Zagazig University Randomized Controlled Ivermectin Study Results Confirms PI Hypothesis: Drug Effective Against COVID-19

A principal investor from Zagazig University, Dr. Waheed Shouman, recently completed a randomized, open label, interventional trial titled “Use of Ivermectin as Prophylactic Option in Asymptomatic Family Close Contact for Patient with COVID-19.” Targeting 340 participants, this study was completed in late August. This included a total of 304 participated, 203 participants in the ivermectin group and 101 in the control group. The goal of this investigation was to determine whether ivermectin could serve as a prophylactic and included a 14 day follow-up period involving a diagnosis for symptoms of COVID-19. The findings reveal that ivermectin demonstrates statistically significant benefits for use as a prophylaxis to prevent symptomatic COVID-19 infection in individuals that have been exposed to close family members diagnosed with COVID-19. This study confirms the author’s hypothesis that ivermectin in fact possesses an antiviral effect and demonstrates efficacy in preventing the development of symptomatic infection for those individuals that have come in close contact to family members diagnosed with COVID-19. Importantly, these findings haven’t been peer reviewed nor published in any medical journals. The study wasn’t’ blinded, the sample size wasn’t that large, etc. Moreover, the study was conducted in Egypt and hence any findings aren’t necessarily relevant for other food and drug jurisdictions, such as those in the United States (FDA), European Union (EMA), and the UK (MHRA) etc. On the other hand, an accumulation of observational, case series and even randomized controlled study data points (completed in Iraq and Bangladesh)  increasingly weigh toward possible benefit for ivermectin as a low cost, highly available consideration inhibiting COVID-19, particularly in low-to middle-income countries (LMICs). The drug has already been in wide use in LMICs for tropical parasites for decades. Regulatory authorities and national research units should at least be open to reviewing the data, rather than exhibiting indifference.

Overview

This study is one of over 30 such clinical trials that investigate the drug repurposing of an FDA approved antiparasitic drug called Ivermectin.  Based on the severity of the COVID-19 pandemic, a number of low-LMICs such as Egypt are assessing possible reuse of drugs that may help reduce the severity of the pandemic. The principal investigator in the study protocol highlights the importance of considering “drug re-purposing” as a “widely used method for rapid response in the face of epidemic.”  An underlying premise: solely focusing on advanced, expensive and complex new investigational drugs (“de novo medicines” at the expense of also experimenting with well known, approved drugs “may not be the perfect rationale” with a rapidly rising death toll.

TrialSite Ivermectin Diaries

TrialSite isn’t “pro” or “anti” ivermectin but rather inadvertently uncovered its use around the world. As the TrialSite  exists to chronicle research around the world, the investigational team followed case series, observational studies and randomized controlled studies around the world. The online media platform contains ever accumulating amounts of information resulting from articles, interviews and reports. TrialSite even completed a documentary in Peru as that nation included ivermectin on its approved list of COVID-19 medicines. TrialSite sought to understand the basis and rationale for that decision. See the 15 minute documentary here. 

Rational for Ivermectin

Based on the study protocol, PI Dr. Shouman notes the use of FDA approved ivermectin. Known for a wide-spectrum of antiviral activity, however only under in vitro condition. While the PI positions that ivermectin can inhibit the nuclear import of host and viral proteins, evidence reveal it can limit infection by some RNA viruses such as influenza, dengue and West Nile viruses.  Dr. Shouman suggests that the antiparasitic medication can act against the DNA virus pseudorabies virus (PRV) both in vitro and in vivo.  And, of course, much like the rest of the world that has accepted ivermectin, the rational for this study: the University of Monash findings that ivermectin is in fact an inhibitor of the SARS-CoV-2, “with a single addition to Vero-hSLAM cells 2 h post infection with SARS-CoV-2 able to effect  ~5000-fold reduction in viral RNA at 48 hours.”

Dr. Shouman notes previous studies evidencing an antiviral role of the study drug and “recent experimental reports highlighted an in vitro capability of stopping SARS-CoV-2 replication. 

TrialSite has chronicled the use of this drug in a number of countries including the original documentary in Peru, which sought to identify the rational or justification for the national government’s listing of the drug for COVID-19.

Study Hypothesis

Sponsored by Zagazig University, the researchers pursued the answer as to whether oral ivermectin can prevent symptomatic COVID-19 infection in family close contacts with patients diagnosed as having the disease by RT-PCR. In a study of a few hundred subjects, can ivermectin in fact demonstrate an antiviral effect and actually prevent the development of symptomatic infection in family close contracts with patients already diagnosed as positive?

The Study

This study sought to determine if ivermectin could serve as a prophylactic for those individuals who had been exposed to someone in their household that was tested positive for COVID-19.  To participate, the subject had to be between the ages of 16 and 70, healthy and confirm that a family member was infected with SARS-CoV-2, the virus behind COVID-19. The study excluded any pregnant or lactating individuals or those with a known hypersensitivity to Ivermectin. Also excluded were any subjects that previously were infected with COVID-19 or evidenced any symptoms suggestive of the condition.

The Zagazig University IRB approved the study on May 31, 2020. It included the following intervention:

All documented asymptomatic family contacts, starting on day of diagnosis of their index case received the study drug based on body weight as follows:

Note for the above the subject is given one dose at day one (diagnosis day); repeated once at day 3. Dr. Shouman claims that based on relevant literature, a subject can receive 60 mcg per Kg of ivermectin daily for 3 days without side effect. References include Smit et al and Navarro et al. 

Dr. Shouman and the Zagazig University study team followed the subjects for two weeks after the diagnosis. They conducted tests such as radiological evaluation if symptoms developed (e.g. HRCT chest), tests including Swabs for SARS-CoV-2 if symptomatic and also worked with participants to record side effects, such as sleepiness, etc.

Statistical Analysis

Standard statistics were utilized including software package SPSS 22.0 and MedCalc 13. Continuous data were checked for normality with Shapiro Walk test. Mann-Whitney U test was employed to compare between two groups of non-normally distributed data. The team used Chi-square or Fisher’s exact test when appropriate for comparing categorical data. Standard statistics for confidence intervals and risks in addition to forest plotting. The team used univariate and multivariate binary logistic regression formulas to identify COVID-19 protection prediction. Moreover, they ran two sided tests including establishment of p-value <0.05 as threshold for statistical significance.

Summary of Findings

Again, TrialSite emphasizes these findings have not been peer reviewed nor published. TrialSite offers a summary and hence no scientific conclusion can be made here. And as a reminder for those living in various jurisdictions, these study results, even if correct, aren’t necessarily relevant in other national jurisdictions.

The Zagazig University results reveal that out of 203 subjects in the ivermectin arm 15 contacts (7.4%) developed COVID-19 as compared to 59 (58.4%) in the non-intervention arm. Note, all of the subjects were symptomatic based on the study protocol, again here. According to the lead author, the difference between the ivermectin arm and the non-intervention arm was “highly significant” (p<0.001).

The author went on to report that the median (range) day for the development of the disease was 2 (2-6) in ivermectin group and 4 (2-10) in the non-intervention group with a significant difference of (p<0.017).

Interestingly, the author notes that within the first 3 days in the ivermectin group, ten (10) contacts (66.6%) developed symptoms while none developed after 6 days. While in the non-intervention arm, 25 (42.3%)  developed symptoms in the first 3 days and continued to the 10 days.

The author depicted so-called “Protection Rates” of ivermectin versus the non-intervention arm and breakdown by a number of categories such as severity index (mild, moderate, severe) and various demographics. TrialSite summarizes that the overall “Protection Rate” was calculated as 92.6% for the intervention (ivermectin) group and 41.6% for the non-intervention arm. When breaking this comparison down by demographic overwhelmingly ivermectin reveals statistically significant benefits according to the Zagazig University investigator analysis.

Ivermectin Role in Preventing SARS-CoV-2 Infection

According to this author’s analysis and findings, ivermectin played a prominent role in preventing SARS-Cov-2 infection.

The investigator reveals that ivermectin had an OR of 12.533 and 11.445 when compared to no intervention in both univariate and multivariate models, respectively. Moreover, the author posits that based on the data analysis protection wasn’t compromised by gender or comorbidities in the multivariate model.

Side Effects

In 11 or 5.4% of the contacts side effects were reported. These included the following: diarrhea (1.5%), nausea (1%), fatigue (1%), sleepiness (0.5%), abdominal pain (0.5%), heartburn (0.5%), tingling and numbness (0.5%) and lastly burning sensation (0.5%)

Zagazig University

Located in the Nile Delta region, Zagazig University is one of Egypt’s largest universities with prominent schools of science and arts. According to at least one ranking, the university ranks 7^th nationwide and places 1364 worldwide.

Established in 1970, the school originated as a branch of Ain Shams University and was the seventh university to be established in Egypt.  A public university it emphasizes research. Its medical school includes a number of research programs. 

Lead Research/Investigator

Waheed Shouman, MD, Professor of Chest Medicine

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