Reviews of ivermectin for COVID-19: evidence from RCTs is still needed
The delayed timeline for global access to vaccinations still leaves an urgent gap for treatments that could reduce the risk of hospitalisation with COVID-19.
Although the antiparasitic drug ivermectin has the profile of being cheap and affordable, the limited evidence of efficacy, often from poorly designed studies, with limited quality of evidence (QoE), has produced conflicting results.
Two recently published meta-analyses also come to different conclusions.
Roman and colleagues reported on outcomes from ten RCTs with 1173 participants, adjusting for risk of bias. Half the studies used standard of care as controls and half used placebo. 
Ivermectin did not reduce all-cause mortality (RR 0.37, 95%CI: 0.12 to 1.13, very low QoE) or length of hospital stay (median 0.72 days, 95%CI: −0.86 to 2.29, very low QoE).
Adverse events, severe events and viral clearance were similar between ivermectin and controls (all outcomes: low QoE). Although all-cause mortality was reduced in three RCTs with a high risk of bias, the authors concluded that ivermectin is not a viable option to treat COVID-19.
A second meta-analysis includes more studies and has a more positive results, but still defers to the need for results from large randomised studies, together with an accompanying editorial. [2, 3]
This paper was based on results from using ivermectin in 24 RCTs with 3328 participants, including studies in the first review above.
In the 11 RCTs of moderate/severe infection, there was a 56% reduction in mortality (RR 0.44, 95%CI 0.25 to 0.77), p=0.004. There was also reduced mortality: 35/1064 (3%) vs 93/1063 (9%) with reduced time to recovery (–1.58 days, 95% CI: –2.8 to –0.35, p=0.01). Also, reduced time in hospital (–4.27 days, 95% CI –8.6 to –0.06, p=0.05).
However, many of these studies were not peer-reviewed and used a wide range of doses.
Ivermectin was also associated with reduced inflammatory markers (C-Reactive Protein, d-dimer and ferritin) and faster viral clearance by PCR.
Viral clearance was related to both the dose of ivermectin and how the length of treatment.
An important complication, and a caution to any positive results – carefully explained in the paper from Andrew Hill – is that pharmacokinetic studies have shown that drug levels achieved with highest tolerable dosing remain too low to have a direct therapeutic effect reported in in vitro studies. Without PK support for a potential mechanism it is difficult to see how ivermectin could work.
Both studies, and an editorial comment that accompanied the paper from HIll et al, is that evidence from adequately powered RCTs is still needed before ivermectin can be recommended. 
Unfortunately, the last two published RCTs did not report a benefit. This included a Columbian study that randomised 476 adults with PCR-confirmed mild COVID-19 disease to either ivermectin (300 μg/kg) or placebo for five days, given as an oral solution. 
There were no significant differences in the time to resolving symptoms between the two groups: 10 vs 12 days; HR: 1.07 (95CI: 0.87 to 1.32), p=0.53, with symptoms resolving in 82% and 79% in the active vs placebo groups respectively.
A second study from Argentina randomised 501 participants (1:1) to ivermectin or placebo in a staggered dose, according to weight, for 2 days. There was no significant difference on the primary endpoint of hospitalisation: 14/250 (5.6%) vs 21/251 (8.4%) in ivermectin vs placebo (OR: 0.65; 95% CI: 0.32 to 1.31), p= 0.227. 
The UK Principle RCT still includes ivermectin. 
Stop press update: Shortly after this HTB article was published, one of the positive RCTs (by Elgazzar et al) was withdrawn due to serious irregularities in the data set.  Removing the 90% benefit reported by this study will significantly affect the results of the meta-analyses report above.
Hill et al. are already reanalysing the data used for all the studies in their review, which included another study that is also being questioned. This will take several weeks, but it will also make it much more difficult to see any benefit from ivermectin.
A further Cochrane review published on 28 July 2021 also failed to find evidence of any benefit. 
- Roman YM et al. Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials. CID ciab591, doi: 10.1093/cid/ciab591. (28 June 2021).
- Hill A et al. Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection. Open Forum Infectious Diseases, ofab358. DOI: 10.1093/ofid/ofab358. (6 July 2021).
- Siedner MJ. Ivermectin for the treatment of COVID-19 disease: Too good to pass up or too good to be true? Open Forum Infectious Diseases, ofab318. (24 June 2021).
- Ivermectin has no impact in treating mild COVID-19 in 400 adults in Columbia. HTB (12 March 2021).
- Vallejos J et al. Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial. BMC Infectious Diseases (21)635. (2 July 2021).
- UK Principle trial. Ivermectin to be investigated as a possible treatment for COVID-19 in Oxford’s PRINCIPLE trial. (23 June 2021).
- The Guardian. Huge study supporting ivermectin as Covid treatment withdrawn over ethical concerns. (20 July 2021).
Popp M et al. Ivermectin for preventing and treating COVID‐19. Cochrane Database of Systematic Reviews 2021, Issue 7. Art. No.: CD015017. DOI: 10.1002/14651858.CD015017.pub2.
This report was first published on 16 July 2021.