Randomized controlled clinical trial on using oral ivermectin in COVID-19 prophylaxis supplying the drug to close contacts of confirmed cases.

SAINT is a double-blind, randomized controlled trial with two parallel groups that evaluates the efficacy of ivermectin in reducing nasal viral carriage at seven days after treatment in SARS-CoV-2 infected patients who are at low risk of progression to severe disease. The trial is currently planned at a single center in Navarra.

Coronavirus disease 2019 was first discovered in December 2019 and subsequently became a global pandemic with serious political, economic, and social implications worldwide. We urgently need to find drugs that can be effective against COVID-19. Among the many observational studies, ivermectin has attracted the attention of many countries. Ivermectin is a broad-spectrum antiparasitic drug that also has some antiviral effects. We reviewed studies related to ivermectin for the treatment of COVID-19 over the last 2 years (2019.12-2022.03) via search engines such as PubMed, Web of Science, and EBSCOhost. Seven studies showed a lower mortality rate in the ivermectin group than in the control group, six studies found that the ivermectin group had a significantly fewer length of hospitalization than the control group, and eight studies showed better negative RT-PCR responses in the IVM group than in the control group. Our systematic review indicated that ivermectin may be effective for mildly to moderately ill patients. There is no clear evidence or guidelines to recommend ivermectin as a therapeutic agent for COVID-19, so physicians should use it with caution in the absence of better alternatives in the clinical setting, and self-medication is not recommended for patients.

BACKGROUND:

Ivermectin, an antiparasitic agent, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in early stages of infection. Currently, evidence on ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting.

OBJECTIVES:

To assess the efficacy and safety of ivermectin plus standard of care compared to standard of care plus/minus placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis).

SEARCH METHODS:

We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), WHO COVID-19 Global literature on coronavirus disease, and HTA database weekly to identify completed and ongoing trials without language restrictions to 16 December 2021. Additionally, we included trials with > 1000 participants up to April 2022.

SELECTION CRITERIA:

We included randomized controlled trials (RCTs) comparing ivermectin to standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity or treatment setting, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms.  For this review update, we reappraised eligible trials for research integrity: only RCTs prospectively registered in a trial registry according to WHO guidelines for clinical trial registration were eligible for inclusion.

DATA COLLECTION AND ANALYSIS:

We assessed RCTs for bias, using the Cochrane RoB 2 tool. We used GRADE to rate the certainty of evidence for outcomes in the following settings and populations: 1) to treat inpatients with moderate-to-severe COVID-19, 2) to treat outpatients with mild COVID-19 (outcomes: mortality, clinical worsening or improvement, (serious) adverse events, quality of life, and viral clearance), and 3) to prevent SARS-CoV-2 infection (outcomes: SARS-CoV-2 infection, development of COVID-19 symptoms, admission to hospital, mortality, adverse events and quality of life).

MAIN RESULTS:

We excluded seven of the 14 trials included in the previous review version; six were not prospectively registered and one was non-randomized. This updated review includes 11 trials with 3409 participants investigating ivermectin plus standard of care compared to standard of care plus/minus placebo. No trial investigated ivermectin for prevention of infection or compared ivermectin to an intervention with proven efficacy. Five trials treated participants with moderate COVID-19 (inpatient settings); six treated mild COVID-19 (outpatient settings). Eight trials were double-blind and placebo-controlled, and three were open-label. We assessed around 50% of the trial results as low risk of bias. We identified 31 ongoing trials. In addition, there are 28 potentially eligible trials without publication of results, or with disparities in the reporting of the methods and results, held in 'awaiting classification' until the trial authors clarify questions upon request. Ivermectin for treating COVID-19 in inpatient settings with moderate-to-severe disease We are uncertain whether ivermectin plus standard of care compared to standard of care plus/minus placebo reduces or increases all-cause mortality at 28 days (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 3 trials, 230 participants; very low-certainty evidence); or clinical worsening, assessed by participants with new need for invasive mechanical ventilation or death at day 28 (RR 0.82, 95% CI 0.33 to 2.04; 2 trials, 118 participants; very low-certainty evidence); or serious adverse events during the trial period (RR 1.55, 95% CI 0.07 to 35.89; 2 trials, 197 participants; very low-certainty evidence). Ivermectin plus standard of care compared to standard of care plus placebo may have little or no effect on clinical improvement, assessed by the number of participants discharged alive at day 28 (RR 1.03, 95% CI 0.78 to 1.35; 1 trial, 73 participants; low-certainty evidence); on any adverse events during the trial period (RR 1.04, 95% CI 0.61 to 1.79; 3 trials, 228 participants; low-certainty evidence); and on viral clearance at 7 days (RR 1.12, 95% CI 0.80 to 1.58; 3 trials, 231 participants; low-certainty evidence). No trial investigated quality of life at any time point. Ivermectin for treating COVID-19 in outpatient settings with asymptomatic or mild disease Ivermectin plus standard of care compared to standard of care plus/minus placebo probably has little or no effect on all-cause mortality at day 28 (RR 0.77, 95% CI 0.47 to 1.25; 6 trials, 2860 participants; moderate-certainty evidence) and little or no effect on quality of life, measured with the PROMIS Global-10 scale (physical component mean difference (MD) 0.00, 95% CI -0.98 to 0.98; and mental component MD 0.00, 95% CI -1.08 to 1.08; 1358 participants; high-certainty evidence). Ivermectin may have little or no effect on clinical worsening, assessed by admission to hospital or death within 28 days (RR 1.09, 95% CI 0.20 to 6.02; 2 trials, 590 participants; low-certainty evidence); on clinical improvement, assessed by the number of participants with all initial symptoms resolved up to 14 days (RR 0.90, 95% CI 0.60 to 1.36; 2 trials, 478 participants; low-certainty evidence); on serious adverse events (RR 2.27, 95% CI 0.62 to 8.31; 5 trials, 1502 participants; low-certainty evidence); on any adverse events during the trial period (RR 1.24, 95% CI 0.87 to 1.76; 5 trials, 1502 participants; low-certainty evidence); and on viral clearance at day 7 compared to placebo (RR 1.01, 95% CI 0.69 to 1.48; 2 trials, 331 participants; low-certainty evidence). None of the trials reporting duration of symptoms were eligible for meta-analysis.

AUTHORS' CONCLUSIONS:

For outpatients, there is currently low- to high-certainty evidence that ivermectin has no beneficial effect for people with COVID-19. Based on the very low-certainty evidence for inpatients, we are still uncertain whether ivermectin prevents death or clinical worsening or increases serious adverse events, while there is low-certainty evidence that it has no beneficial effect regarding clinical improvement, viral clearance and adverse events. No evidence is available on ivermectin to prevent SARS-CoV-2 infection. In this update, certainty of evidence increased through higher quality trials including more participants. According to this review's living approach, we will continually update our search.

BACKGROUND:

The aim of the present theoretical essay is to evaluate evidence published on the characteristics of the transcription of SARS-CoV-2 and explain the mechanism of action of ivermectin that may justify its therapeutic use in clinical practice for the treatment of COVID-19.

METHODS:

Laboratory studies, narratives, editorials and expert opinions on the subject were identified through a systematic search of the literature in the Medline/PubMed, Cochrane Library, Web of Science and Embase databases. Two blinded, independent reviewers selected studies published up to May 17, 2020 based on the eligibility criteria.

RESULTS:

The search of the databases led to the retrieval of 25 articles. After the different phases of the selection process, eight articles were included in the present review for the extraction of relevant data. The results suggest that ivermectin inhibits the viral replication of SARS-CoV-2 through the action of the hypoxia-inducible factor (HIF-1α) and consequent destabilization of importin α/β1 proteins.

CONCLUSIONS:

Ivermectin inhibits the viral replication of SARS-CoV-2. Laboratory and clinical studies are needed to provide more evidence in terms of the best posology and possible associations with other drugs for combatting COVID-19.

ABSTRACT OBJECTIVE:

To evaluate the efficacy and safety of ivermectin in the prevention and treatment of COVID-19.

METHODS:

This is a systematic review of randomized clinical trials. We searched the electronic databases PubMed (1966-2021), EMBASE (1974-2021) and Clinical Trials (2021) and two evidence megabusers: Turning Research Into Practice (TRIP) database (2021) and Epstemonikos (2021). There was no geographic or language restriction, using DeCS descriptors and terms (Health Sciences Descriptors). The synthesis method involved the combination of similar studies in a narrative review.

RESULTS:

463 citations were identified, and 2 studies were included, following the inclusion and exclusion criteria. Both studies showed very low quality and reduced sampling.

CONCLUSION:

The studies completed and published to date do not support the use of ivermectin in the prevention or treatment of COVID-19. It is suggested to carry out new quality clinical trials to elucidate the issue.

DESCRIPTORS:

 Coronavirus infections, Pneumonia, Ivermectin, COVID-19, Systematic review.

RESUMO OBJETIVO:

 Avaliar a eficacia e seguranca da ivermectina na prevencao e tratamento da COVID-19.

METODO:

Trata-se de revisao sistematica de ensaios clinicos randomizados. Procedeu-se a busca nas bases eletronicas de dados PubMed (1966-2021), EMBASE (1974-2021) e Clinical Trials (2021) e em dois megabuscadores de evidencias: Turning Research Into Practice (TRIP) database (2021) e Epstemonikos (2021). Nao houve restricao geografica e de idioma, sendo utilizados descritores e termos do DeCS (Descritores em Ciencias da Saude). O metodo de sintese envolveu a combinacao de estudos semelhantes em uma revisao narrativa.

RESULTADOS:

Foram identificadas 463 citacoes e 2 estudos foram incluidos, seguindo os criterios de inclusao e exclusao. Ambos os estudos apresentaram muito baixa qualidade e reduzida amostragem.

CONCLUSAO:

Os estudos concluidos e publicados ate o momento nao suportam o uso da ivermectina na prevencao ou tratamento COVID-19. Sugere-se a realizacao de novos ensaios clinicos de qualidade para elucidacao da questao.

DESCRITORES:

Infeccoes por coronavirus, Pneumonia, Ivermectina, COVID-19, Revisao sistematica.

This article has no abstract

Context: COVID-19 is a viral disease that has recently emerged and is associated with severe respiratory distress syndrome (SARS). Its potential for severity and impact on the health of the population and the global economy is a prime object in the search for effective therapy and ivermectin has been recommended for prevention and treatment. Objective: To evaluate the evidence in the literature regarding the use of ivermectin for the prevention and treatment of cases of COVID-19. Study design: This is a synopsis of evidence. Methods: We searched the electronic databases PubMed (1966-2021), EMBASE (1974-2021) and Clinical Trials (2021) and two evidence megabusers: Turning Research Into Practice (TRIP) database (2021) and Epstemonikos (2021). There was no geographic or language restriction, using DeCS descriptors and terms (Health Sciences Descriptors). The synthesis method involved the combination of similar studies in a narrative review. Results: 527 citations were identified and 5 studies were included. There are few completed clinical trials, all of which have a small sample size. Discussion: Most of the studies available in the literature are based on in vitro therapeutic responses and the recommendation for use in humans has been based on the findings of these studies. The question cannot be answered with current studies, and quality clinical trials are recommended. Conclusions: There is currently no support in the literature for the use of ivermectin in the prevention or treatment of COVID-19.

A group of senior doctors with vast clinical experience met on 19th July'20 under the aegis of Academy of Advanced Medical Education. The panel looked at Ivermectin, one of the old molecule and evaluated it's use in COVID 19 (Novel Coronavirus Disease 2019) management. After critical panel discussion, all the attending doctors came to a conclusion that Ivermectin can be a potential molecule for prophylaxis and treatment of people infected with Coronavirus, owing to its anti-viral properties coupled with effective cost, availability and good tolerability and safety.

Ivermectin (IVM), an approved anthelminthic drug, has been reported to have antiviral, antibacterial, and anticancer activities. Antiviral activity is due to the inhibition of nuclear cargo importin (IMP) protein. The anti-SARS CoV-2 activity through in vitro study was first reported by an Australian team. Later, many studies were conducted, and most of the study results were available as non-peer reviewed preprints. In this narrative review, literature on the clinical studies conducted with ivermectin from published articles, preprints, and unpublished evidence are collected till 13th June 2021 and they are discussed based on the severity of COVID-19 disease. Out of the 23 peer-reviewed published articles, 13 studies were randomized controlled trials and the remaining were either prospective interventional, prospective observational, retrospective cohort, cross-sectional, or case series type of studies; additionally, there were 10 randomized controlled trials available as preprints. In most of the studies, ivermectin was used in combination with doxycycline, azithromycin or other drugs. Some of the studies suggested either higher dose and/ or increased duration of ivermectin use to achieve favorable effects. In this review, articles on the prophylactic role of ivermectin in COVID-19 are also discussed - wherein the results are more promising. Despite accumulating evidence suggest the possible use of ivermectin, the final call to incorporate ivermectin in the management of COVID-19 is still inconclusive.