The antiparasitic drug ivermectin, used orally in the treatment of scabies for example, has been shown to have in vitro activity against Sars-CoV-2, the coronavirus responsible for covid-19 (1). On the basis of these laboratory data, patients with covid-19 in various countries received this drug, and a few retrospective studies have shown it to have little or no efficacy. But in vitro studies and non-comparative trials provide very weak evidence (2). What results are available in early February 2021 from comparative clinical trials of ivermectin in the treatment and prevention of covid-19?

This article summarises the main evidence identified in our literature search, based on consulting the clinical trials registries ClinicalTrials.gov (US), EudraCT (Europe) and ICTRP (World Health Organization) on 5 February 2021, and on analysing a website that collates and reviews covid-19 data with weekly updates (3).

Many trials, few published results. A great many trials of ivermectin are listed in clinical trial registries. For example, among the trial protocols described in the most frequently used registry, ClinicalTrials.gov, 12 trials with clinical endpoints are marked as completed, while the planned completion date of several others has passed, including some that were due to end in June 2020. But the results of only 5 of these 12 trials have been reported (4). About 15 other randomised trials appear to be still in progress. When the results of a large number of trials remain unpublished, study publication bias is highly likely. In other words, results that appear to favour the use of ivermectin are probably published more readily than negative results.

Clinical results are available, in one form or another, from a total of 11 randomised clinical trials of oral ivermectin, alone or combined with another treatment (5-15). They were conducted in Asia and Africa. The comparator in most of the trials was a treatment considered standard at the time the trial was conducted.

No strong evidence of efficacy. Ivermectin was not shown to be effective against the clinical effects of covid-19 in 9 of the 11 clinical trials from which results are available (5-7,10-15). Mortality was reported in 5 trials but, although there appeared to be fewer deaths with ivermectin, the difference between the ivermectin and comparator groups was not statistically significant
(7-9,12,13).

Only two randomised trials showed ivermectin to have some efficacy on clinical outcomes in covid-19 (8,9).

A double-blind placebo-controlled trial was conducted in Bangladesh in 400 patients with laboratory-confirmed covid-19 who remained at home and received follow-up via remote consultations (8). A single 12-mg dose of ivermectin was combined with the antibiotic doxycycline at a dose of 200 mg per day for 5 days. The only results available are on the registry ClinicalTrials.gov, and little detail is provided. The characteristics of the enrolled patients are not known, except for the fact that 60% of them were men, and their average age was 58 years. The results on the two primary endpoints (clinical improvement on days 7 and 12) suggest that ivermectin + doxycycline has some efficacy: 60.7% of patients showed improvement on day 7, versus 44.4% in the placebo group (p<0.03); and 77.0% had improved on day 12 versus 62.8% (p<0.004). Clinical deterioration was less common in the ivermectin + doxycycline group: 8.7% versus 17.8% in the placebo group (p=0.01) (8). It is impossible to tell whether ivermectin would be effective without doxycycline from these data.

Ivermectin was investigated as a preventive treatment in a non-blinded Egyptian trial in 340 people living with someone with confirmed Sars-CoV-2 infection. The only results reported are on the registry ClinicalTrials.gov, and few details have been provided (9). A smaller proportion of participants in the ivermectin prophylaxis group developed symptoms compatible with covid-19: 7.4% versus 58.4% without ivermectin. Although the endpoints stated in the protocol include confirmed cases of covid-19, these results have not been reported, which weakens the quality of the evidence provided by the trial. It is further weakened by the fact that the investigators and the participants knew which treatment participants had received.

Adverse effects reported for only two trials. At the doses used in scabies (single oral dose of 200 microg/kg, i.e. 12 mg for an adult weighing 60 kg) and other parasitoses, the adverse effects of ivermectin are generally mild and infrequent. They mainly include: headache, dizziness, blurred vision; diarrhoea, vomiting, abdominal pain; joint pain; and haematuria (16). Adverse events were reported for only two double-blind trials in covid-19, with no further information provided (8,15). Some patients are more vulnerable to ivermectin’s neurological effects than others (17).

In practice: no proven efficacy against the clinical consequences of covid-19. Many comparative randomised trials have been conducted using ivermectin in the treatment or prevention of covid-19. A few results have been reported, in various forms and rarely in a peer-reviewed form. Study publication bias is very likely to have occurred, causing the efficacy of ivermectin to be overestimated. The evidence collected is therefore very weak. Most of the results show no statistically significant difference in clinical outcomes between patients who received ivermectin and the comparator group. The results suggesting a reduction in mortality with ivermectin can probably therefore be ignored. The results of one trial showing clinical deterioration occurred less frequently with ivermectin were not confirmed in other trials. In short, as of early February 2021, despite the dozens of trials that have been conducted, ivermectin has not been shown to be effective in the treatment or prevention of covid-19.

©Prescrire 13 February 2021

Translated from:

• "Covid-19 et ivermectine : beaucoup d'essais, peu de résultats et pas de preuve d'efficacité clinique" Application Prescrire, 13 February 2021.

Sources:

1. Kim MS et al. "Comparative efficacy and safety of pharmacological interventions for the treatment of covid-19 : a systematic review and network meta-analysis" PLoS Med December 2020; 17 (12): e1003501. > HERE
2. Castañeda-Sabogal A et al. "Outcomes of ivermectin in the treatment of covid-19: a systematic review and meta-analysis" 27 January 2021; 2021.01.26.21250420. medrxiv.org accessed 5 February 2021. > HERE
   
3. "Ivermectin". In : "The COVID-NMA initiative. A living mapping and living systematic review of Covid-19 trials". covid-nma.com accessed 8 February 2021. > HERE
4. "Ivermectin | covid19". In : "US National Library of MedHEREne. ClinicalTrials.gov". clinicaltrials.gov accessed 5 February 2021. > HERE
5. Chachar AZK et al. "Effectiveness of ivermectin in Sars-CoV-2/covid-19 patients". Int J Sci 2020; 9 (9): 3135. > HERE
6. Chowdhury ATMM "A randomized trial of ivermectin-doxycycline and hydroxychloroquine-azithromycin therapy on covid-19 patients" 14 July 2020; rs.3.rs-38896/v1. > HERE
7. Okumuş N "Ivermectin for severe covid-19 management. NCT04646109". clinicaltrials.gov accessed 5 February 2021. > HERE
8. Mahmud DR "Clinical trial of ivermectin plus doxycycline for the treatment of confirmed covid-19 Infection. NCT04523831". clinicaltrials.gov accessed 5 February 2021. > HERE
   
9. Shouman W "Prophylactic ivermectin in Covid-19 contacts. NCT04422561" August 2020; clinicaltrials.gov accessed 5 February 2021. > HERE
   
10. Podder CS et al. "Outcome of ivermectin treated mild to moderate covid-19 cases : a single-centre, open-label, randomised controlled study" IMC J Med Sci 2020; 14 (2): 002, 1-8. > HERE
    
11. Ahmed S et al. "A five-day course of ivermectin for the treatment of covid-19 may reduce the duration of illness"  Int J Infect Dis 2021; 103: 214216. > HERE
12. Ravikirti et al. "Ivermectin as a potential treatment for mild to moderate COVID-19 - A double blind randomized placebo-controlled trial" 2021.01.05.21249310.  medrxiv.org accessed 9 January 2021. > HERE
13. Hashim HA et al. "Controlled randomized clinical trial on using ivermectin with doxycycline for treating covid-19 patients in Baghdad, Iraq" 2020.10.26.20219345. medrxiv.org accessed 5 February 2021. > HERE
    
14. Babalola OE et al. "Ivermectin shows clinical benefits in mild to moderate Covid-19 : a randomised controlled double blind dose response study in Lagos" 2021.01.05.21249131. medrxiv.org accessed 5 February 2021. > HERE
15. Chaccour C et al. "The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19 : A pilot, double-blind, placebo-controlled, randomized clinical trial" EClinicalMedicine 19 January 2021. > HERE
16. Prescrire Rédaction "Gale. L'essentiel sur les soins de premier choix" updated October 2020.
17. Prescrire Rédaction "Ivermectine : coma chez un enfant" Rev Prescrire 2021; 41 (447): 23.
     

For more information:

• "Covid-19: Follow Prescrire's independent, evidence-based analysis of the pandemic" > HERE