analysis set (male [%], mean age: 68.9%, 47.9 years [ivermectin]; 62.3%, 47.5 years [placebo]). No significant difference was observed in the occurrence of negative RT-PCR tests between the groups (hazard ratio, 0.96; 95% confidence interval [CI] 0.70-1.32; p = 0.785). Median (95% CI) time to a negative RT-PCR test was 14.0

Ethics statement The studies involving human participants were reviewed and approved by the IRB of Kitasato University Shirokane Campus, affiliation: Kitasato University. The patients/participants provided their written informed consent to participate in this study. Author contributions KY contributed towards conceptualization and drafting the work. YK contributed towards conceptualization, drafting the work, and revising it critically for important intellectual content. MS, TM, JA, KN, MI, MT, MM, MK, and KK contributed towards conceptualization, drafting the work, and revising it critically for important intellectual content. MH, HA, MN, KI, ES, YI, NK, SK, SO, RK, KM, and YM contributed towards acquisition, analysis, or interpretation of data for the work, drafting the work, and revising it critically for important intellectual content. TW contributed towards conceptualization, acquisition, analysis, or interpretation of data for the work, and drafting the work. YO contributed towards the data analysis, drafting the work, and revising it critically for important intellectual content. All authors provide approval for publication of the content and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could..

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Late treatment
is less effective

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