Cluster Randomised Trials - Ivermectin Repurposing For COVID-19 Treatment Of Outpatients With Mild Disease In Primary Health Care Centers
Abstract
Background The emergency of COVID-19, along with the current difficulties in responding to the high demand for vaccines, requests to the scientific community to find alternative treatments based on reuse of drugs as a strategy to prevent the progression of the disease in patients infected with SARS COV 2. This study aims to evaluate the use of ivermectin in mild-stage patients to increase outpatient discharge and prevent the progression to moderate or severe stages of the disease.
Methods Cluster Randomised Trials in outpatients care, n = 254. The subjects were divided into experimental (EG: n = 110) and control groups (CG: n = 144). The EG received ivermectin orally 4 tablets 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 using proportion, bivariate and logistic regression. P-value was considered significant at the p < 0·05 threshold. This study was registered at ClinicalTrials.gov Identifier NCT04784481.
Findings Both groups were similar in age, sex, and comorbidities (EG: median age = 40·0, range: 18·0–75·0, 42·11% Female; CG: median age = 36, range: 18·0–71·0, 57·89% Female). A significant reduction in the percentage of participants with symptoms (PPS) was observed in the EG and CG when the clinical evaluation of symptoms was performed from 5th to 9th (p = 0·0005). When the clinical evaluation was performed from 10th to 14th day there was no significant difference. A higher proportion of outpatient discharge was observed in EG (98·2%) vs. CG (86·1%) (p-Value = 0·0007). EG showed 8 times more chance of receiving discharge than CG (8·71 CI = [1·99, 38·12]; p = 0·004). The treatment effect with ivermectin to obtain discharge from outpatient care was analyzed by the logistic regression. Then, the chance to obtain outpatient discharge was independent of variables sex, age, and comorbidities.
Interpretation Treatment with ivermectin in outpatients care with mild disease of COVID-19 managed to slightly reduce PPS. Also, this treatment improved the clinical state to obtain outpatient discharge, 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.
This study was designed to evaluate the potential of ivermectin as a repositionable drug, for the treatment of mild cases of COVID-19. Ivermectin has shown an effect on clinical manifestations of COVID-19, including a decrease in the percentage of symptoms reported in the medical examination and an increase in the chance for medical release in EG.
Currently, many studies about ivermectin and its potential against SARS-CoV-2 are complete or in development. A pilot study that evaluates the effect of early treatment with ivermectin for COVID-19, sheds some light on the potential of ivermectin in a tendency to lower viral loads and lower IgG titers(23). Other work, either from Argentina shows a faster viral clearance in treated participants(13). Chaccour et al. reported that patients treated with ivermectin experienced a significant diminution of 50% anosmia/ hyposmia than those in the placebo group (76 vs. 158 patient-days of anosmia/hyposmia)(23). The ivermectin group also reported 30% fewer coughs (68 vs. 97 patient-days of cough). However, in this study, there were no major differences between ivermectin and placebo in the reported patient days of fever, general malaise, headache, or nasal congestion(23).
In line with these results, in our study, outpatients report a significant drop in the percentage of upper airway symptoms in COVID-19 (taste and/or smell disturbance, odynophagia, cough), see Table 2. Concomitantly, the results reported here show that the use of ivermectin produces a decrease in the number of symptoms reported by patients, such as fever and diarrhea, but above all, a significant decrease in taste and smell loss, which is related to the effects of viral load on upper air vials in patients with mild COVID-19. No patient from either group progressed to severe disease.
Recently, Lopez Medina et al. published a study of ivermectin concerning the time resolution of symptoms in mild patients(24). Although they do not recommend the use of ivermectin as a treatment for COVID-19, there are some similarities (and differences) with the results of the present study. We agree that there are no significant differences between both groups at 14 days (see Fig. 2), but our main finding shows that the effect of treatment is observed between 5 and 8 days after the patient starts treatment. This difference may be due to the administration of the dose, which in our case is weekly and not daily. The clinical follow-up of the patients was carried out in person in the Primary Health Centers, which is more accurate concerning symptom recording.
There are results that provide evidence of the potential benefit of early intervention with ivermectin for the treatment of patients diagnosed with mild stages of COVID-19, as Elgazzar et al. trial(14). Many studies present the potential of ivermectin for a viral load reduction, as has been suggested by Caly et al. in vitro. This could have the potential effect on disease progression and spread. (13, 14, 23, 25)
Conclusion
Treatment with ivermectin in a population of outpatients with COVID-19 mild disease managed to significantly reduce the number of symptoms when clinical evaluation was performed from 5th to 9th. Subsequent clinical evaluation from day 10th to 14th did not show significant differences. Participants received ivermectin had a greater chance of medical release vs. CG (p = 0.0007). This proposed treatment brings additional benefits in relation to the improvement in the patient's clinical condition, without this having an impact on adherence.
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