ABSTRACT
BackgroundThe emergence of COVID-19 requires alternative treatments based on the reuse of drugs as a strategy to prevent the progression of the disease in patients infected with SARS-COV-2. The goal was to evaluate the use of ivermectin in mild stage outpatients to heal and / or reverse the progression of COVID-19 disease towards the development of moderate or severe stages. MethodsCluster Assigned Clinical Trial (2:1) in outpatients, n = 234. The subjects were divided into experimental (EG: n = 110) and control groups (CG: n = 62). The EG received ivermectin orally 4 drops of 6 mg = 24 mg every 7 days for 4 weeks. All participants were diagnosed by positive RT-PCR for COVID-19 and were evaluated by clinical examination, at the beginning and the end of protocol. Data analyzed were applied the proportion, bivariate, and logical regression tests with level significance p < 0{middle dot}05. This study was registered at ClinicalTrials.gov Identifier NCT04784481. FindingsBoth groups were similar in age, sex, and comorbidities (EG: 56F, median age= 40{middle dot}0, range: 18{middle dot}0 - 75{middle dot}0; CG: 34F, median age = 37{middle dot}5, range: 18{middle dot}0 - 71{middle dot}0). A significant reduction in the symptom numbers was observed in the EG when the medical examination was performed from 5th to 9th days, after starting treatment (p = 0{middle dot}0026). Although, medical examination from 10th to 14th day, showed a progressive reduction of the percentage symptom numbers, these were not significative in both groups. A higher proportion of medical release was observed in EG (98{middle dot}2%) vs CG (87{middle dot}1%) (p = 0{middle dot}003). EG showed 8 times more chance of receiving medical release than CG (OR 7{middle dot}99, 95% CI: 1{middle dot}64 -38{middle dot}97, p = 0{middle dot}003). The treatment effect with ivermectin to obtain medical release was analyzed by the logistic regression model based in the following control variables: sex, age, and comorbidities. Then, the chance to obtain medical release was maintained in EG (OR 10{middle dot}37, 95% CI: 2{middle dot}05 - 52{middle dot}04, p = 0{middle dot}005). InterpretationTreatment with ivermectin in outpatients with mild stage COVID-19 disease managed to slightly reduce the symptom numbers. Also, this treatment improved the clinical state to obtain medical release, even in the presence of comorbidities. The treatment with ivermectin could significantly prevent the evolution to serious stages since the EG did not present any patient with referral to critical hospitalization. Clinical Trials registry number is NCT04784481 FundingMinistry of Public Health. Tucuman, Argentina. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSCurrently there are no specific therapies approved for COVID-19 treatment by the FDA, that is why different repositionable drugs are being studied in clinical trials and compassionate use protocols based on in vitro activity. ivermectin is a broad spectrum antiparasitic agent that has been shown to have antiviral activity against a wide range of viruses. A study by Caly et al. (2020) suggested thatnuclear transport inhibitory activity of ivermectin may be effective against SARS-CoV-2. Since the publication of that work, numerous clinical trials were started to study ivermectin potential for COVID-19 treatment. At the end of March 2021, there were about 60 studies registered in https://www.clinicaltrials.gov, and 43 studies listened https://www.who.int/clinical-trials-registry-platform about the safety and effectiveness of ivermectin in COVID-19 patients, for treatment and prophylaxis. Most of these studies are from developing countries, which shows the need of emerging economies to find alternative therapies to contain the spread of the disease and the collapse of health systems. Added value of this studyWe found that an early intervention with ivermectin has impacted on the score of symptoms related to COVID-19 in ambulatory patients, between the 5th and 9th day. The patients who received the treatment changed from score 2 to score 1 in the WHO ordinal scale. In any case, patients evolved to higher scores. Also the treatment increased the probability to obtain medical release, even in the presence of comorbidities. Implications of all available evidenceAccording to the COVID-19 Treatment Guidelines by the NIH, most trials have several limitations. It needs results from adequately powered and well-designed clinical trials to provide evidence-based guidance on the role of ivermectin in the treatment of COVID-19. However, our study shows overlaps in benefits with other authors, and taking together, these results are encouraging for further study about repurposing ivermectin for the treatment of COVID-19.
