22/06/2021
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Inadequate evidence to recommend Ivermectin in the prophylaxis and treatment of COVID-19

By Professor Dr Moy Foong Ming

Evidence-based medicine (EBM) is conscious, specific, reasonable use of modern, best evidences in making decisions about treatment of patients.

Doctor chooses the best possible solution for his patients by the use of the best possible evidence to provide the optimum health care in every aspect.

It is also used to avoid major mistakes in the course of treatment, by providing better quality health care to the patients, ultimately to save the lives of patients.

During the current pandemic of COVID-19, clinicians and researchers are actively exploring various methods of prophylaxis and treatment of COVID-19.

Besides vaccination for prophylaxis and symptomatic treatment of the disease, currently there is a very strong voice in advocating Ivermectin for the prophylaxis and treatment of COVID-19 globally as well as in our country.

Ivermectin is a broad-spectrum antiparasitic agent approved by the US Food and Drug Administration (FDA) and is proved to be safe at the conventional dose of ≤200 µg/kg, although severe adverse effects ranging from ataxia to seizures were occasionally reported.

Due to its in vitro antiviral activity against a broad range of viruses, it has been used off-label for the treatment of some viral diseases.

However, regulatory bodies including the US FDA and the European EMA as well as the Malaysian Ministry of Health (MOH) concluded that there was insufficient evidence to support the use of Ivermectin as treatment of COVID-19.

The WHO also issued guidelines against the routine use of Ivermectin in the treatment of COVID-19 except in clinical trial settings.

The MOH has initiated a RCT using Ivermectin among the severe COVID-19 patients which will only complete by September 2021.

The Malaysians Alliance for Effective COVID control (MAECC) is actively pursuing Ivermectin to be included as routine drug in the prophylaxis and treatment of COVID-19.

The MAECC has a large number of followers, including clinicians and patients.

There was even a police report launched against the Ministry of Health for not approving Ivermectin in the treatment of COVID-19.

Most of the justifications in proposing Ivermectin as prophylaxis and treatment for COVID-19 presented were from randomized controlled trials (RCTs) or systematic reviews of low quality. Among the RCTs, there are considerable heterogeneity in the population receiving Ivermectin who were family contacts of confirmed COVID-19 cases as a prophylactic measure, mild to moderate infected or severe hospitalized patients using Ivermectin for treatment.

Applied doses and outcomes of interest were also highly variable. Additionally, patients in the control groups received different kinds of comparators ranging from placebo or no intervention to standard care or even hydroxychloroquine.

The sample sizes of these RCTs were also small. Most of the RCTs were not registered with the Trial Registration Platform and were in the form of pre-prints, not peer reviewed nor published in journals.

Registering clinical trials before they begin and making results peer reviewed overcome publication and selective outcome reporting biases.

I would like to share a latest high quality RCT published in the Journal of American Medical Association (JAMA) (doi:10.1001/jama.2021.3071).

The trial was among 400 patients with mild COVID-19, with Ivermectin of 300ug/kg of body weight per day for five days or placebo, with the primary outcome as the time to resolution of symptoms within a 21-day follow up period.

The results showed that by day 21, 82% of the Ivermectin and 79% of the placebo groups had resolved symptoms. The conclusion is that among the adults with mild COVID-19, a five-day course of Ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of Ivermectin for treatment of mild COVID-19.

The highest level of evidence comes from systematic review with meta-analysis from RCTs, however the quality of evidence generated depends greatly on the quality of the included RCTs.

There is a latest systematic review and meta-analysis (doi: 10.1097/MJT.0000000000001402) published in the American Journal of Therapeutics, reported that Ivermectin reduced risk of death computed with no Ivermectin (average risk ratio of 0.38, 95% confidence interval 0.19–0.73; n = 2438) with moderate-certainty evidence).

However, when we read the full text, it was found that there are many issues which are of concern.

This review included a total of 24 trials (with 21 RCTs and three quasi-RCT). The included patients were widely variable: asymptomatic, mild and moderate infected individuals who were outpatients or inpatients; severe hospitalized patients were included in the treatment modality; while healthcare workers, health care workers' family members and close contacts were included for prophylaxis purpose.

The intervention was Ivermectin with widely variable doses and treatment duration, while the comparison had either placebo, standard of care (SOC) only, placebo + SOC, Ritonavir/lopinaviror etc.

The primary outcome was all cause mortality, while the secondary outcomes were improvement or deterioration of COVID-19 symptoms, which how these outcomes were derived were unclear.

Among the included trials, only eight were peer reviewed (published), the rest were from pre-print or communication with researchers.

Although there was mentioned of "most trials were registered", the evidence was not presented.

Sources of funding were not reported among ten trials, with three trials were pharma sponsored and the rest either self-funded or institution funded.

On the results, sub-group analyses were carried out for mild to moderate and severe COVID patients separately and the results for these sub-groups were either not significant or marginally significant with wide confidence intervals.

However, the authors pooled all sub-groups and presented the pool results giving "more precise and significant estimates", with high heterogeneity (up to 60%).

The authors claimed that the findings indicate with moderate certainty that Ivermectin treatment in COVID-19 provides a significant survival benefit from the pool estimates for all sub-groups.

Considering all the above, I considered the evidence to be of low quality and there is insufficient evidence from the review to recommend Ivermectin as treatment or prophylaxis for COVID-19 infection.

In conclusion, most of the current research related to Ivermectin in COVID-19 has serious methodological limitations resulting in very low certainty of the evidence.

Recommendation in using this drug for prophylaxis or treatment for COVID-19 should be based on trustworthy evidence, with proven patients' safety and efficacy.

More RCTs which are well planned and peer reviewed, without conflict of interest, ethically approved are required.

(Professor Dr Moy Foong Ming, Professor in Epidemiology. Center of Evidence Based Practice and Clinical Epidemiology, Department of Social & Preventive Medicine, Faculty of Medicine, Universiti Malaya.)

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