RCT very low risk patients (mean age 35.7, SpO2 97.4) showing no significant differences with rapid recovery and almost no progression in both groups.
The groups were unbalanced. There were 41% more patients with dyspnea at baseline in the treatment group. Similarly, at baseline patients with 4+ symptoms scored 2+ were more common in the treatment group - 7% for ivermectin vs. 4% for placebo.
Table S8 shows only one case of COVID-19 pneumonia. Authors report 3 and 1 cases of progression, this matches the 3 and 1 cases of the adverse event "COVID-19" in Table S8. It's unclear how the COVID-19 adverse events were defined since all patients are meant to have COVID-19. Authors definition of progression includes "use of COVID-19 therapeutic agents" and therefore the significance for progression of disease is not clear.
The study is designed to produce a null result with very low risk patients, administration on an empty stomach, the primary outcome including symptoms that are expected side effects of ivermectin, and only 3 day treatment.
The inclusion criteria were changed after starting the trial to further favor finding no effect - including even younger low-risk patients, including patients without fever, and allowing a larger delay in specimen collection (Table S2).
The most serious symptom reported is dyspnea. Notably, per symptom results show much faster initial recovery of dyspnea with ivermectin, with 50% recovered within ~26.5 hours for ivermectin compared to ~42.5 hours for placebo.
Diarrhea and abdominal pain were worse with ivermectin, however these are typical side effects. Ivermectin may cause gastrointestinal upset, especially when taken on an empty stomach.
Authors include patients that were PCR- at baseline - 14% for ivermectin and 17% for placebo.
For viral clearance, the number of patients with results does not match the event counts and percentages.
The informed consent date statistics suggest that randomization resulted in
confounding by time, with 45% vs 41% in the second period reported, and 41% vs. 44% in the third period.
This study is excluded in the after exclusion results of meta
analysis:
very low risk group with almost no progression leaves little room for improvement, unbalanced baseline dyspnea and high symptom scores, design and post-hoc changes favor null result.
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COVID-19 pneumonia, 205.0% higher, RR 3.05, p = 0.49, treatment 1 of 502 (0.2%), control 0 of 527 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), Table S8.
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use of therapeutic agents, oxygen, transfer, hospitalization, death, 214.9% higher, RR 3.15, p = 0.36, treatment 3 of 502 (0.6%), control 1 of 527 (0.2%).
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risk of no improvement, 4.0% higher, HR 1.04, p = 0.62, treatment 502, control 527, 168hr, improving trend, primary outcome.
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risk of no recovery, 4.0% lower, HR 0.96, p = 0.72, treatment 502, control 527, 168hr, clinical resolution, Figure S3.
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risk of no recovery, 4.0% lower, HR 0.96, p = 0.64, treatment 502, control 527, 240hr, clinical resolution, Figure S3.
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dyspnea median recovery time, 37.6% lower, RR 0.62, treatment 55, control 39, dyspnea.
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Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
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Mikamo et al., 26 Sep 2022, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, 19 authors, study period 12 November, 2021 - 7 August, 2022, dosage 300μg/kg days 1-3, trial
NCT05056883 (history).
Contact:
mikamo@aichi-med-u.ac.jp.
Efficacy and safety of ivermectin in patients with mild COVID-19 in Japan and Thailand
M.D Hiroshige Mikamo, M.D Satoshi Takahashi, M.D Yuka Yamagishi, Ph.D Akihiro Hirakawa, M.D Toshiyuki Harada, M.D Hirotaka Nagashima, M.D Chiaki Noguchi, M.D Kentaro Masuko, M.D Hiromitsu Maekawa, M.D Tatsuhiko Kashii, Hiroyuki Ohbayashi, Shinichiro Hosokawa, Katsuyuki Maejima, Masaya Yamato, Weerawat Manosuthi, Supachai Paiboonpol, Hideki Suganami, Ryohei Tanigawa, Hitoshi Kawamura
Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2023.12.012
Background: Ivermectin is an antiparasitic drug administered to hundreds of millions of people worldwide. Fundamental research suggests that ivermectin is effective against coronavirus disease 2019 (COVID-19); therefore, we investigated the efficacy and safety of ivermectin as a COVID-19 treatment option.
Methods: This multi-regional (Japan and Thailand), multicenter, placebo-controlled, randomized, double-blind, parallel-group, Phase III study evaluated the efficacy and safety of ivermectin in patients with mild COVID-19 (IVERMILCO Study). The participants took a specified number of the investigational product (ivermectin or placebo) tablets of, adjusted to a dose of 0.3-0.4 mg/kg, orally on an empty stomach once daily for three days. The primary efficacy endpoint was the time at which clinical symptoms first showed an improving trend by 168 h after investigational product administration.
Results: A total of 1,030 eligible participants were assigned to receive the investigational product; 502 participants received ivermectin and 527 participants received a placebo. The primary efficacy endpoint was approximately 96 h (approximately four days) for both ivermectin and placebo groups, which did not show statistically significant difference (stratified log-rank test, p=0.61). The incidence of adverse events and adverse drug reactions did not show statistically significant differences between the ivermectin and placebo groups (chi-square test, p=0.97, p=0.59).
Conclusions: The results show that ivermectin(0.3-0.4 mg/kg), as a treatment for patients with mild COVID-19, is ineffective; however, its safety has been confirmed for participants, J o u r n a l P r e -p r o o f Confidential including minor participants of 12 years or older. (IVERMILCO Study ClinicalTrials.gov number, NCT05056883.
Conflict of Interest assistance with an earlier version of the manuscript and Kowa employees, Masaya Tanahashi and Tatsuya Muto for statistical analysis and interpretation of this study results. We also thank to Editage (www.editage.com) for English language editing.
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