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High dose ivermectin for the early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof of concept trial

Buonfrate et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2021.106516 (date from preprint), COVER, NCT04438850

Sep 2021

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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.

4,000+ studies for 60+ treatments. c19ivm.org

Early terminated 89 patient RCT with 29 high dose and 32 very high dose ivermectin patients, showing dose dependent viral load reduction, although not reaching statistical significance due to early termination. Since most patients have low viral load at day 7, there is little room for improvement with a treatment at day 7. Intermediate results may show significantly greater improvement, but are not provided. Authors note that ivermectin remained safe even at the very high dose used, although tolerability was reduced. Adherence was very low in the very high dose arm (~60%).

The paper reports 4 SAEs, all resolved, with 3 patients hospitalized in the very high dose ivermectin arm, 1 in the high dose arm, and 0 in the control arm. However, the supplementary data is contradictory, showing 2 grade 3 events in both ivermectin arms (2 infections and infestations, and 2 COVID-19 pneumonia). While this result is not statistically significant, it may be in part due to randomization failure because three times as many patients were randomized in a hospital setting in the ivermectin arms (12/58) compared to the placebo arm (2/29), as shown in supplemental table 2, suggesting higher baseline severity in the ivermectin arms. The very high dose ivermectin arm also had more male patients (73% vs. 45%), higher median weight (79 vs. 70kg), and higher baseline cough (56% vs 42%), pyrexia (56% vs 33%), and anosmia (33% vs 17%) as per supplemental table 2.

Authors administered ivermectin on an empty stomach. Ivermectin is a lipophilic drug with low aqueous solubility and is better absorbed when given with food, especially high-fat meals. Administration with a high-fat meal can significantly increase plasma and tissue concentrations (~2.5x plasma concentration in Guzzo) and reduce time to onset of action. Standard practice for systemic use of ivermectin is administration with food (for intestinal parasitic infections, systemic distribution may not be required). Specifying fasted administration may avoid or delay the attainment of therapeutic concentrations and raises concerns about possible investigator bias.

This is the 30th of 49 COVID-19 RCTs for ivermectin, which collectively show efficacy with p=0.00000038.

This is the 62nd of 102 COVID-19 controlled studies for ivermectin, which collectively show efficacy with p<0.0000000001 (1 in 560 quintillion).

This study is excluded in the after exclusion results of meta analysis: significant unadjusted group differences, with 3 times as many patients in the ivermectin arms having the baseline visit in a hospital setting, and arm C having large differences in baseline gender, weight, cough, pyrexia, and anosmia, excessive dose for arm C.

1. 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.

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risk of hospitalization, 210.7% higher, RR 3.11, p = 0.47, treatment 1 of 28 (3.6%), control 0 of 31 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), arm B.

risk of hospitalization, 610.0% higher, RR 7.10, p = 0.11, treatment 3 of 30 (10.0%), control 0 of 31 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), arm C, very high dose, poorly tolerated with low compliance.

relative change in viral load, RR 0.80, p = 0.59, treatment mean 2.5 (±2.2) n=28, control mean 2.0 (±4.4) n=29, day 7, arm B, primary outcome.

relative change in viral load, RR 0.69, p = 0.07, treatment mean 2.9 (±1.6) n=30, control mean 2.0 (±2.1) n=29, day 7, arm C, primary outcome.

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Buonfrate et al., 6 Sep 2021, Double Blind Randomized Controlled Trial, Italy, peer-reviewed, 18 authors, study period 31 July, 2020 - 8 June, 2021, average treatment delay 4.0 days, dosage 1200μg/kg days 1-5, arm B 600µg/kg, arm C 1200µg/kg, trial NCT04438850 (history) (COVER).

This Paper Ivermectin All

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

MD Dora Buonfrate, MD Fabio Chesini, MD Davide Martini, MSc Maria Carla Roncaglioni, MSc Maria Luisa Ojeda Fernandez, MSc Maria Francesca Alvisi, MSc Irene De Simone, PhD Eliana Rulli, PhD Alessandro Nobili, MD Giacomo Casalini, Prof Spinello Antinori, PharmD Marco Gobbi, MD Caterina Campoli, PhD Michela Deiana, PhD Elena Pomari, PharmD Gianluigi Lunardi, PharmD Roberto Tessari, PhD Zeno Bisoffi

International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2021.106516

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

47 years (Q1[first quartile]-Q3[third quartile] 31.0-58.0). The majority were Europeans (97%). Comorbidities were reported by one third of the participants. Eighty (86%) participants were symptomatic with a median duration of 4 days, cough being the most frequent symptom, followed by fever and fatigue. The severity score was 1 for 78 participants (84%), and 2 for 15 (16%). Details of main physical findings, baseline laboratory exams and concomitant treatments are summarized in Supplementary Tables 3, 4 and 5. Summary of treatment compliance is reported in Table 2 . Fourteen participants (4.3%) discontinued the treatment: 1 (3.1%) in arm A, 2 (6.9%) in arm B and 11 (34.4%) in arm C. The interruptions in arm C were all due to tolerability. Seven participants received only one day of treatment, three received two and three days, respectively, and one received four days (Supplementary Table 6 ). No SADRs were observed in any of the study groups. Results on the viral load (Log10) at day 7 versus baseline, are summarized in Table 3 . In arm C, the mean reduction of the viral load was 2.9 (SD 1.6), versus 2.5 (2.2) in arm B and 2.0 (2.1) in arm A. The observed effect size (versus arm A) was 0.48 for arm C and 0.21 for arm B. Differences were not normally distributed (Shapiro-Wilk test p value <0.0001 for both comparisons), thus Wilcoxon exact test was also performed. The differences were not significant (p=0.099 and 0.122 for C versus A and B versus A, respectively). Results..

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