Non-effectiveness of Ivermectin on Inpatients and Outpatients With COVID-19; Results of Two Randomized, Double-Blinded, Placebo-Controlled Clinical Trials

Abstract

BackgroundIvermectin which was widely considered as a potential treatment for COVID-19, showed uncertain clinical benefit in many clinical trials. Performing large-scale clinical trials to evaluate the effectiveness of this drug in the midst of the pandemic, while difficult, has been urgently needed.MethodsWe performed two large multicenter randomized, double-blind, placebo-controlled clinical trials evaluating the effectiveness of ivermectin in treating inpatients and outpatients with COVID-19 infection. The intervention group received ivermectin, 0.4mg/kg of body weight per day for 3 days. In the control group, placebo tablets were used for 3 days.ResultsData for 609 inpatients and 549 outpatients were analyzed. In hospitalized patients, complete recovery was significantly higher in the ivermectin group (37%) compared to placebo group (28%; RR, 1.32 [95% CI, 1.04–1.66]; p-value = 0.02). On the other hand, the length of hospital stay was significantly longer in the ivermectin group with a mean of 7.98 ± 4.4 days compared to the placebo receiving group with a mean of 7.16 ± 3.2 days (RR, 0.80 [95% CI, 0.15–1.45]; p-value = 0.02). In outpatients, the mean duration of fever was significantly shorter (2.02 ± 0.11 days) in the ivermectin group versus (2.41 ± 0.13 days) placebo group with p value = 0.020. On the day seventh of treatment, fever (p-value = 0.040), cough (p-value = 0.019), and weakness (p-value = 0.002) were significantly higher in the placebo group compared to the ivermectin group. Among all outpatients, 7% in ivermectin group and 5% in placebo group needed to be hospitalized (RR, 1.36 [95% CI, 0.65–2.84]; p-value = 0.41). Also, the result of RT-PCR on day five after treatment was negative for 26% of patients in the ivermectin group versus 32% in the placebo group (RR, 0.81 [95% CI, 0.60–1.09]; p-value = 0.16).ConclusionOur data showed, ivermectin, compared with placebo, did not have a significant potential effect on clinical improvement, reduced admission in ICU, need for invasive ventilation, and death in hospitalized patients; likewise, no evidence was found to support the prescription of ivermectin on recovery, reduced hospitalization and increased negative RT-PCR assay for SARS-CoV-2 5 days after treatment in outpatients. Our findings do not support the use of ivermectin to treat mild to severe forms of COVID-19.Clinical Trial Registrationwww.irct.ir IRCT20111224008507N5 and IRCT20111224008507N4.

Outpatient regimens to reduce COVID-19 hospitalisations: a systematic review and meta-analysis of randomized controlled trials

“…Additionally, 15 repurposed drugs tested in 23 outpatient RCTs were included in our analysis for context: metformin 13 , fluvoxamine 13, 34, 35 , ivermectin 13, 36, 37, 38 , hydroxychloroquine 33, 39, 40, 41, 42 , nitazoxanide 43 , colchicine 44 , niclosamide 45 , four antithrombotics-aspirin, apixaban 46 , sulodexide 47 , enoxaparin 48, 49 , inhaled ciclesonide 50 , the herbal mixture Saliravira 51 , azithromycin 52, 53 , and resveratrol 54 .…”

Ivermectin Affects Neutrophil-Induced Inflammation through Inhibition of Hydroxylysine but Stimulation of Cathepsin G and Phenylalanine Secretion

“…Recent studies have also revealed the antiviral activity of ivermectin associated with the ability to inhibit flavivirus replication by targeting the NS3 helicase [ 61 ], block the importin alpha/beta-mediated nuclear transport of viral proteins, capable of inhibiting the replication of HIV-1 and dengue virus [ 62 ], and inhibit SARS-CoV-2 replication in vitro [ 63 ]. Currently, the possibility of using ivermectin for the prevention and treatment of inflammatory processes induced by viral diseases [ 8 , 9 , 10 , 11 , 12 , 13 ], as well as for the treatment of cancer patients [ 14 ], is being studied. We assumed that the therapeutic effect of ivermectin is associated not only with antiviral activity, but also with its effect on human innate immunity, namely, with its effect on neutrophil function.…”

“…Some case series analysis demonstrates the ability of ivermectin to alleviate disease-associated severity and recovery rate [ 10 , 11 ]. Another analysis failed to demonstrate the efficacy of ivermectin in the treatment of COVID-19 [ 12 , 13 ]. The therapeutic effect of ivermectin is highly dependent on the phase of the disease in which the patient receives the drug [ 11 ].…”

Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: Multilayered cross-talks in the setting of coinfections and comorbidities

“…These hypotheses need to be tested and verified using animal models [ 236 ]. It should be noted that ivermectin was studied as an antiviral in multiple clinical trials of SARS-CoV-2-infected patients [ 237 – 239 ] and was uniformly found to not change acute outcomes such as progression to more severe disease. It is unlikely that many of the patients in these series were concurrently parasite infected as this was not a selection criterion (or prevalence assessed), so the effect of antihelminthics on Th1 versus Th2 bias in virus and parasite coinfected individuals has not yet been tested.…”