Ivermectin: A missed opportunity?

By Dr Upul Wijayawardhana

In recent times, no drug has aroused more controversy than Ivermectin, an anti-parasitic discovered in 1975, originally used in veterinary medicine. It was approved for human use in the late 1980s and is on the World Health Organization’s List of Essential Medicines. William Campbell and Satoshi Omura won the 2015 Nobel Prize in Physiology or Medicine for its discovery and applications which include mass administration in the prevention of lymphatic filariasis and river blindness. In addition to anti-parasitic activity, Ivermectin has been shown to have anti-viral activity as well as anti-inflammatory activity.

Laboratory tests showed Ivermectin activity against the Covid-19 virus at high concentrations, and, therefore, it was initially thought that toxicity might be a problem if used in very high dosage. However, as some observational studies showed benefit at normal doses, Ivermectin was promoted as a ‘miracle’ drug through social media, mostly by anti-vaxxers. A big impetus for Ivermectin came from a randomised clinical trial of 400 patients from Egypt, published in early 2021, which showed a 90% reduction of death rates. However, a British medical student who studied the trial in detail found many discrepancies including plagiarism and data manipulation, which led to the retraction of the article in July 2021.

The first step in proving the efficacy of a drug or any other intervention is by observational studies. If they show likely benefit, then Randomised Clinical Trials (RCT) are done, where one group receives the drug and the other gets a placebo of similar appearance. The most rigorous of all are the double-blind RCTs, where neither the patients nor the triallists are aware who is on what unyil the trial is concluded, and this which helps eliminate any form of bias. The validity of the trial increases as the numbers treated increase. In fact, there are instances where a drug that had been shown to be effective in small RCTs were proven to be ineffective when large RCTs were conducted. This has led to the concept of mega-trials, where thousands of patients are included. The earliest and the best known are the ISIS trials conducted by the Oxford Research Group, which showed the efficacy of clot-busters in the treatment of heart attacks.

However, it is not always easy to do large trials which could be expensive and time consuming. Therefore, statisticians have developed a new method of pooling comparable trials and analysing data, which is called meta-analysis. The August issue of the American Journal of Therapeutics carried a meta-analysis of Ivermectin trials by Bryant et al from the UK, which concluded: “Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using Ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally”. Unfortunately, this meta-analysis included data from the disgraced Egyptian study.

Another meta-analysis, also from the UK by Hill et al, published in ‘Open Forum Infectious Diseases’ initially showed positive results including a 56% reduction in mortality, but a revised publication, after deleting the data from the Egyptian trial, concluded that Ivermectin did not show a statistically significant effect on survival though it displayed a borderline significant effect on duration of hospitalisation in comparison with standard care. This clearly illustrates how the conclusions from a meta-analysis can change due to what is included in the analysis. In fact, statistics can be manipulated to get the desired result!

Perhaps, the important message from these two meta-analyses is that Ivermectin may do some good and does not seem to be doing any harm. Maybe, it was this message that Prof Saroj Jayasinghe wished to convey in his article “Ivermectin and Covid: no time to lose and lives to save” (The Island, 17 September 2021). Although some non-medical scientists were critical that his suggestions were unscientific, it is to his credit that, in a grave situation, he made sensible recommendations, giving good reasons why he was doing so. It may well be that the medical fraternity in Sri Lanka listened to the words of wisdom by a respected senior colleague of the profession, which has resulted in the relatively very low death rate in Sri Lanka. Whereas the average daily deaths are around 20 in Sri Lanka, it is around 182 in the UK: three times the rate when adjusted to the size of the population in spite of having better health care facilities and higher vaccination rates. In fact, on 8 January the UK joined the US, Brazil, India, Russia, Mexico and Peru, as the seventh country to have more than 150,000 Covid-19 deaths during this pandemic.

When it was announced in June that Ivermectin is to be investigated as a possible treatment for COVID-19 in Oxford’s PRINCIPLE trial, there was optimism that the issue of effectiveness of Ivermectin would be resolved, at last. This was because of the reputation of the Oxford Group, which has done pioneering research during the pandemic, in addition to producing the most widely used vaccine with the collaboration of AstraZeneca. However, when I searched for an update, I found this disappointing headline in ‘Medpage Today’ website: “Ivermectin Arm of PRINCIPLE Trial Put on Hold — Trial website cites supply issues”. It went on to state:

“The website does not offer any details on what caused the Ivermectin supply difficulties in PRINCIPLE, which is investigating possible treatments for COVID-19 and being led by the University of Oxford in England. A full response from the trial’s press team was promised, but had not reached MedPage Today by press time.

Ivermectin manufacturer Merck did not directly comment on the supply issues affecting PRINCIPLE. However, as part of a longer statement on the drug provided to MedPage Today via email, the company said that it has “concluded that the probability of ivermectin providing a potentially safe and efficacious treatment option for SARS-CoV-2 infection is low and have prioritised internal efforts towards the development of alternate candidates that provide a higher probability of success for the treatment of COVID-19.”

The alternative candidate they refer to, of course, is Molnupiravir which would be hugely profitable for Merck unlike Ivermectin, which is off-patent. Although initial studies suggested a 50% reduction of hospitalisation with a course of Molnupiravir tablets, final data shows only a modest reduction of 30%. Merck has allowed Indian drug firms to manufacture and sell Molnupiravir at low cost in developing countries. Still, a course will cost around Rs. 4,000 whereas a course of Ivermectin costs less than Rs 200!

It seems very surprising that Oxford Group has difficulties in obtaining a cheap drug and I do not know whether they are obliged to obtain their supplies from the original manufacturer. It is even more interesting that no other news channel has highlighted this problem. On 6 October 2021, BBC website printed a lengthy investigative report titled “Ivermectin: How false science created a Covid ‘miracle’ drug”. I would have expected these investigative journalists to follow the progress of Ivermectin studies but they seem to be silent!

Let us hope Oxford Group obtains supplies and concludes the trial. Otherwise, their reputation too will be at stake. It would be interesting if Ivermectin, a repurposed drug, outperforms Molnupiravir, a targeted drug developed specifically for Covd-19. Repurposing is not a new phenomenon. Many drugs introduced for one purpose sometimes become more useful in other conditions. Thalidomide, introduced as a cure for morning-sickness, fell into disrepute as it caused foetal deformities but has found a new life as an anti-cancer drug. Of course, the best known is Sildenafil, a vasodilator that was trialled by Pfizer for angina; it produced an interesting side effect, which led to it being marketed as Viagra, one of the biggest money-spinners for Pfizer!