We respectfully disagree with the Director-General (DG) of Health Tan Sri Dr Noor Hisham Abdullah when he stated on 16 May 2021 that there is no conclusive evidence for the use of Ivermectin against COVID-19.
We understand that the officials and staffs of MOH are currently overwhelmed with the rising infective and mortality rates of the disease.
Our team of researchers are pleased to do the homework pointing to the numerous peer-reviewed scientific studies showing Ivermectin Is an effective prophylaxis and treatment for COVID-19.
Ivermectin has already been proven to be very safe as it has been used safely and successfully (to treat other tropical diseases) over 40 years and by four billion people.
We feel that many people are dying every day and getting infected with COVID-19 so unnecessarily.
What have we got to lose in trying out a tried and tested medicine (Ivermectin) which is increasingly being used in other countries against COVID-19 and its new variants, that has been proven very safe over 40 years by four billion people and with many recent credible studies around the world confirming that it can reduce the risk of infection against COVID-19 by 88% and the mortality rate by 83%?
There is no official treatment protocol against COVID-19 at the moment.
The studies listed below are randomized controlled trials (RCT) considered gold standard in evidence-based medicine, peer-reviewed, reproducible, using only Ivermectin and no add-on.
Randomization circumvents the problem with confounding, while the single investigative agent used without add-on, i.e., only Ivermectin, should leave no doubt that any positive result shown is specifically due to the investigative agent.
Most of the RCTs conducted on Ivermectin were of small and medium scale studies. This is Not an issue if the trials were well designed and properly conducted, and the results show statistical significance. Individual doctors who have no ulterior motive or vested interest other than altruistic intent, funded most of the studies. The above points answer the Health DG's criticism towards the Ivermectin studies.
The following RCTs show positive results of Ivermectin on COVID-19:
Babalola et al (2021) in a double-blinded RCT of 62 patients found a significant difference in viral clearance between both the low-dose and high-dose treatment groups and controls.1
Chaccour et al (2021) in a small double-blind RCT, randomized 24 patients to Ivermectin and placebo, found statistically significant decreases in viral loads, patient days of anosmia, and patient days with cough.2
Elgazzar et al (2020) randomized among four treatment groups of 100 hospitalized patients in each group.
Groups 1 and 2 were mild to moderate illness patients given either Ivermectin plus standard care or hydroxychloroquine plus standard care.
Groups 3 and 4 were severely ill patients, either given Ivermectin plus standard care or hydroxychloroquine plus standard care.
In both the groups given Ivermectin the rate of disease progression was lower. Mortality rate for the Ivermectin groups was also significantly lower.3
Niaee et al (2020) in a randomized placebo-controlled multicenter trial at five hospitals found a dramatic reduction in mortality with Ivermectin use and also improvement in several other clinical parameters.4
There are also observational controlled trials (OCT), although not considered the gold standard, but nevertheless contribute significantly to the body of scientific knowledge regarding Ivermectin and its therapeutic usefulness. The followings are the OCTs:
Rajter et al (2020) performed a retrospective OCT on 280 consecutively treated patients and compared those treated with Ivermectin to those without and found statistically significant lower mortality among Ivermectin-treated patients.
In a subgroup of patients with severe pulmonary disease, mortality was much reduced when treated with Ivermectin.5
Khan et al (2020) compared 115 patients treated with Ivermectin to a standard care cohort of 113 patients and found that those receiving Ivermectin became SARs-CoV-2 negative more quickly, fewer developed respiratory distress, and had shorter hospital stay. There was lower mortality rate in the Ivermectin-treated patients.6
Portmann-Baracco et al (2020) in a large OCT that included nearly 1,500 patients reported that in 704 hospitalized patients treated with a single dose of Ivermectin, compared with 704 controls, overall mortality was reduced. For those patients on mechanical ventilation, mortality was also reduced.7
There are a number of studies showing Ivermectin's ability to prevent COVID-19. The followings are the prophylaxis studies:
Elgazzar et al (2020) randomized 200 healthcare workers and households who had contact with COVID-19 patients where the intervention group of 100 was given Ivermectin and wore personal protective equipment (PPE), and a control of 100 wore PPE. The study found a large and statistical significant reduction in contacts testing positive by RT-PCR when treated with Ivermectin versus control.8
Shoumann et al (2021) conducted a RCT involving family members of patients PCR-positive for COVID-19.
Ivermectin group included 203 contacts, while non-intervention group included 101 contacts. 15 in the Ivermectin arm developed COVID-19 compared to 59 in the non-intervention arm after a two weeks follow up.
The result also showed a large and statistically significant decrease in COVID-19 symptoms among household members treated with Ivermectin.9
Alam et al (2020) conducted a prospective OCT at a hospital with 118 healthcare providers evenly divided into experimental group receiving a single dose of Ivermectin 12 mg per month for four months, and the control group.
Both groups were exposed to COVID-19 positive patients. Results of the symptomatic subjects and tested positive with RT-PCR showed 73.3% in the control group were positive for COVID-19 compared to only 6.9% in the experimental group.10
Hellwig and Maia (2021) studied countries with routine mass drug administration including prophylactic Ivermectin and found that these countries have a significantly lower incidence of COVID-19. This reported correlation is significant to show a possible causal connection.11
A few countries in South America provided good information supporting a role of Ivermectin in COVID-19 decreasing transmission rates. Countries like Peru, Brazil and Paraguay initiated Ivermectin distribution program to their citizens after their countries were hard hit by the pandemic in April 2020. Some cities started the Ivermectin program earlier than others. Large decreases in case counts for the cities soon after receiving Ivermectin in comparison to those cities that started the campaign late.12, 13
In evidence-based medicine (EBM), the systematic review and meta-analysis of RCTs occupies the top hierarchy of evidence. The study of Bryant et al (2021), Ivermectin for the prevention and treatment of COVID-19 infection: a systematic review and meta-analysis, included 21 RCTs involving 2,741 participants and meta-analysis conducted on 13 trials.
The result showed Ivermectin reduced risk of death compared to no Ivermectin. Ivermectin prophylaxis reduced COVID-19 infection by an average 86%.14
Dr Tess Lawrie (2021) conducted a systematic review and meta-analysis of 15 RCTs and 6 OCTs and confirmed that Ivermectin substantially reduced the risk of a person dying from COVID-19 by 83%. When used as a prophylaxis among healthcare workers and contacts, Ivermectin substantially reduced COVID-19 infection by 88%.15
The studies mentioned above are all well designed studies, peer-reviewed, and mostly RCTs, Not 'circumstantial hype' as mentioned by the Health DG.
There are several other studies, many of them RCTs that also include add-on therapeutic agent, case series, and poorly designed studies, studies having a certain degree of bias, and studies that did not consider for confounding factors; were omitted. In short, the studies mentioned are all of high quality.
There are also two systematic reviews and meta-analysis of RCTs. These are studies of the highest quality, the gold standard, and occupy the highest order of evidence in the evidence-based medicine.
With regards to dosage of Ivermectin, most of the studies mentioned used around 12 mg in a single dose or an additional dose after a few days for the duration of the study. None used mega doses of Ivermectin, as news report quoting the Health DG had unwittingly implied.
Looking at the conclusion of the studies mentioned above, the evidence is compelling and appear conclusive that Ivermectin has prophylactic and therapeutic value.
The Health DG chose to look at two studies showing negative results on Ivermectin – Chaccour et al (2021) (2), and Lopez-Medina et al (2021) 16; of which we are happy to give counter views.
Chaccour and colleagues conducted a pilot RCT with the Ivermectin arm (a single dose of 400 mcg/kg (n=12) or placebo (n=12). All the subjects recruited had some mild symptoms of COVID-19.
Although the Ivermectin group had non-statistically significant lower viral loads at day 4 and day 7, and also non-statistically significant lower IgG titers at day 21 post treatment, the study results had clinical significance.
Patients in the Ivermectin group recovered earlier from anosmia (loss of sense of smell), had reduced cough, lower viral loads and lower IgG titers, which are all positive signs.
The reason for non-significant result is because the sample size was too small to show a large difference. Had the sample size ranged into thousands, the result would have been positive.
Lopez-Medina and colleagues conducted a RCT that included 476 patients with mild disease symptoms randomized to receive Ivermectin, 300mcg/kg of body weight per day for five days (n=200), or placebo (n=197).
The primary outcome was time to resolution of symptoms within a 21-day period. The median time to resolution of symptoms was ten days in the Ivermectin group compared with 12 days in the placebo group.
By 21 days 82% in the Ivermectin group and 79% in the placebo group had resolved symptoms. The results showed no statistical significance.
The media had quoted the Health DG as saying "the results (of Lopez-Medina study) showed there was no significant improvement in COVID-19 symptoms resolution time".
This is incorrect. There is a big difference in the meaning of the word 'significant' and 'statistical significant'. The proper words to use was the latter as it was a scientific study to compare one arm with the other, a relative comparison.
The study also showed slightly less adverse events reported in the Ivermectin group compared to the control group – 77% vs 81.3%.
For clinical purpose, the two days difference in symptoms resolution and the lesser adverse events are all significant.
Both the leading authors of the study disclosed they received grants and fees from two conglomerates that are also producing the mRNA vaccines that have been delayed in approval. From the way the trial was designed – relatively small sample size, types of outcome measure, age group of subjects, study duration; it appears the study was destined to turn negative.
Officials from our Health Ministry should look at the current scientific information pertaining to Ivermectin.
Many RCTs on Ivermectin and COVID-19 only got published in February and March 2021.
The BMJ article, 'Drug treatments for COVID-19: living systematic review and network meta-analysis', that was mentioned in the Health DG's statement was published in July 2020 with updated data as at 6 April 2021 as claimed.
However, in the report there is no mention of Ivermectin trial results for mortality, adverse events leading to discontinuation, duration of hospital stay, ventilator-free days, and time to symptom resolution. Clearly there is selection bias in this BMJ report.
We have no malice in being critical of Health DG's statements. We are saddened to see the pandemic has claimed many lives, caused so much of hardship, and used up so much of human and financial resources. We genuinely believe, and are confident that if Ivermectin is mass-distributed, the epidemic in our country will be quickly brought under control.
References:
1 Babalola OE, Bode CO, Ajayi AA, et al. Ivermectin shows clinical benefits in mild to moderate COVID19 disease: a randomized controlled double blind dose response study in Lagos. medRxiv. 2021;hcab035. doi: 10.1093/qjmed/hcab035.
2 Chaccour C, Casellas A, Blanco-Di Matteo A, et al. The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedicine. 2021;32:100720.
3 Elgazzar A, Hany B, Youssef SA, Hafez M, Moussa H, eltaweel A. Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. Res Square. 2020. Doi: 10.21203/rs.3.rs-100956/v3.
4 Niaee MS, Gheibi N, Namdar P, et al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial. Res Square. 2020. doi: 10.21203/rs.3.rs-109670/v1.
5 Rajter JC, Sherman MS, Fatteh N, et al. Use of ivermectin is associated with lower mortality in hospitalized patients with COVID-19 (ICON study). Chest. 2021;159:85–92.
6 Khan MSI, Khan MSI, Debnath CR, et al. Ivermectin treatment may improve the prognosis of patients with COVID-19. Archivos de Bronconeumología. 2020;56:828–830.
7 Portmann-Baracco A, Bryce-Alberti M, Accinelli RA. Antiviral and anti-inflammatory properties of ivermectin and its potential use in COVID-19. Arch Bronconeumol. 2020;56:831.
8 Elgazzar A, Hany B, Youssef SA, Hafez M, Moussa H, eltaweel A. Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. Res Square. 2020. Doi: 10.21203/rs.3.rs-100956/v3.
9 Shoumann WM, Hegazy AA, Nafae RM, et al. Use of Ivermectin as a Potential Chemoprophylaxis for COVID-19 in Egypt: A Randomized Clinical Trial. J Clin Diagn Res. 2021;15.
10 Alam M, RM, PFG, et al. Ivermectin as pre-exposure prophylaxis for COVID 19 among healthcare providers in a selected tertiary hospital in Dhaka an observational study. Eur J Med Health Sci. 2020;2:1–5.
11 Hellwig MD, Maia A. A COVID-19 Prophylaxis? Lower incidence associated with prophylactic administration of Ivermectin. Int J Antimicrob Agents. 2021;57:106248.
12 Kory, Pierre,; Meduri, Gianfranco Umberto; Varon, Joseph; Iglesias, Jose; Marik, Paul E. Review of the emerging evidence demonstrating the efficacy of ivermectin in the prophylaxis and treatment of COVID-19. American Journal of Therapeutics: May/June 2021 – Volume 28 – Issue 3 – p e299-e318. doi: 10.1097/MJT.0000000000001377
13 Chamie J. Real-world evidence: the case of Peru. In: Causality between Ivermectin and COVID-19 Infection Fatality Rate; 2020.
14 Bryant, A., Lawrie, T. A., Dowswell, T., Fordham, E., Scott, M., MD, Hill, S. R., & Tham, T. C. (2021, March 11). Ivermectin for prevention and treatment of COVID-19 infection: a systematic review and meta-analysis.
15 Lawrie, T. (2021). Ivermectin reduces the risk of death from COVID-19 – a rapid review and meta-analysis in support of the recommendation of the Front Line COVID-19 Critical Care Alliance.
16 Lopez-Medina E, Lopez P, Hurtado IC et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomised clinical trial. JAMA. 2021; 325(14):1426-1435. doi: 10.1001/jama.2021.3071.
Captain (Rtd) Dr Wong Ang Peng, Research Scientist
Prof Dr Mustafa Ali Mohd, Senior Pharmacologist & Toxicologist
Dr Saifuzzaman Yusoff, Medical Doctor
Dr Zawawi Abdullah, Medical Doctor
Dr Durairajoo Govindarajoo, Medical Doctor
Dato' Nadzim Johan, Chairman, Coalition on Integrity of Vaccines & Drugs Against COVID-19 (CIVDAC)
Brigadier General (Rtd) Dato' Mohd Arshad Raji, Persatuan Patriot Kebangsaan (PATRIOT)
Dr Abd Kadir Warsi Mohamad (Phd), Persatuan Pengguna Islam Malaysia (PPIM)
Police Commissioner (Rtd) Dato' Shabudin Abdul Wahab, COVID Research Centre (AHM Group)
Tunku Azwil Tunku Abd Razak. Gabungan NGO Islam (GNI)
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