Since coronavirus disease 2019 (COVID-19) first emerged, healthcare workers have been frustrated by the lack of effective treatments. Patients who progress to severe disease are given supplemental oxygen or need to receive invasive mechanical ventilation, but early on very few drugs could help infected individuals.
Unfortunately, there have been constant rumors about drugs that later prove to be ineffective – hydrochloroquine received significant media attention. Researchers from hospitals around Malaysia have been looking into the efficacy of the controversial drug ivermectin.
High-risk patients were enrolled in the randomized clinical trial at 20 different government hospitals across Malaysia, including a COVID-19 quarantine center. As all COVID-19 cases in Malaysia must be reported to health authorities, patients who are at risk of progression to severe disease are referred for hospitalization or quarantine centers for closer monitoring. These patients were then enrolled in the study if they met certain criteria, including a positive reverse-transcriptase polymerase chain reaction (RT-PCR) test, at least one comorbidity, and if they were at least 50 years old. Asymptomatic patients and those who had progressed to the point of needing supplemental oxygen or showed other risk signs for severe disease were excluded, as were those who had taken any drugs reported to be effective against COVID-19 within the last seven days.
Following randomization, the patients in the ivermectin group received 0.4mg/kg ivermectin for five days, calculated to the nearest 6mg or 12mg whole tablet dose. This was administered with or after food. The primary outcome investigated was the progression to severe disease – which was determined to be the point at which the patient required supplemental oxygen, but other factors were also investigated, including time of progression to severe disease, mortality rates, admission to intensive care units and rates of adverse and serious adverse events, among others.
Statistical analysis was performed to determine any efficacy or danger to patients following administration, with sensitivity analyses for all patients. Means and standard deviations were used for descriptive data, while categorical data were analyzed using the Fisher exact test and continuous variables tested using either the t-test or Mann-Whitney U test. Risk ratios were used to estimate primary and categorical secondary outcomes.
In total, the study included 500 patients, investigated between May and October 2021. Following randomization, four patients were excluded due to failure to meet inclusion criteria or extensive comorbidities such as dengue coinfection and acute coronary syndrome. Six more patients withdrew consent. Out of the 490 remaining patients, 249 were enrolled in the control group, and 241 were given doses of ivermectin. 232 of these finished all five doses. The average age of participants was 62.5, and men and women were roughly equally represented. 51.8% of patients were fully vaccinated. Many had comorbidities including hypertension, diabetes and obesity.
Out of the 490 patients included in the final analysis, 95 progressed to severe disease during the study. Fifty-two of these had received the standard treatment as well as ivermectin, and 43 had received standard of care. As these numbers suggest, statistical analysis revealed no significant differences between ivermectin and control groups, and this trend continued when examining secondary outcomes. In patients who progressed to severe disease, the ivermectin groups took 3.2 days to progress to severe disease compared to 2.9 for the control groups. There were no significant differences between groups when examining mechanical ventilation and intensive care unit admission either. The 28-day in-hospital mortality rate was also very similar for both groups, as was the mean length of hospital stay. Finally, the pathology of both groups showed no distinct differences.
When examining adverse events the scientists found that 55 had occurred in 44 different patients – a rate of 9%. Thirty-three of these patients were from the ivermectin group. Most were relatively mild, but five events were serious adverse events, including severe anemia, hypovolemic shock, and two myocardial infarctions in the ivermectin group. Only one serious adverse event occurred in the control group – the patient suffered from inferior epigastric arterial bleeding. While there were a total of 13 deaths, none of these were attributed to ivermectin treatment.
The research has found no evidence for the efficacy of ivermectin for patients at risk of progressing to severe COVID-19. This is supported by multiple other studies that have shown no effect on disease outcomes. While initial media attention to the drug has led many to believe that it can prevent disease, there have been very few studies to show any positive effect, and there is significant controversy surrounding the robustness and replicability of those papers. Therefore, this study may allow researchers to focus on more promising candidates in the future.