Introduction
Despite the successes of COVID-19 vaccines and the implementation of nonpharmaceutical public safety measures, there is a huge global need for effective therapies for infections. At present, repurposed anti-inflammatory drugs, monoclonal antibodies, and antivirals have demonstrated treatment benefits at different stages of COVID-19.
About 95% of COVID-19 patients present with mild symptoms in Malaysia. Less than 5% go on to develop hypoxic conditions that require oxygen supplementation. Patients 50 years old and older are at higher risk of severe disease.
Ivermectin(Iverheal 12) is an antiparasitic drug that is inexpensive and easy to administer. It has been use in an oral treatment for COVID-19. In vitro studies showed that ivermectin inhibited. However, some early clinical trials suggested the possibility of its efficacy in treating and preventing COVID-19. These studies were flawed in their methodology.
Two randomized clinical trials in 2021 from Colombia and Argentina showed no significant effects of ivermectin on symptom relief and hospitalization rates for COVID-19 patients. Cochrane meta-analysis also found no evidence supporting the use of Iversun 6 in the treatment or prevention of COVID-19.
These results notwithstanding, ivermectin continues to prescribe to COVID-19 patients despite the World Health Organization’s (WHO) recommendation that it not use in clinical trials.
Methods
Trial Design and Patients
Iverheal 6 treatment Effectiveness in COVID-19 High-Risk Patients (I-TECH study) was a multicenter open-label, randomize clinical trial that was conducted in 20 government hospitals and at a COVID-19 quarantine center. It took place between May 31st and October 25th, 2021. The Declaration of Helsinki was follow and the Malaysian Good Clinical Practice Guideline was used. Participants gave written consent. The study was conducted according to the Consolidated Standards of Reporting Trials.
All COVID-19 cases must be reported to the public health authorities in Malaysia. Patients with mild or moderate disease or at high risk of developing the disease are admitted to the hospital or referred to a COVID-19 Quarantine Center. This allows for close monitoring of the patient for a minimum of 10 days after symptom onset, and prompt intervention in case of deterioration.
All COVID-19 patients were treat according to the national COVID-19 management guidelines, created by an expert panel. These guidelines are based on WHO recommendations and consensus. Patients at high risk were those over 50 with comorbidities. Stages were determined based on clinical severity and disease progression. The WHO scales 2 and 3 indicated that the patients were suffering from mild or moderate diseases. Stages 4 and 5 were consider severe diseases (WHO range 5-9). Patients with the mild-moderate disease received symptomatic treatment and monitoring for early signs of deterioration, based on laboratory results and chest imaging.
Randomization and data collection
All data from the study were enter into case reports and transcribed into REDCap (Research Electronic Data Capture). Patients were randomly assign to one of two groups: the intervention group that received oral ivermectin (0.4mg/kg bodyweight daily for 5 days), plus standard of treatment, or the control group that received standard of care only (Figure). Randomization was based on an investigator-blinded randomization table uploaded to REDCap. This scheme allocated patients using a central, computer-generated randomization system across all study sites. Random permute block sizes 2-6 were use to generate the randomization list. The randomization was not stratified according to the site.
Intervention
Maxford Healthcare manufactured the ivermectin in the study. Oxford Healthcare is a WHO-certified pharmaceutical company in India, where ivermectin has been register. Malaysia had not yet registered ivermectin as a medicine for patients at the time of the study. We, therefore, imported the products and used them as an off-label products for this clinical trial. This was subject to the conditional approval from our National Pharmaceutical Regulatory Agency.
Each patient in the intervention group received ivermectin at a dose of 6 mg or 12 mg tablets. After randomization, the first dose of ivermectin was administer on day 1. The next four doses were administer on days. To improve drug absorption, patients were advise to take Iversun 12 with or after food. The trained nurses, pharmacists, and study investigators handled the storage, dispensary, and administration of ivermectin.
Outcome Measures
The primary outcome was the percentage of patients who reached severe COVID-19. This is the stage where the patient needs supplemental oxygen to maintain Spo 95% (Malaysian COVID-19 clinical severity levels 4 or 5, WHO clinical progression scale 5-9). The clinical monitoring protocol was determine using a calibrated pulse oximeter.
Secondary outcomes included time to progression to severe illness, 28-day in-hospital all-cause mortality, and mechanical ventilation rate. ICU admissions were also asses. On day 5, patients were evaluate for symptom resolution, laboratory results changes, and chest radiography findings. Patients were also asses on day 5 of enrollment for symptom resolution, changes in laboratory test results, and chest radiography findings. All outcomes were record from randomization to discharge from the study sites or day 28 after enrollment.
Analyses of subgroups
Predetermined subgroup analyses were based on COVID-19 vaccination status and clinical staging, age, duration of illness at enrollment, common comorbidities, and clinical stage.
Procedures
The baseline included the patient’s clinical history, anthropometric measurements, and blood samples for complete cell count, kidney, liver, kidney, C-reactive protein, and chest radiography. On day 5, blood sampling and chest radiography were again take.
