Ivermectin has no impact in treating mild COVID-19 in 400 adults in Columbia

12 March 2021. Related: COVID-19: investigational drugs, COVID-19.

Simon Collins, HIV i-Base

Results from a randomised placebo controlled study published in JAMA, report no benefit from using the antiparasitic drug ivermectin to treat mild COVID-19. This follows months of speculation that ivermectin might provide a low cost oral treatment that could be used globally.

Between July and November 2020, this study randomised 476 adults with PCR-confirmed mild COVID-19 disease to either combinectin (300 μg/kg) or placebo for five days, given as an oral solution. Mild disease was defined by having had symptoms for less than seven days and not requiring oxygen and participants could be treated at home or in hospital. The study was run at a single site in Columbia.

The original primary endpoint, expected in 18% of participants was worsening symptoms by two points in an eight point ordinal scale. This included participants who progressed to hospitalisation of oxygen were combined as an esclation endpoint. 

However, fewer progression endpoints during the study and the primary endpoint was changed to time to symptoms recovery, during 21-days follow-up, using the same eight-point scale.

Also, for 17 days at the beginning of October, labelling error meant that all participants received ivermectin. Where these had been new participants, they were excluded from the primary analysis and new patients were recruited, but retained for sensitivity analyses. This meant that overall there were 275 participants in the ivermectin arm and 200 in the placebo group, although the primary analyses included 200 and 198 participants, respectively.

Consent and follow-up was conducted by phone for participants at home.

Baseline characteristics included median age 37 (IQR: 29 to 48), 58% were women, and 79% had no recorded comorbidities. Just over 58% were still at home. Median time from symptoms to randomisation was 5 days (IQR: 4 to 6) in each arm. Most were 1 on the ordinal scale (59% vs 55%) or 2 (39% vs 43%), in the active vs placebo arms respectively.

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. Similar results were reported in sensitivity analyses.

Few participants progressed by two points, again with no significant difference between groups: 2 % vs 3.5%, difference –1.53 (95%CI: –4.75 to 1.69).There was also no difference in participants whose care escalated to hospitalisation or oxygen: absolute difference −3.05 (95% CI: −6.67 to 0.56); OR, 0.38 (95% CI: 0.12 to 1.24). Although these numerical results favour ivermectin, this was not statistically significant and results were further attenuated when four participants with very early hospitalisation (median of 3.5 hours after randomisation) were excluded.

The discussion did note the low age and risk of participants and that measuring impact on more serious progressions would need larger studies. However, it also noted that pharmacokinetic models don’t support ivermectin reaching effective plasma and total concentrations to be active, even using a dose ten times higher than currently approved.

Adverse events were also similar between the two arms.

comment

Although this study had many problems the lack of any significant benefit is disappointing – and also sobering. Several community medical organisations have been lobbying for compassionate access to ivermectin in the US and South Africa. [2, 3, 4]

Several meta-analysis have reported a potential benefit from ivermectin, including well-publicised presentation on YouTube by Andrew Hill, also reported in a pre-review paper that includes more than 2000 participants. Although many of the included studies were small, unpublished and with very different designs and doses, the presentation notes that another 45 studies with >7000 participants are ongoing. [5, 6]

Given the history of negative results from other repurposed medicines without clear PK support for the mechanism of action finding out efficacy will depend on results from randomised controlled studies. In addition to the study here from Columbia, two similar sized studies in Brazil and Argentina are due to report this month. [7, 8]

Their results should decide whether or not other ongoing studies should continue, including the large international ANTICOV study proposing to use ivermectin in 13 African countries.

References

1. López-Medina E et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial. JAMA. doi:10.1001/jama.2021.3071. (4 March 2021).
   https://jamanetwork.com/journals/jama/fullarticle/2777389
2. Sax P. Ivermectin for COVID-19 — breakthrough treatment or hydroxychloroquine redux? MEJM Blog post. (4 January 2021).
   https://blogs.jwatch.org/hiv-id-observations/index.php/ivermectin-for-covid-19-breakthrough-treatment-or-hydroxychloroquine-redux/2021/01/04
3. Marik P, Kory P. Front line covid-19 critical care alliance (FLCCC). FLCCC alliance response to the NIH Guideline Committee recommendation on ivermectin use in COVID-19. (14 January 2021).
   https://covid19criticalcare.com
   https://covid19criticalcare.com/wp-content/uploads/2021/01/FLCCC-Alliance-Response-to-the-NIH-Guideline-Committee-Recommendation-on-Ivermectin-use-in-COVID19-2021-01-18.pdf  (PDF)
4. Heywood M. South Africa’s medicines regulator finds middle ground to authorise ‘compassionate use’ of ivermectin, whilst still stating that there is not yet sufficient evidence for full registration. Daily Maverick. (27 January 2021).
   https://www.dailymaverick.co.za/article/2021-01-27-ivermectin-and-covid-19-sa-drug-regulator-allows-controlled-compassionate-access
5. Hill A. Ivermectin meta analysis. Presentation to UNITAIDS. YouTube.
   https://www.youtube.com/watch?v=yOAh7GtvcOs (since removed)
   https://www.youtube.com/watch?v=FyuIDxn9_lQ (similar lecture reposted)
6. Hill A. Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection. (19 January 2021).
   https://www.researchsquare.com/article/rs-148845/v1
7. Comparative study of hydroxychloroquine and ivermectin in COVID-19 prophylaxis.
   https://www.clinicaltrials.gov/ct2/show/NCT04447235
8. Ivermectin to prevent hospitalizations in COVID-19 (IVERCORCOVID19)
   https://www.clinicaltrials.gov/ct2/show/NCT04529525
9. ANTICOV study.
   https://dndi.org/research-development/portfolio/anticov

This report was first posted on 6 March 2021.