https://brieflands.com/articles/jjhs-146703

Ivermectin as a Potential Addition to the Limited Anti-COVID-19 Arsenal: A Double-Blinded Clinical Trial

Authors:
avatar
Mehran Varnaseri
ORCID
1
,
avatar
Fatemeh Amini

2
,
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Ramin Jamshididan
1
,
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Mehrdad Dargahi
3
,
avatar
Nematollah Gheibi
ORCID
3
,
avatar
Sara Abolghasemi
ORCID
3
,
avatar
Mohammadreza Dayer
4
,
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Negar Varnasseri
3
,
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Khojasteh Hoseinynejad
5 , *
,
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Sahar Kheradhoosh
3
,
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Pedram Nazari
6 , **
,
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Ebrahim Babadi
7
,
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Seyedeh Maryam Mousavinezhad
6
,
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Pouya Ebrahimi
ORCID
8

1
Infectious and Tropical Diseases Research Centre, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2
Department of Persian Medicine and Pharmacy, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
3
Department of Pulmonology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
4
Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
5
Department of Physiology, Faculty of Medicine, Persian Gulf Physiology Research Centre, Medical Basic Sciences Research Institute, Jundishapur University of Medical Sciences, Ahvaz, Iran
6
Cancer Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
7
Department of Microbiology, Faculty of Agricultural Sciences and Modern Technologies, Shiraz Branch, Islamic Azad University, Shiraz, Iran
8
Tehran Heat Center, Tehran University of Medical Sciences, Tehran, Iran
Corresponding Authors:
* Corresponding Author: Department of Physiology, Faculty of Medicine, Persian Gulf Physiology Research Centre, Medical Basic Sciences Research Institute, Jundishapur University of Medical Sciences, Ahvaz, Iran. Email: khoseinynejad@yahoo.com
** Corresponding Author: Cancer Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Email: dr.pedramnazari@gmail.com

Jundishapur Journal of Health Sciences: Vol.16, issue 2; e146703
Published Online: April 30, 2024
Article Type: Research Article
Received: March 10, 2024
Revised: April 8, 2024
Accepted: April 9, 2024

How To Cite: Varnaseri M, Amini F, Jamshididan R, Dargahi M, Gheibi N, et al. Ivermectin as a Potential Addition to the Limited Anti-COVID-19 Arsenal: A Double-Blinded Clinical Trial. Jundishapur J Health Sci. 2024;16(2):e146703.

https://doi.org/10.5812/jjhs-146703. DOI:

Abstract
Background: Addressing the Coronavirus disease 2019 (COVID-19) pandemic remains a significant challenge for healthcare systems globally. Despite the absence of a proven cure, ivermectin has been proposed as a potentially effective agent against it.
Objectives: This study aimed to evaluate the therapeutic effects of ivermectin compared to a placebo group in non-critically ill confirmed COVID-19 patients.
Methods: A double-blind, randomized clinical trial was conducted on 110 patients with moderate-to-severe (non-critical) confirmed COVID-19 infection. The patients were equally divided into two groups, with one group receiving ivermectin tablets (14 mg every 12 hours for three days) and the other group receiving a placebo. The efficacy and safety of ivermectin were assessed in both groups.
Results: A total of 110 patients, including 62 (56.4%) men and 48 (43.6%) women, with an average age of 53.36 ± 15.10 years, were enrolled in our double-blind, randomized clinical trial. The baseline characteristics of the two groups were similar. The findings demonstrated that ivermectin significantly reduced the need for Intensive Care Unit admission (32.7% vs. 5.5%; P < 0.001), hospitalization duration (six vs. four days; P < 0.001), and median time to symptom resolution period (P < 0.05) in COVID-19 patients compared to the placebo group, without any serious side effects (P > 0.05).
Conclusions: Ivermectin appears to be a potentially effective and safe medication for COVID-19 patients with moderate disease.
Keywords
COVID-19 Ivermectin Treatment Efficacy Drug Safety Randomized Controlled Trial

1. Background
One of the major global health challenges is the Coronavirus disease 2019 (COVID-19) pandemic. The SARS-CoV-2 virus responsible for this disease belongs to the beta-coronavirus family and is the seventh member of the coronavirus family (1). According to statistics from the World Health Organization (WHO), as of June 18th, 2021, a total of 3 840 223 individuals had lost their lives due to this infection (2). On a positive note, there have been significant advancements in developing effective vaccines against COVID-19, which have substantially reduced morbidity and mortality rates and instilled hope for disease control (3). Despite numerous studies investigating potential treatments for COVID-19, no confirmed cure for this virus has been found, and proposed treatments have not proven to be efficient (4). Although vaccination has had a significant impact on controlling the COVID-19 pandemic, certain populations, such as older adults and immunosuppressed individuals, still benefit from treatment for this viral infection, especially if they have been vaccinated (5).

Hence, further robust studies are necessary to discover more effective treatments for the virus. Ivermectin has recently emerged as a relatively safe, cost-effective, and readily available treatment option. This medication is a broad-spectrum antiparasitic drug approved by the US Food and Drug Administration (6). In a recent in vitro study by Caly et al., it was demonstrated that the addition of a single dose of ivermectin to Vero-hSLam cells infected with SARS-CoV-2 resulted in a 500-fold decrease in viral RNA levels over 48 hours. Theoretically, it seems that by inhibiting the beta receptor's entry, which serves as a crucial element in transmitting the virus into target cells, as well as its proliferation and resistance to antibiotic agents, this medication possesses potent antiviral properties (4, 7). Additionally, the findings of some recent observational studies have indicated that ivermectin is effective in reducing mortality among patients admitted to the intensive care unit (ICU) with COVID-19 infection (P-value = 0.005, 95% CI = 0.04 - 0.57, OR = 0.15). However, the decrease in mortality rates was insignificant among moderate to severe patients who had not initially been admitted to the ICU (8). A recent review study by Bhowmick et al., which examined 19 clinical trials and observational studies, revealed that none of the investigations could confirm or refute ivermectin as monotherapy or an adjunct therapeutic agent (9).

2. Objectives
Given the discrepancies in the findings of previous studies and the need for more rigorous investigations into the therapeutic approach for the infection, the authors decided to conduct a clinical trial to examine the efficacy and safety of ivermectin among COVID-19 patients.

3. Methods
3.1. Study Design
This study was a double-blind, randomized clinical trial involving 110 patients diagnosed with confirmed COVID-19 infection, who were referred to Razi and Sina Hospital in Ahvaz, Iran, from July 30th, 2020, to June 15th, 2021. Initially, it received approval from the Research Ethics Committee of Ahvaz Jundishapur University of Medical Sciences and the Iran National Committee for Ethics in Biomedical Research. Subsequently, it was registered with the code number IRCT20200404046937N4 at the Iranian Clinical Trial Registry. All participants provided informed written consent, and patients retained the right to discontinue the trial at any time.

3.2. Participants
One hundred ten patients diagnosed with confirmed COVID-19 infection based on real-time PCR results were included in the study. All participants were randomly assigned to two groups using the block randomization method, resulting in 55 patients in the ivermectin arm and 55 patients in the placebo arm (1:1 ratio). The placebo tablets were identical to the ivermectin tablets in appearance and physical properties, including size, shape, color, taste, smell, and packaging. Placebo medications were manufactured by the Pharmacy Faculty of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, and administered to patients in a manner similar to ivermectin.

Both the individuals administering the medication and the participants were unaware of whether they were receiving placebo or ivermectin. The packages were coded before tablet administration, and only the investigators responsible for statistical analysis had access to these codes.

3.3. Inclusion and Exclusion Criteria
The eligibility criteria for participation in the study included confirmation of COVID-19 infection based on PCR results, moderate to severe disease (non-critical illness) (10), age above 18, hospitalization, consent to participate in the study, and no participation in any other investigations in the preceding 28 days. Exclusion criteria encompassed patients with critical conditions or mild illness, those requiring ICU admission at the outset of the study, a history of sensitivity to ivermectin, severe renal, hepatic, or cardiac disease, pregnancy, intent to become pregnant, or breastfeeding.

Baseline characteristics, such as gender, marital status, occupation, place of residence, height, weight, vaccination status, smoking history, medical history, and medication history, were documented for all participants. Additionally, patients' signs and symptoms, including fever, chills, cough, dyspnea, nausea and vomiting, myalgia, sore throat, diarrhea, vital signs, O2 saturation, ward or ICU treatment status, level of lung involvement based on chest computed tomography (CT) scan findings, and laboratory data including lactate dehydrogenase (LDH), qualitative C-Reactive Protein (CRP), polymorphonuclear leukocyte (PMN), and lymphocyte cell counts, were recorded at the outset of the study. Clinical evaluation and treatment of all patients involved in the study were conducted by an infectious disease specialist specializing in COVID-19 management.

Adverse medical events assessment was conducted by an objective team of clinicians with expertise in infectious diseases and pharmacology (pre-determined Adjudicating team) to ensure the accuracy and consistency of the clinical truth of each event. They reviewed the provided clinical event information and based their assessment on that data without bias or partiality. Moreover, the Data and Safety Monitoring Board (consisting of specialists in pharmacology, infectious diseases, and pulmonary diseases) was tasked with monitoring the clinical conditions of patients enrolled in these trials. They screened the trial for early detection of efficacy, findings of harm, and futility in obtaining a meaningful outcome. The DSMB members were committed to keeping the scientific and clinical questions under investigation foremost in their minds as they reviewed the collected data.

3.4. Intervention Protocols
In the intervention group, patients were treated with ivermectin (14 mg every 12 hours for three days) in addition to the standard treatment based on Iran's Internal Guidelines (11). In contrast, the second group received standard therapy with a placebo administered once every 12 hours for three days.

Based on Iran's National Guidelines for COVID-19 treatment protocol, dexamethasone 8 mg (IVI) for a maximum of 10 days, Remdesivir 200 mg (IVI) on the first day, and then 100 mg (IVI) daily for five days, enoxaparin 40 mg subcutaneously once daily (for venous thromboembolism prophylaxis), were administered to all participants as standard treatment. Additionally, supplemental oxygen and symptomatic therapy (for fever, pain, cough, malaise, sore throat, etc.) were applied if needed. Both groups measured all cases' signs and symptoms, conducted physical examinations, and assessed laboratory test results daily. Furthermore, a low-dose chest CT-scan without contrast was performed on all patients on admission and discharge day. All findings were recorded in a standard checklist.

3.5. Outcomes
Primary endpoints included improving the patient's general condition, maintaining O2 saturation ≥ 94% in ambient air without respiratory distress, and being fever-free for at least 72 hours. Secondary endpoints in the study included the requirement for patient transfer to the ICU throughout the study, intubation rate, morbidity and mortality rates, duration of hospitalization, time required for resolution of signs and symptoms, chest CT-scan findings, and laboratory data upon admission and on the last day of the study (at discharge or at the conclusion of the previous chest CT-scan in deceased patients). The Visual Analog Scale was used as a questionnaire to assess the time needed to resolve the patient’s signs and symptoms during hospitalization. The time to symptom resolution was defined as the period between the onset of the patients’ symptoms and the first day they rated their symptoms as 0 (the lowest possible score) (12). We compared the level of lung involvement in the two groups before and after the trial using chest CT-scan intensity grading (grade 1 = mild, grade 2 = moderate, and grade 3 = severe) as mentioned in the study by Saeed et al. (13). All patients were clinically assessed for side effects, allergies, and possible reactions to ivermectin. Additionally, we measured the six-minute walking distance (6-MWD) as an objective measure for respiratory recovery in both groups and compared the results (14).

3.6. Sample Size Calculation
Considering the clinical trial design of the study and the main binary outcomes (survival and ICU admission), assuming alpha = 0.05 and power = 0.8 (β = 0.20), and the proportion of cases exposed to adverse outcomes and good prognosis in each parallel group based on the findings of previous similar studies (12), the following formula was used to calculate the sample size in both parallel groups:

Considering the effect size (x) of 0.2, the required sample size for each group was at least 17 cases. However, this clinical trial was continued to obtain more accurate results until the maximum sample size of eligible patients was fully investigated.

3.7. Statistical Analysis
In this study, continuous variables were reported as mean ± SD or median, and differences between groups were examined using the independent sample t-test or the Mann-Whitney test. Categorical variables were reported as number and percentage, and the differences in categorical variables were assessed using the chi-square or Fisher's exact test. Data were analyzed using SPSS 21, and P-values < 0.05 were considered statistically significant.

4. Results
Our investigation was conducted from July 2020 to June 2021. During the study period, three disease waves occurred, including 20A (B.1.36), 20B (B.1.1.413), and 20I (B.1.1.7), respectively, in Ahvaz, Iran (1).

In this study, 134 patients infected with COVID-19 were initially assessed for eligibility criteria, and 110 cases were ultimately assigned to two groups receiving either ivermectin or placebo equally (Figure 1).

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https://brieflands.com/articles/jjhs-146703

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