Oxford is trialling Ivermectin - the path to this point has been rocky, why?

By Associate Professor Justin Denholm, Principal Investigator on ASCOT

The PRINCIPLE trial recently announced that their ongoing platform will now add ivermectin to the list of drugs being evaluated. PRINCIPLE’s focus is on treatment for people in the UK community who have recently developed symptoms of COVID-19, and will give three days of ivermectin to look at whether fewer are admitted to hospital than compared with standard of care. REMAP-CAP has also just announced they will be testing ivermectin for critically ill patients.

While PRINCIPLE will likely be the largest study to consider ivermectin (there are more than 5,000 patients enrolled in the trial so far), whatever the results it may not definitively satisfy everyone. Some of the reasons for this are related to the design of the study, which is pragmatic and will enrol people who have symptoms consistent with COVID-19, even without a test to confirm the diagnosis, and is not placebo-controlled.

However, ivermectin has also had a complicated political pathway after initially being found to inhibit SARS-Co-V 2 in the lab in high doses. Ivermectin is commonly used as an anti-parasite drug around the world, and is known to be cheap, safe and widely available. It was enthusiastically adopted by some clinicians and healthcare systems before any significant human trials were conducted, and subsequent trials have been largely small and conflicted. Now, a number of retrospective reviews and meta-analyses have been released, which mostly agree that studies to date have generally been of low quality and high risk of bias, but offering different conclusions about whether ivermectin improves outcomes. As stated by the REMAP-CAP investigators: “Therefore, ivermectin needs to be tested in a larger (not single-centred) high-quality randomised trial.” 

Unfortunately, in recent weeks, the ivermectin story has been further marred by at least one of the largest studies to date suggesting benefit being withdrawn due to apparent fraud, with independent reviewers finding that the study was likely fabricated entirely. While research misconduct like this doesn’t provide evidence one way or the other about the usefulness of ivermectin, it certainly sours enthusiasm for further research.

Perhaps the biggest problem in this story has been the aggressive promotion of ivermectin as an effective treatment without appropriate clinical trial evidence. In Australia, Federal MP Craig Kelly has been criticised for repeatedly making erroneous statements about the effectiveness of ivermectin. This has created an environment where generating good data about ivermectin has been more difficult than needed, with some arguing that ivermectin should already be given as part of routine care while others state that it’s proven not to work and so shouldn’t be considered further, even in research. Although a few large and well-conducted clinical trials early in the pandemic could have provided much better information about ivermectin, the highly political and rapidly changing conditions have contributed to making funding, recruitment and implementation of such trials difficult.

The ASCOT team is very aware of the challenges of developing and conducting randomised trials in pandemic conditions, but we’re committed to it because clinical trials are the best way to offer patients new therapies and generate the evidence needed to use them ethically. Hopefully the PRINCIPLE trial will provide some clear data on the real-world impact of ivermectin for this patient group, as we continue to need a range of new and well-studied treatments for better control of the COVID-19 pandemic.