BY Dr. Sumedha S. Amarasekara

Ivermectin is a drug that has been increasingly occupying medical attention, following its possible role in the treatment and prevention of SARS-CoV-2 (Covid-19). A news item in the The Sunday Times of 05.09.2021 says, ‘Ivermectin divides doctors while NMRA gives waiver to import drug to stop black market sales’.

Ivermectin:

Ivermectin was discovered in 1975 and had come into medical use by 1981. It is an antiparasitic drug that has antiviral and anti-inflammatory properties. It is a well-known drug, approved as an antiparasitic agent by both the FDA (U.S. Food and Drug Administration) and the WHO (World Health Organization). It is on the list of the WHO’s Essential medicines. It is considered to be extremely safe in the recommended dose (0.2 to 0.4 mg/kg). Over the last 20 to 30 years the medical/scientific community has begun to investigate /appreciate its antiviral and anti-inflammatory properties (Kircik LH, Del Rosso JQ, Layton AM, Schauber J. Over 25 Years of Clinical Experience with Ivermectin: An Overview of Safety for an Increasing Number of Indications. J Drugs Dermatol. 2016 Mar;15(3):325-32. PMID: 26954318)

Ivermectin is also an extremely cheap drug. A 12mg tablet –the normal recommended dose for a 60 kg adult- is around US $ 0.03 -3 cents. The manufacturing cost is estimated at US $ 168 for 1 kilogram. Therefore, as one can work out, to manufacture 12 mg will cost: 168 divided by 1,000,000 and multiplied by 12 = US $ 0.002. Hence the bulk of the cost of the drug is in fact in converting the drug into tablets, packaging and distribution!

Evidence of the use of Ivermectin :

There is an increasing number of news items and journal publications showing the efficacy of Ivermectin’s role in reducing the mortality of Covid-19 and reducing the spread (prophylaxis) of Covid-19 among the population. A case-control study done at the All India Institute of Medical Sciences concluded that two-doses of Ivermectin prophylaxis at a dose of 300μg/kg with a gap of 72 hours was associated with a 73% reduction of SARS-CoV-2 (Covid-19) infection among health care workers for the following month (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886121/). A meta-analysis published in June this year shows a probable reduction of mortality (i.e. deaths) by 62%, when Ivermectin was used as a therapeutic agent and a possible reduction of spread by 86% when Ivermectin was used as a prophylactic agent(American Journal of Therapeutics 28, e434–e460 (2021).

In fact the control of Coivd-19 in the Northern states of India and across a number of other countries has been attributed to the use of Ivermectin. An increasing number of countries has stated that they are adding Ivermectin on to their arsenal in combating Covid-19 (https://www.youtube.com/c/WhiteboardDoctor/playlists- Ivermectin and Covid-19).

However, the NIH (National Institute of Health) maintains that there isn’t sufficient data to recommend Ivermectin for or against, in the treatment of Covid-19, which is the same stance that has been taken up by the National Medicines Regulatory Authority (NMRA) of this country as well. The WHO’s stand is still that, Ivermectin should not be used outside a clinical trial.

Conducting clinical trials:

To understand this apparent discrepancy between the results of the clinical trials and the stance of the NIH, WHO, etc., requires an insight into the interpretation of clinical trials. In today’s world conducting and interpreting clinical trials is almost a separate discipline on its own and is well beyond the scope of this article (and mine as well!).

However, an understanding of clinical trials and their interpretation is necessary to understand the clinical trials themselves and the decision-making process of these authorities. There is a variety of trials that could be done. The basis of all these trials is that one group of patients is given Ivermectin and the other group is not given Ivermectin. Following the trial, by comparing the mortality rates and spread of Covid-19 (the results) between the two groups, scientists would be able to say what effect Ivermectin has on the mortality and spread of Coivid-19. For the results to be valid, apart from the Ivermectin, everything else between these two groups needs to be the ‘same’, such as the male to female ratio of patients, other illnesses they have, other medication they take, smoking habits, alcohol consumption, etc. As one can see it is not easy to get two comparable groups. Thereafter, if one is treating for Covid -19, both groups need to have the same degree of sickness i.e. the average number of mild to moderate to severe cases should match up. If one is checking for prevention (prophylaxis) then their exposure to ‘known Covid-19 cases’ and ‘potential cases’ needs to match up as well. For example starting from, do they wear one or two masks, what type of masks, do they wear a face shield, do they maintain social distancing; all the time or some of the times, have they been exposed to any known Covid-19 patients, have they attended any weddings, funerals, parties, ‘get togethers’, do they live in apartments or individual houses, do they travel to work using public transport, do they shop on line or in person, etc… etc… As one can see this is even more complex than trying to match groups for treatment. This is what leads to the term Controlled. Thereafter, scientists need to make sure that every patient has an equal chance of either receiving the Ivermectin or not. In other words, there is no bias in who receives and who does not receive the drug. Because inadvertently one might be influenced by whom one gives the drug to i.e. the drug may be given to someone considered sick who needs the drug and not given to one with a milder disease. This process of randomly allocating the treatment leads to the term Randomised. From a patient’s point of view, they may feel psychologically let down by not having received the drug or psychologically boosted by receiving the drug. This can affect their response to the treatment. The doctors monitoring the patient can be influenced as well, if they know whether a patient is taking the drug or not. To eliminate this phenomenon everybody receives ‘the drug’- either the drug or the placebo –originating from the Latin phrase ‘I shall please’. Therefore only those who actually run the trial know, who gets what. So the person/s who gives the ‘drug’ and monitors the patients do not know what they are giving and neither do the patients know what they are receiving which is called a double blind. If all these elements are combined then we arrive at a randomised, double blind, controlled study which is considered as the golden standard.

Interpretation of clinical trials:

So the trial is done and the results are out. Now a complex issue remains as to how certain the scientists are that these results are due to Ivermectin and not due to a natural variation of events. To illustrate this we can look at a hypothetical situation of 10,000 Covid -19 patients that have an overall mortality of 2% i.e. 200 deaths. If we were to divide these patients into lots of 1000, it is extremely unlikely that these deaths would be distributed equally for every lot of 1000 patients. Some lots would have had more deaths, other lots would have had less, averaging out at 20 per group of 1000 i.e. 2%. Now let us assume that the two groups of patients selected of a 1000 each for the study, were to have 10 deaths in one group and 30 deaths in the other –averaging out at 2%. The critical issue to grasp is that, which group is which is not known. Assume Ivermectin was given to the group that was to have 30 deaths and as a result of Ivermectin the death rate was halved and ended up being 15 –a 50% reduction- this is 50% (5) more than that of the control group, so it could be erroneously concluded that Ivermectin does not work, when it actually does work. On the other hand Ivermectin may not actually work, but in this instance it was given to the group that was to have 10 deaths, so erroneously the conclusion is that Ivermectin does work, when in fact it doesn’t. If things were not as complex as it were, it is worthwhile to remember that this natural variation exists for all of the characteristics mentioned above between the two groups as well. This needs to be taken in to account.

So when scientists interpret data, these variations are taken into consideration and there are three main aspects that they consider. The first is the power of the study. That basically means, are there sufficient numbers of patients in the study for the scientists to be able to pick up a true difference that goes beyond the natural variation. The hypothetical study shown above, has very little power; as one could see that the results could not be interpreted due to the natural variation. Next is significance. That is a measure of allowing for chance to be involved in the result. For most studies the significance level, known commonly as a P value is set below 0.05 (P< 0.05). In this context it would mean that, there is less than a 5% chance that the decrease in mortality is, not due to Ivermectin i.e. the chance of Ivermectin causing the decrease in mortality is more than 95%. Thirdly, there is the concept of ‘a confidence interval’. Broadly speaking the narrower the confidence interval the more valid the results are.

Clinical interpretation and Ivermectin:

It is a deficiency of some of the above factors in the clinical trials so far conducted and their subsequent interpretation that have resulted in this stance of the various authorities. Therefore the vital aspect to understand in going forward is that the issue is not primarily to do with the results from all these trials (and other evidence) that have been conducted across the world; that have shown that Ivermectin does work. But, it is to do with the validity of these results. Therefore the view put forward by those who are guarded in their recommendation in the use of Ivermectin, is that the validity (certainty) of these trials is not strong enough for the use of Ivermectin to be recommended. Which of course is not the same as saying that Ivermectin does not work.

This view needs to be counterbalanced by the following facts. Firstly, there have been no significant adverse effects reported in any of the trials conducted using Ivermectin. Secondly, there is only an extremely limited number of drugs that have been recommended in the treatment of Covid-19 and none of these is ‘curative’ in the strictest sense of the word. Thirdly, though vaccination makes a significant difference to the outcome if one were to get Covid-19, it has not been as successful in preventing its spread.

Available options:

The WHO apart from the vaccines, has only recommended a few drugs to be used in the treatment of Covid-19. Remdesivir is one such drug. This is however, only to be used in the treatment of Covid-19 patients, essentially in a hospital environment. A vial of this drug costs over US $ 500. Not exactly a practical solution for us! Besides there are no clinical trials scheduled by the major pharmaceutical companies comparing Remdesivir (US $ 500) with Ivermectin (US $0.03) to be seen in the near horizon. Countries that have already used Ivermectin and are satisfied with its outcomes are not going to be conducting trials to assess a drug that they already find works.

One option is to evaluate all the existing evidence and start using Ivermectin. Prof. Saroj Jayasinghe (Faculty of Medicine, University of Colombo) a highly respected clinician has already written to the Ministry of Health recommending that Ivermectin should be used in the treatment of Covid-19.

However, to take a national stance on a drug not approved by the WHO could be considered ‘irresponsible’ and may jeopardise our future with regard to health and safety issues on an international forum.

Therefore, another option would be to follow the guidelines of the WHO and conduct a clinical trial. The issue that would now cross one’s mind is given in this discussion; conducting a trial that would give valid results would be an extremely complex and arduous undertaking. How does one organise these matching groups etc..?

The solution:

An islandwide clinical trial with the use of Ivermectin.

With regard to an islandwide clinical trial, the numbers will be huge running into millions. This leads to an enormous power and thereby an incredible validity of the study. It also ironically means that the amount of extra data that one needs to record, to make sure that one has matching groups, etc., becomes minimal as well. As a point of illustration, if we were to have a randomised clinical trial–blind or not-across the 14,022 Grama Niladhari Wasams involving around 22 million adults and children, where half are given Ivermectin; the outcome would be dependent on the use of Ivermectin, as the chance of another confounding factor or natural variation affecting one group-of roughly 11 million- and not the other would be almost nonexistent!

Let us not forget that we are probably one of the few countries in the world where countrywide elections are held and the results are given within a day or so.

The WHO will/should give its blessing and if need be, provide help with the necessary expertise (and resources?) to conduct this trial.

This is essentially a win, win

and win situation

An acceptable clinical trial is required to provide the definitive answers-what the WHO, the NIH and our NMRA need. The medical sector would be happy to get the findings they require with a ‘controlled opening of the country’. The country needs to be opened in some manner to assess the prophylactic role of Ivermectin and the ‘government’ would find it feasible and more than willing to do so for economic reasons. The people would be happy to get ‘a drug that would/could work’ and more importantly an easily affordable one in their hour of need.

The advantage of an island wide clinical trial:

There are a number of important points that are extremely favourable in terms of conducting an islandwide clinical trial with Ivermectin.

1. Ivermectin is an extremely safe drug at the prescribed doses. It can be given to children as well, leading to a comprehensive island\wide clinical trial. This is particularly important as we still do not have a proper handle on vaccination when it comes to children.

Given that Ivermectin is already used as an antiparasitic agent and given to children, it can be used separately in an islandwide clinical trial to re-open the schools.

2. Ivermectin is an extremely cheap drug. This is most relevant to us in our current economic predicament. The cost of treating an adult with Covid-19 and /or using Ivermectin as a prophylactic drug (the loading dose and the required tablets for three months) on average will be less than Rs. 500 per person. As the dose is based on body weight, the cost will be less for children.

3. When used as a prophylactic drug, it has an extremely simple dosing schedule – a loading dose administered a couple of days apart then a maintenance dose once a week or at a prescribed interval.

4. The existing trials show a considerable impact from this drug. Based on the existing trials, if Ivermectin were to work, we should be expecting at least a 50% reduction of mortality and at least the same reduction in the spread of the disease, or there about. Therefore the effects of using this drug would be extremely easy to monitor.

5. A very important point, the prevention (i.e. prophylactic) aspect of Ivermectin, starts once the drug has got absorbed into the system – pretty much immediately. When one considers the vaccine, the first dose needs to be given, then a period of at least four weeks has to pass for the body to generate a sufficient immune response for the second dose to be given. Thereafter, a further two to three weeks need to elapse before one is considered to be immune i. e. close upon almost two months. With Ivermectin, if one takes the tablet at night, by morning one is ‘good to go’.

6. Finally, another significant and interesting aspect is that we would be able to evaluate the relative efficacy and interactions between Ivermectin and our vaccines. How does Ivermectin impact on those who have completed both vaccine doses or only had one or have not been vaccinated at all? Looking to the future, how does Ivermectin-given that it has therapeutic as well as prophylactic properties- compare with Vaccination?

The country still faces a dilemma of opening the country vs having an uncontrolled spread of Covid-19. The reality is that we will need to ‘reopen the country’. This is the best time while the country is in a lock down to organise an islandwide clinical trial. Plan what type of trial/trials we want to execute, formulate the primary and secondary questions that need to be answered, identify the significant sub groups, determine what monitoring processes are required, etc. Make necessary plans to reopen the country systematically with an islandwide clinical trial in place.

Hopefully, we shall see the light at the end of the tunnel.