Despite early studies suggesting potential, the PRINCIPLE trial's findings – published in the Journal of Infection - indicate that ivermectin does not lead to clinically significant improvements in COVID-19 recovery times, hospital admissions, or mortality rates. While a modest two-day reduction in symptom duration, from 16 days to 14 days, was observed, this did not translate into clinically meaningful benefits or improvements in longer-term health outcomes.
The PRINCIPLE trial, commissioned by the UK Department of Health and Social Care during the height of COVID-19 pandemic and funded in open competition and after peer-review through its rapid research response fund – via the National Institute for Health and Social Care – aimed to identify existing drugs that could be repurposed to treat COVID-19 patients in community settings. The trial focused on testing drugs that might speed recovery, reduce hospitalisations and deaths, and, later, on improve longer-term health outcomes compared to usual care, particularly for patients at highest risk of complications.
Ivermectin, with antiparasitic and anti-inflammatory qualities, was initially considered a promising candidate based on early laboratory studies and small trials. However, this study finds that ultimately it is ineffective in altering the outcomes of COVID-19 infection in a largely vaccinated population. The researchers conclude that ivermectin should not be prescribed as a treatment for COVID-19 in such populations and recommend against conducting further trials on ivermectin for this purpose.
Professor Richard Hobbs, Co-chief investigator of PRINCIPLE, and Head of Department at the Nuffield Department of Primary Care Health Sciences said:
“These latest data in the ivermectin arm follows the four arms already reported and an additional one to be published soon. PRINCIPLE, a large platform trial, was operationalised incredibly quickly at the start of the pandemic by a fantastic trials team at the Nuffield Department of Primary Care Health Sciences to test commonly used drugs for benefit and safety in serious COVID-19 when, at the time, there were no proven therapies and before vaccines were available. The final two drugs, which include ivermectin, were tested after vaccines became available and all have been followed up for a year.”
In this multi-centre, open-label, adaptive randomised controlled trial*, participants with confirmed SARS-CoV-2 infection were randomly assigned to receive a medication, in this case ivermectin (taken at the recommended dose and duration at the time) plus usual NHS care, or usual NHS care alone. 94% of the participants were vaccinated against COVID-19.
The study evaluated two important main outcomes: time to self-reported recovery and COVID-19-related hospitalisations or deaths. While the study found a statistically significant reduction of approximately two days in the time to self-reported recovery for those taking ivermectin (a reduction from 16 to 14 days), the researchers emphasise that this difference is unlikely to be clinically meaningful. The hazard ratio was only 1.14, which fell short of the study’s pre-defined threshold for a clinically significant benefit (a hazard ratio of 1.2). Moreover, and importantly for both patients and reducing the burden on healthcare systems, ivermectin did not reduce the risk of COVID-19-related hospitalisations or deaths compared to usual care.
The study also examined whether ivermectin had any effect on long-term health outcomes following COVID-19 infection. Over the course of twelve months after their infection, participants were asked to report on their wellbeing, symptoms, healthcare contacts, and time away from work or studies. While the researchers found that there were statistically significant differences between the ivermectin and usual care groups in some of these outcomes, the size of these differences was not large enough to be considered clinically meaningful.
In other words, although the mathematical analysis showed that the differences between the groups were unlikely to be due to chance alone, the actual impact of these differences on the participants' daily lives was quite small. This suggests that ivermectin did not provide any meaningful benefit to long-term health outcomes after COVID-19 infection compared to the usual care group.
"The results of this study add certainty to the existing evidence that ivermectin has no place in the treatment of COVID-19 in a largely vaccinated population," said Professor Chris Butler, Professor of Primary Care at the Nuffield Department of Primary Care Health Sciences and Co-chief investigator of PRINCIPLE. "Completing rigorous clinical trials which evaluate long-term health outcomes is vital to establish effective treatments for those at higher risk from severe illness. Findings from the PRINCIPLE trial fill gaps in our understanding of how to treat COVID-19, helping policymakers and healthcare professionals make informed decisions about patient care and resource allocation. Finding out what does not work is critically important, because it saves people from unnecessary risk of drug side effects and reduces waste in the healthcare system.
The PRINCIPLE trial also discovered that the anti-inflammatory drug, colchicine, did not make people with COVID-19 feel better, and that the antibiotics doxycycline and azithromycin should not be used to treat COVID-19. This changed practice world-wide, and enhanced antimicrobial stewardship. On the other hand, we found that inhaled budesonide, a steroid commonly used to treat asthma, improved recovery and had a high probability of reducing the need for hospital admission."
Further medications for treatment of COVID-19 in community settings, specifically focussing on anti-viral mediations, are being evaluated in the PANORAMIC trial also being conducted by the Nuffield Department of Primary Care health Sciences at the University of Oxford.
The PRINCIPLE team would also like to offer their heartfelt thanks to the thousands of participants, health and care professionals and other organisations and individuals that all helped the trial to be a success.
Read the paper ‘Ivermectin for COVID-19 in adults in the community (PRINCIPLE): an open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes’ in The Journal of Infection.
To find out more about the PRINCIPLE trial, read our UNDERSTANDING THE PRINCIPLE TRIAL: A GUIDE FOR PATIENTS AND THE PUBLIC.
Visit the PRINCIPLE trial’s website.
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* In straightforward terms, this was a rigorous study conducted across multiple sites that openly tested ivermectin against usual care, along with other treatments. The flexible design allowed ineffective treatments to be stopped quickly, while prioritising evaluation of promising ones. Participants were randomly assigned to treatment groups to ensure fair comparisons.