Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities

The I-TECH Randomized Clinical Trial February 18, 2022

Authors:

Steven Chee Loon Lim, MRCP1Chee Peng Hor, MSc2,3Kim Heng Tay, MRCP4et alAnilawati Mat Jelani, MMed5Wen Hao Tan, MMed6Hong Bee Ker, MRCP1Ting Soo Chow, MRCP7Masliza Zaid, MMed8Wee Kooi Cheah, MRCP6Han Hua Lim, MRCP9Khairil Erwan Khalid, MRCP10Joo Thye Cheng, MRCP2Hazfadzila Mohd Unit, MRCP11Noralfazita  An, MMed12Azraai Bahari Nasruddin, MRCP13Lee Lee Low, MRCP14Song Weng Ryan Khoo, MRCP15Jia Hui Loh, MRCP16Nor Zaila Zaidan, MMed17Suhaila Ab Wahab, MMed18Li Herng Song, MD19Hui Moon Koh, MClinPharm20Teck Long King, BPharm21Nai Ming Lai, MRCPCH22Suresh Kumar Chidambaram, MRCP4Kalaiarasu M. Peariasamy, MSc23

for the I-TECH Study Group Article Information

Abstract

Importance  Ivermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19. Evidence-based data to recommend either for or against the use of ivermectin are needed.

Objective  To determine the efficacy of ivermectin in preventing progression to severe disease among high-risk patients with COVID-19.

Design, Setting, and Participants  The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was an open-label randomized clinical trial conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. Within the first week of patients’ symptom onset, the study enrolled patients 50 years and older with laboratory-confirmed COVID-19, comorbidities, and mild to moderate disease.

Interventions  Patients were randomized in a 1:1 ratio to receive either oral ivermectin, 0.4 mg/kg body weight daily for 5 days, plus standard of care (n = 241) or standard of care alone (n = 249). The standard of care consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging.

Main Outcomes and Measures  The primary outcome was the proportion of patients who progressed to severe disease, defined as the hypoxic stage requiring supplemental oxygen to maintain pulse oximetry oxygen saturation of 95% or higher. Secondary outcomes of the trial included the rates of mechanical ventilation, intensive care unit admission, 28-day in-hospital mortality, and adverse events.

Results  Among 490 patients included in the primary analysis (mean [SD] age, 62.5 [8.7] years; 267 women [54.5%]), 52 of 241 patients (21.6%) in the ivermectin group and 43 of 249 patients (17.3%) in the control group progressed to severe disease (relative risk [RR], 1.25; 95% CI, 0.87-1.80; P = .25). For all prespecified secondary outcomes, there were no significant differences between groups. Mechanical ventilation occurred in 4 (1.7%) vs 10 (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P = .17), intensive care unit admission in 6 (2.4%) vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P = .79), and 28-day in-hospital death in 3 (1.2%) vs 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09). The most common adverse event reported was diarrhea (14 [5.8%] in the ivermectin group and 4 [1.6%] in the control group).

Conclusions and Relevance  In this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study findings do not support the use of ivermectin for patients with COVID-19.

Trial Registration  ClinicalTrials.gov Identifier: NCT04920942Introduction

Despite the success of COVID-19 vaccines and the implementation of nonpharmaceutical public health measures, there is an enormous global need for effective therapeutics for SARS-CoV-2 infection. At present, repurposed anti-inflammatory drugs (dexamethasone, tocilizumab, and sarilumab),13 monoclonal antibodies,46 and antivirals (remdesivir, molnupiravir, and nirmatrelvir/ritonavir)79 have demonstrated treatment benefits at different stages of COVID-19.10

In Malaysia, about 95% of patients with COVID-19 present early with mild disease, and less than 5% progress to a hypoxic state requiring oxygen supplementation. Notably, patients 50 years and older with comorbidities are at high risk for severe disease.11 Potentially, an antiviral therapy administered during the early viral replication phase could avert the deterioration. Although molnupiravir and nirmatrelvir/ritonavir have shown efficacy in the early treatment of COVID-19,8,9 they can be too expensive for widespread use in resource-limited settings.

Ivermectin, an inexpensive, easy-to-administer, and widely available antiparasitic drug, has been used as an oral therapy for COVID-19. An in vitro study demonstrated inhibitory effects of ivermectin against SARS-CoV-2.12 Although some early clinical studies suggested the potential efficacy of ivermectin in the treatment and prevention of COVID-19,13,14 these studies had methodologic weaknesses.15

In 2021, 2 randomized clinical trials from Colombia16 and Argentina17 found no significant effect of ivermectin on symptom resolution and hospitalization rates for patients with COVID-19. A Cochrane meta-analysis18 also found insufficient evidence to support the use of ivermectin for the treatment or prevention of COVID-19.

These findings notwithstanding, ivermectin is widely prescribed for COVID-19, contrary to the World Health Organization (WHO) recommendation to restrict use of the drug to clinical trials.19 In the present randomized clinical trial, we studied the efficacy of ivermectin for preventing progression to severe disease among high-risk patients with COVID-19 in Malaysia.MethodsTrial Design and Patients

The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was a multicenter, open-label, randomized clinical trial conducted at 20 government hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. The study was approved by the local Medical Research and Ethics Committee (NMRR-21-155-58433) and registered in ClinicalTrials.gov (NCT04920942). This trial was conducted in accordance with the Declaration of Helsinki and the Malaysian Good Clinical Practice Guideline. All participants provided written informed consent. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.

In Malaysia, mandatory notification to public health authorities applies to all COVID-19 cases. Patients with mild to moderate disease at risk of disease progression are referred for hospitalization or admitted to a COVID-19 quarantine center to allow close monitoring for 10 or more days from symptom onset and timely intervention in the event of deterioration.

The study enrolled patients with reverse transcriptase–polymerase chain reaction (RT-PCR) test–confirmed or antigen test–confirmed COVID-19 who were 50 years or older with at least 1 comorbidity and presented with mild to moderate illness (Malaysian COVID-19 clinical severity stage 2 or 3; WHO clinical progression scale 2-4)20,21 within 7 days from symptom onset. Patients were excluded if they were asymptomatic, required supplemental oxygen, or had pulse oximetry oxygen saturation (Spo2) level less than 95% at rest. Other exclusion criteria were severe hepatic impairment (alanine transaminase level >10 times of upper normal limit), acute medical or surgical emergency, concomitant viral infection, pregnancy or breastfeeding, warfarin therapy, and history of taking ivermectin or any antiviral drugs with reported activity against COVID-19 (favipiravir, hydroxychloroquine, lopinavir, and remdesivir) within 7 days before enrollment. Eligibility criteria are detailed in the study protocol (Supplement 1). Study investigators collected information on ethnicity based on the patient’s Malaysian identification card or passport (for non-Malaysian citizens).

All patients with COVID-19 were managed in accordance with the national COVID-19 Management Guidelines,20 developed by a local expert panel based on consensus, WHO recommendations, and the US National Institutes of Health guidelines. High-risk patients were defined as those aged 50 years or older with comorbidity. Patients were staged according to clinical severity at presentation and disease progression: stage 1, asymptomatic; stage 2, symptomatic without evidence of pneumonia; stage 3, evidence of pneumonia without hypoxia; stage 4, pneumonia with hypoxia requiring oxygen supplementation; and stage 5, critically ill with multiorgan involvement. Stages 2 and 3 were classified as mild and moderate diseases (WHO scale 2-4), while stages 4 and 5 were referred to as severe diseases (WHO scale 5-9). The standard of care for patients with mild to moderate disease consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging.Randomization and Data Collection

All study data were recorded in case report form and transcribed into the REDCap (Research Electronic Data Capture) platform.22,23 Patients were randomized in a 1:1 ratio to either the intervention group receiving oral ivermectin (0.4 mg/kg body weight daily for 5 days) plus standard of care or the control group receiving the standard of care alone (Figure). The randomization was based on an investigator-blinded randomization list uploaded to REDCap, which allocated the patients via a central, computer-generated randomization scheme across all study sites during enrollment. The randomization list was generated independently using random permuted block sizes 2 to 6. The randomization was not stratified by site.Intervention

The ivermectin dosage for each patient in the intervention arm was calculated to the nearest 6-mg or 12-mg whole tablets (dosing table in the study protocol, Supplement 1). The first dose of ivermectin was administered after randomization on day 1 of enrollment, followed by 4 doses on days 2 through 5. Patients were encouraged to take ivermectin with food or after meals to improve drug absorption. Storage, dispensary, and administration of ivermectin were handled by trained study investigators, pharmacists, and nurses.Outcome Measures

The primary outcome was the proportion of patients who progressed to severe COVID-19, defined as the hypoxic stage requiring supplemental oxygen to maintain Spo2 95% or greater (Malaysian COVID-19 clinical severity stages 4 or 5; WHO clinical progression scale 5-9). The Spo2 was measured using a calibrated pulse oximeter per the clinical monitoring protocol.

Secondary outcomes were time of progression to severe disease, 28-day in-hospital all-cause mortality, mechanical ventilation rate, intensive care unit admission, and length of hospital stay after enrollment. Patients were also assessed on day 5 of enrollment for symptom resolution, changes in laboratory test results, and chest radiography findings. Adverse events (AEs) and serious AEs (SAEs) were evaluated and graded according to Common Terminology Criteria for Adverse Events, version 5.0.24 All outcomes were captured from randomization until discharge from study sites or day 28 of enrollment, whichever was earlier.Subgroup Analyses

Subgroup analyses were predetermined according to COVID-19 vaccination status, age, clinical staging, duration of illness at enrollment, and common comorbidities.Procedures

Patients’ clinical history, anthropometric measurements, blood samples for complete blood cell count, kidney and liver profiles, C-reactive protein levels, and chest radiography were obtained at baseline. Blood sampling and chest radiography were repeated on day 5 of enrollment. Study investigators followed up patients for all outcome assessments and AEs. All study-related AEs were reviewed by an independent Data and Safety Monitoring Board.Sample Size Calculation

The sample size was calculated based on a superiority trial design and primary outcome measure. The expected rate of primary outcome was 17.5% in the control group, according to previous local data of high-risk patients who presented with mild to moderate disease.11 A 50% reduction of primary outcome, or a 9% rate difference between intervention and control groups, was considered clinically important. This trial required 462 patients to be adequately powered. This sample size provided a level of significance at 5% with 80% power for 2-sided tests. Considering potential dropouts, a total of 500 patients (250 patients for each group) were recruited.Statistical Analyses

Primary analyses were performed based on the modified intention-to-treat principle, whereby randomized patients in the intervention group who received at least 1 ivermectin dose and all patients in the control group would be followed and evaluated for efficacy and safety. In addition, sensitivity analyses were performed on all eligible randomized patients, including those in the intervention group who did not receive ivermectin (intention-to-treat population).

Descriptive data were expressed as means and SDs unless otherwise stated. Categorical data were analyzed using the Fisher exact test. Continuous variables were tested using the t-test or Mann-Whitney U test. The primary and categorical secondary outcome measures were estimated using relative risk (RR). The absolute difference of means of time of progression to severe disease and lengths of hospitalization between the study groups were determined with a 95% CI. Mixed analysis of variance was used to determine whether the changes of laboratory investigations were the result of interactions between the study groups (between-patients factor) and times (within-patient factor), and P < .05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 22.0 (IBM Corp).

Interim analyses were conducted on the first 150 and 300 patients, with outcome data retrieved on July 13 and August 30, 2021, respectively. The overall level of significance was maintained at P < .05, calculated according to the O’Brien-Fleming stopping boundaries. Early stopping would be considered if P < .003 for efficacy data. The results were presented to the Data and Safety Monitoring Board, which recommended continuing the study given no signal for early termination.Results

Between May 31 and October 9, 2021, 500 patients were enrolled and randomized. The last patient completed follow-up on October 25, 2021. Four patients were excluded after randomization. One patient in the control arm was diagnosed with dengue coinfection; in the intervention arm, 2 failed to meet inclusion criteria owing to symptom duration greater than 7 days and negative COVID-19 RT-PCR test result, while 1 had acute coronary syndrome before ivermectin initiation. In addition, 6 patients in the intervention arm withdrew consent before taking a dose of ivermectin. The modified intention-to-treat population for the primary analysis included 490 patients (98% of those enrolled), with 241 in the intervention group and 249 in the control group (Figure). Drug compliance analysis showed that 232 patients (96.3%) in the intervention group completed 5 doses of ivermectin.

Baseline demographics and characteristics of patients were well balanced between groups (Table 1). The mean (SD) age was 62.5 (8.7) years, with 267 women (54.5%); 254 patients (51.8%) were fully vaccinated with 2 doses of COVID-19 vaccines. All major ethnic groups in Malaysia were well represented in the study population. The majority had hypertension (369 [75.3%]), followed by diabetes mellitus (262 [53.5%]), dyslipidemia (184 [37.6%]), and obesity (117 [23.9%]).

The mean (SD) duration of symptoms at enrollment was 5.1 (1.3) days. The most common symptoms were cough (378 [77.1%]), fever (237 [48.4%]), and runny nose (149 [30.4%]). Approximately two-thirds of patients had moderate disease. The average baseline neutrophil-lymphocyte ratio and serum C-reactive protein level were similar between groups. There were no significant differences in the concomitant medications prescribed for both groups. In sensitivity analyses, baseline characteristics were similar in the intention-to-treat population (eTable 1 in Supplement 2).Primary Outcome

Among the 490 patients, 95 (19.4%) progressed to severe disease during the study period; 52 of 241 (21.6%) received ivermectin plus standard of care, and 43 of 249 (17.3%) received standard of care alone (RR, 1.25; 95% CI, 0.87-1.80; P = .25) (Table 2). Similar results were observed in the intention-to-treat population in the sensitivity analyses (eTable 2 in Supplement 2).Secondary Outcomes

There were no significant differences between ivermectin and control groups for all the prespecified secondary outcomes (Table 2). Among patients who progressed to severe disease, the time from study enrollment to the onset of deterioration was similar across ivermectin and control groups (mean [SD], 3.2 [2.4] days vs 2.9 [1.8] days; mean difference, 0.3; 95% CI, −0.6 to 1.2; P = .51). Mechanical ventilation occurred in 4 patients (1.7%) in the ivermectin group vs 10 (4.0%) in the control group (RR, 0.41; 95% CI, 0.13 to 1.30; P = .17) and intensive care unit admission in 6 (2.5%) vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27 to 2.20; P = .79). The 28-day in-hospital mortality rate was similar for the ivermectin and control groups (3 [1.2%] vs 10 [4.0%]; RR, 0.31; 95% CI, 0.09 to 1.11; P = .09), as was the length of hospital stay after enrollment (mean [SD], 7.7 [4.4] days vs 7.3 [4.3] days; mean difference, 0.4; 95% CI, −0.4 to 1.3; P = .38).

By day 5 of enrollment, the proportion of patients who achieved complete symptom resolution was comparable between both groups (RR, 0.97; 95% CI, 0.82-1.15; P = .72). Findings of chest radiography without pneumonic changes or with resolution by day 5 were also similar (RR, 1.03; 95% CI, 0.76-1.40; P = .92). No marked variation was noted in blood parameters (eTable 3 in Supplement 2). There was no significant difference in the incidence of disease complications and highest oxygen requirement (eTables 4 and 5 in Supplement 2).Subgroup Analyses

Subgroup analyses for patients with severe disease were unremarkable (Table 3). Among fully vaccinated patients, 22 (17.7%) in the ivermectin group and 12 (9.2%) in the control group developed severe disease (RR, 1.92; 95% CI, 0.99-3.71; P = .06). Post hoc analyses on clinical outcomes by vaccination status showed that fully vaccinated patients in the control group had a significantly lower rate of severe disease (P = .002; supporting data in eTable 6 in Supplement 2).Adverse Events

A total of 55 AEs occurred in 44 patients (9.0%) (Table 4). Among them, 33 were from the ivermectin group, with diarrhea being the most common AE (14 [5.8%]). Five events were classified as SAEs, with 4 in the ivermectin group (2 patients had myocardial infarction, 1 had severe anemia, and 1 developed hypovolemic shock secondary to severe diarrhea), and 1 in the control group had inferior epigastric arterial bleeding. Six patients discontinued ivermectin, and 3 withdrew from the study owing to AEs. The majority of AEs were grade 1 and resolved within the study period.

Among the 13 deaths, severe COVID-19 pneumonia was the principal direct cause (9 deaths [69.2%]). Four patients in the control group died from nosocomial sepsis. None of the deaths were attributed to ivermectin treatment.Discussion

In this randomized clinical trial of early ivermectin treatment for adults with mild to moderate COVID-19 and comorbidities, we found no evidence that ivermectin was efficacious in reducing the risk of severe disease. Our findings are consistent with the results of the IVERCOR-COVID19 trial,17 which found that ivermectin was ineffective in reducing the risk of hospitalization.

Prior randomized clinical trials of ivermectin treatment for patients with COVID-19 and with 400 or more patients enrolled focused on outpatients.16,17 In contrast, the patients in our trial were hospitalized, which permitted the observed administration of ivermectin with a high adherence rate. Furthermore, we used clearly defined criteria for ascertaining progression to severe disease.

Before the trial started, the case fatality rate in Malaysia from COVID-19 was about 1%,25 a rate too low for mortality to be the primary end point in our study. Even in a high-risk cohort, there were 13 deaths (2.7%). A recent meta-analysis of 8 randomized clinical trials of ivermectin to treat SARS-CoV-2 infection, involving 1848 patients with 71 deaths (3.8%), showed that treatment with the drug had no significant effect on survival.26

The pharmacokinetics of ivermectin for treating COVID-19 has been a contentious issue. The plasma inhibitory concentrations of ivermectin for SARS-CoV-2 are high; thus, establishing an effective ivermectin dose regimen without causing toxic effects in patients is difficult.27,28 The dose regimens that produced favorable results against COVID-19 ranged from a 0.2-mg/kg single dose to 0.6 mg/kg/d for 5 days2932; a concentration-dependent antiviral effect was demonstrated by Krolewiecki et al.29 Pharmacokinetic studies have suggested that a single dose of up to 120 mg of ivermectin can be safe and well tolerated.33 Considering the peak of SARS-CoV-2 viral load during the first week of illness and its prolongation in severe disease,34 our trial used an ivermectin dose of 0.4 mg/kg of body weight daily for 5 days. The notably higher incidence of AEs in the ivermectin group raises concerns about the use of this drug outside of trial settings and without medical supervision.Limitations

Our study has limitations. First, the open-label trial design might contribute to the underreporting of adverse events in the control group while overestimating the drug effects of ivermectin. Second, our study was not designed to assess the effects of ivermectin on mortality from COVID-19. Finally, the generalizability of our findings may be limited by the older study population, although younger and healthier individuals with low risk of severe disease are less likely to benefit from specific COVID-19 treatments.Conclusions

In this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study findings do not support the use of ivermectin for patients with COVID-19.

Accepted for Publication: January 22, 2022.

Published Online: February 18, 2022. doi:10.1001/jamainternmed.2022.0189

Corresponding Author: Steven Chee Loon Lim, MRCP, Department of Medicine, Raja Permaisuri Bainun Hospital, Jalan Raja Ashman Shah, 30450 Ipoh, Perak, Malaysia (stevenlimcl@gmail.com).

Author Contributions: Dr S. Lim and Mr King had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: S. Lim, Tan, Chow, Cheah, Cheng, An, Low, Song, Chidambaram, Peariasamy.

Acquisition, analysis, or interpretation of data: S. Lim, Hor, Tay, Mat Jelani, Tan, Ker, Zaid, Cheah, H. Lim, Khalid, Mohd Unit, An, Nasruddin, Khoo, Loh, Zaidan, Ab Wahab, Koh, King, Lai.

Drafting of the manuscript: S. Lim, Hor, Tay, Mat Jelani, Tan, Zaid, H. Lim, An, Low, Ab Wahab, King, Peariasamy.

Critical revision of the manuscript for important intellectual content: S. Lim, Hor, Tan, Ker, Chow, Cheah, Khalid, Cheng, Mohd Unit, An, Nasruddin, Khoo, Loh, Zaidan, Song, Koh, King, Lai, Chidambaram.

Statistical analysis: S. Lim, Hor, Tan, King, Lai.

Administrative, technical, or material support: S. Lim, Hor, Tay, Mat Jelani, Tan, Ker, Chow, Zaid, Cheah, H. Lim, Khalid, Low, Khoo, Loh, Zaidan, Ab Wahab, Song, Koh, Chidambaram.

Supervision: S. Lim, Tan, Ker, Chow, Zaid, Cheng, Khoo, Loh, Song, Peariasamy.

Conflict of Interest Disclosures: None reported.

The I-TECH Study Group: Members of the I-TECH Study Group are listed in Supplement 3.

Data Sharing Statement: See Supplement 4.

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29.Krolewiecki  A, Lifschitz  A, Moragas  M,  et al.  Antiviral effect of high-dose ivermectin in adults with COVID-19: a proof-of-concept randomized trial.   EClinicalMedicine. 2021;37:100959. doi:10.1016/j.eclinm.2021.100959PubMedGoogle Scholar

30.Ahmed  S, Karim  MM, Ross  AG,  et al.  A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness.   Int J Infect Dis. 2021;103:214-216. doi:10.1016/j.ijid.2020.11.191PubMedGoogle Scholar

31.Abu Taiub Mohammed Mohiuddin  C, Mohammad  S, Md Rezaul  K, Johirul  I, Dan  G, Shuixiang  H.  A comparative study on ivermectin doxycycline and hydroxychloroquine azithromycin therapy on COVID-19 patients.   Research Square. 2021.Google Scholar

32.Hashim  HA, Maulood  MF, Rasheed  AM, Fatak  DF, Kabah  KK, Abdulamir  AS.  Controlled randomized clinical trial on using ivermectin with doxycycline for treating COVID-19 patients in Baghdad, Iraq.   medRxiv. 2020. doi:10.1101/2020.10.26.20219345Google Scholar

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Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities

The I-TECH Randomized Clinical Trial

Authors: Steven Chee Loon Lim, MRCP1Chee Peng Hor, MSc2,3Kim Heng Tay, MRCP4et al

JAMA Intern Med. Published online February 18, 2022. doi:10.1001/jamainternmed.2022.0189

Key Points

Question  Does adding ivermectin, an inexpensive and widely available antiparasitic drug, to the standard of care reduce the risk of severe disease in patients with COVID-19 and comorbidities?

Findings  In this open-label randomized clinical trial of high-risk patients with COVID-19 in Malaysia, a 5-day course of oral ivermectin administered during the first week of illness did not reduce the risk of developing severe disease compared with standard of care alone.

Meaning  The study findings do not support the use of ivermectin for patients with COVID-19.Abstract

Importance  Ivermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19. Evidence-based data to recommend either for or against the use of ivermectin are needed.

Objective  To determine the efficacy of ivermectin in preventing progression to severe disease among high-risk patients with COVID-19.

Design, Setting, and Participants  The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was an open-label randomized clinical trial conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. Within the first week of patients’ symptom onset, the study enrolled patients 50 years and older with laboratory-confirmed COVID-19, comorbidities, and mild to moderate disease.

Interventions  Patients were randomized in a 1:1 ratio to receive either oral ivermectin, 0.4 mg/kg body weight daily for 5 days, plus standard of care (n = 241) or standard of care alone (n = 249). The standard of care consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging.

Main Outcomes and Measures  The primary outcome was the proportion of patients who progressed to severe disease, defined as the hypoxic stage requiring supplemental oxygen to maintain pulse oximetry oxygen saturation of 95% or higher. Secondary outcomes of the trial included the rates of mechanical ventilation, intensive care unit admission, 28-day in-hospital mortality, and adverse events.

Results  Among 490 patients included in the primary analysis (mean [SD] age, 62.5 [8.7] years; 267 women [54.5%]), 52 of 241 patients (21.6%) in the ivermectin group and 43 of 249 patients (17.3%) in the control group progressed to severe disease (relative risk [RR], 1.25; 95% CI, 0.87-1.80; P = .25). For all prespecified secondary outcomes, there were no significant differences between groups. Mechanical ventilation occurred in 4 (1.7%) vs 10 (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P = .17), intensive care unit admission in 6 (2.4%) vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P = .79), and 28-day in-hospital death in 3 (1.2%) vs 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09). The most common adverse event reported was diarrhea (14 [5.8%] in the ivermectin group and 4 [1.6%] in the control group).

Conclusions and Relevance  In this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study findings do not support the use of ivermectin for patients with COVID-19.

Trial Registration  ClinicalTrials.gov Identifier: NCT04920942Introduction

Despite the success of COVID-19 vaccines and the implementation of nonpharmaceutical public health measures, there is an enormous global need for effective therapeutics for SARS-CoV-2 infection. At present, repurposed anti-inflammatory drugs (dexamethasone, tocilizumab, and sarilumab),13 monoclonal antibodies,46 and antivirals (remdesivir, molnupiravir, and nirmatrelvir/ritonavir)79 have demonstrated treatment benefits at different stages of COVID-19.10

In Malaysia, about 95% of patients with COVID-19 present early with mild disease, and less than 5% progress to a hypoxic state requiring oxygen supplementation. Notably, patients 50 years and older with comorbidities are at high risk for severe disease.11 Potentially, an antiviral therapy administered during the early viral replication phase could avert the deterioration. Although molnupiravir and nirmatrelvir/ritonavir have shown efficacy in the early treatment of COVID-19,8,9 they can be too expensive for widespread use in resource-limited settings.

Ivermectin, an inexpensive, easy-to-administer, and widely available antiparasitic drug, has been used as an oral therapy for COVID-19. An in vitro study demonstrated inhibitory effects of ivermectin against SARS-CoV-2.12 Although some early clinical studies suggested the potential efficacy of ivermectin in the treatment and prevention of COVID-19,13,14 these studies had methodologic weaknesses.15

In 2021, 2 randomized clinical trials from Colombia16 and Argentina17 found no significant effect of ivermectin on symptom resolution and hospitalization rates for patients with COVID-19. A Cochrane meta-analysis18 also found insufficient evidence to support the use of ivermectin for the treatment or prevention of COVID-19.

These findings notwithstanding, ivermectin is widely prescribed for COVID-19, contrary to the World Health Organization (WHO) recommendation to restrict use of the drug to clinical trials.19 In the present randomized clinical trial, we studied the efficacy of ivermectin for preventing progression to severe disease among high-risk patients with COVID-19 in Malaysia.MethodsTrial Design and Patients

The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was a multicenter, open-label, randomized clinical trial conducted at 20 government hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. The study was approved by the local Medical Research and Ethics Committee (NMRR-21-155-58433) and registered in ClinicalTrials.gov (NCT04920942). This trial was conducted in accordance with the Declaration of Helsinki and the Malaysian Good Clinical Practice Guideline. All participants provided written informed consent. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.

In Malaysia, mandatory notification to public health authorities applies to all COVID-19 cases. Patients with mild to moderate disease at risk of disease progression are referred for hospitalization or admitted to a COVID-19 quarantine center to allow close monitoring for 10 or more days from symptom onset and timely intervention in the event of deterioration.

The study enrolled patients with reverse transcriptase–polymerase chain reaction (RT-PCR) test–confirmed or antigen test–confirmed COVID-19 who were 50 years or older with at least 1 comorbidity and presented with mild to moderate illness (Malaysian COVID-19 clinical severity stage 2 or 3; WHO clinical progression scale 2-4)20,21 within 7 days from symptom onset. Patients were excluded if they were asymptomatic, required supplemental oxygen, or had pulse oximetry oxygen saturation (Spo2) level less than 95% at rest. Other exclusion criteria were severe hepatic impairment (alanine transaminase level >10 times of upper normal limit), acute medical or surgical emergency, concomitant viral infection, pregnancy or breastfeeding, warfarin therapy, and history of taking ivermectin or any antiviral drugs with reported activity against COVID-19 (favipiravir, hydroxychloroquine, lopinavir, and remdesivir) within 7 days before enrollment. Eligibility criteria are detailed in the study protocol (Supplement 1). Study investigators collected information on ethnicity based on the patient’s Malaysian identification card or passport (for non-Malaysian citizens).

All patients with COVID-19 were managed in accordance with the national COVID-19 Management Guidelines,20 developed by a local expert panel based on consensus, WHO recommendations, and the US National Institutes of Health guidelines. High-risk patients were defined as those aged 50 years or older with comorbidity. Patients were staged according to clinical severity at presentation and disease progression: stage 1, asymptomatic; stage 2, symptomatic without evidence of pneumonia; stage 3, evidence of pneumonia without hypoxia; stage 4, pneumonia with hypoxia requiring oxygen supplementation; and stage 5, critically ill with multiorgan involvement. Stages 2 and 3 were classified as mild and moderate diseases (WHO scale 2-4), while stages 4 and 5 were referred to as severe diseases (WHO scale 5-9). The standard of care for patients with mild to moderate disease consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging.Randomization and Data Collection

All study data were recorded in case report form and transcribed into the REDCap (Research Electronic Data Capture) platform.22,23 Patients were randomized in a 1:1 ratio to either the intervention group receiving oral ivermectin (0.4 mg/kg body weight daily for 5 days) plus standard of care or the control group receiving the standard of care alone (Figure). The randomization was based on an investigator-blinded randomization list uploaded to REDCap, which allocated the patients via a central, computer-generated randomization scheme across all study sites during enrollment. The randomization list was generated independently using random permuted block sizes 2 to 6. The randomization was not stratified by site.Intervention

The ivermectin dosage for each patient in the intervention arm was calculated to the nearest 6-mg or 12-mg whole tablets (dosing table in the study protocol, Supplement 1). The first dose of ivermectin was administered after randomization on day 1 of enrollment, followed by 4 doses on days 2 through 5. Patients were encouraged to take ivermectin with food or after meals to improve drug absorption. Storage, dispensary, and administration of ivermectin were handled by trained study investigators, pharmacists, and nurses.Outcome Measures

The primary outcome was the proportion of patients who progressed to severe COVID-19, defined as the hypoxic stage requiring supplemental oxygen to maintain Spo2 95% or greater (Malaysian COVID-19 clinical severity stages 4 or 5; WHO clinical progression scale 5-9). The Spo2 was measured using a calibrated pulse oximeter per the clinical monitoring protocol.

Secondary outcomes were time of progression to severe disease, 28-day in-hospital all-cause mortality, mechanical ventilation rate, intensive care unit admission, and length of hospital stay after enrollment. Patients were also assessed on day 5 of enrollment for symptom resolution, changes in laboratory test results, and chest radiography findings. Adverse events (AEs) and serious AEs (SAEs) were evaluated and graded according to Common Terminology Criteria for Adverse Events, version 5.0.24 All outcomes were captured from randomization until discharge from study sites or day 28 of enrollment, whichever was earlier.Subgroup Analyses

Subgroup analyses were predetermined according to COVID-19 vaccination status, age, clinical staging, duration of illness at enrollment, and common comorbidities.Procedures

Patients’ clinical history, anthropometric measurements, blood samples for complete blood cell count, kidney and liver profiles, C-reactive protein levels, and chest radiography were obtained at baseline. Blood sampling and chest radiography were repeated on day 5 of enrollment. Study investigators followed up patients for all outcome assessments and AEs. All study-related AEs were reviewed by an independent Data and Safety Monitoring Board.Sample Size Calculation

The sample size was calculated based on a superiority trial design and primary outcome measure. The expected rate of primary outcome was 17.5% in the control group, according to previous local data of high-risk patients who presented with mild to moderate disease.11 A 50% reduction of primary outcome, or a 9% rate difference between intervention and control groups, was considered clinically important. This trial required 462 patients to be adequately powered. This sample size provided a level of significance at 5% with 80% power for 2-sided tests. Considering potential dropouts, a total of 500 patients (250 patients for each group) were recruited.Statistical Analyses

Primary analyses were performed based on the modified intention-to-treat principle, whereby randomized patients in the intervention group who received at least 1 ivermectin dose and all patients in the control group would be followed and evaluated for efficacy and safety. In addition, sensitivity analyses were performed on all eligible randomized patients, including those in the intervention group who did not receive ivermectin (intention-to-treat population).

Descriptive data were expressed as means and SDs unless otherwise stated. Categorical data were analyzed using the Fisher exact test. Continuous variables were tested using the t-test or Mann-Whitney U test. The primary and categorical secondary outcome measures were estimated using relative risk (RR). The absolute difference of means of time of progression to severe disease and lengths of hospitalization between the study groups were determined with a 95% CI. Mixed analysis of variance was used to determine whether the changes of laboratory investigations were the result of interactions between the study groups (between-patients factor) and times (within-patient factor), and P < .05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 22.0 (IBM Corp).

Interim analyses were conducted on the first 150 and 300 patients, with outcome data retrieved on July 13 and August 30, 2021, respectively. The overall level of significance was maintained at P < .05, calculated according to the O’Brien-Fleming stopping boundaries. Early stopping would be considered if P < .003 for efficacy data. The results were presented to the Data and Safety Monitoring Board, which recommended continuing the study given no signal for early termination.Results

Between May 31 and October 9, 2021, 500 patients were enrolled and randomized. The last patient completed follow-up on October 25, 2021. Four patients were excluded after randomization. One patient in the control arm was diagnosed with dengue coinfection; in the intervention arm, 2 failed to meet inclusion criteria owing to symptom duration greater than 7 days and negative COVID-19 RT-PCR test result, while 1 had acute coronary syndrome before ivermectin initiation. In addition, 6 patients in the intervention arm withdrew consent before taking a dose of ivermectin. The modified intention-to-treat population for the primary analysis included 490 patients (98% of those enrolled), with 241 in the intervention group and 249 in the control group (Figure). Drug compliance analysis showed that 232 patients (96.3%) in the intervention group completed 5 doses of ivermectin.

Baseline demographics and characteristics of patients were well balanced between groups (Table 1). The mean (SD) age was 62.5 (8.7) years, with 267 women (54.5%); 254 patients (51.8%) were fully vaccinated with 2 doses of COVID-19 vaccines. All major ethnic groups in Malaysia were well represented in the study population. The majority had hypertension (369 [75.3%]), followed by diabetes mellitus (262 [53.5%]), dyslipidemia (184 [37.6%]), and obesity (117 [23.9%]).

The mean (SD) duration of symptoms at enrollment was 5.1 (1.3) days. The most common symptoms were cough (378 [77.1%]), fever (237 [48.4%]), and runny nose (149 [30.4%]). Approximately two-thirds of patients had moderate disease. The average baseline neutrophil-lymphocyte ratio and serum C-reactive protein level were similar between groups. There were no significant differences in the concomitant medications prescribed for both groups. In sensitivity analyses, baseline characteristics were similar in the intention-to-treat population (eTable 1 in Supplement 2).Primary Outcome

Among the 490 patients, 95 (19.4%) progressed to severe disease during the study period; 52 of 241 (21.6%) received ivermectin plus standard of care, and 43 of 249 (17.3%) received standard of care alone (RR, 1.25; 95% CI, 0.87-1.80; P = .25) (Table 2). Similar results were observed in the intention-to-treat population in the sensitivity analyses (eTable 2 in Supplement 2).Secondary Outcomes

There were no significant differences between ivermectin and control groups for all the prespecified secondary outcomes (Table 2). Among patients who progressed to severe disease, the time from study enrollment to the onset of deterioration was similar across ivermectin and control groups (mean [SD], 3.2 [2.4] days vs 2.9 [1.8] days; mean difference, 0.3; 95% CI, −0.6 to 1.2; P = .51). Mechanical ventilation occurred in 4 patients (1.7%) in the ivermectin group vs 10 (4.0%) in the control group (RR, 0.41; 95% CI, 0.13 to 1.30; P = .17) and intensive care unit admission in 6 (2.5%) vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27 to 2.20; P = .79). The 28-day in-hospital mortality rate was similar for the ivermectin and control groups (3 [1.2%] vs 10 [4.0%]; RR, 0.31; 95% CI, 0.09 to 1.11; P = .09), as was the length of hospital stay after enrollment (mean [SD], 7.7 [4.4] days vs 7.3 [4.3] days; mean difference, 0.4; 95% CI, −0.4 to 1.3; P = .38).

By day 5 of enrollment, the proportion of patients who achieved complete symptom resolution was comparable between both groups (RR, 0.97; 95% CI, 0.82-1.15; P = .72). Findings of chest radiography without pneumonic changes or with resolution by day 5 were also similar (RR, 1.03; 95% CI, 0.76-1.40; P = .92). No marked variation was noted in blood parameters (eTable 3 in Supplement 2). There was no significant difference in the incidence of disease complications and highest oxygen requirement (eTables 4 and 5 in Supplement 2).Subgroup Analyses

Subgroup analyses for patients with severe disease were unremarkable (Table 3). Among fully vaccinated patients, 22 (17.7%) in the ivermectin group and 12 (9.2%) in the control group developed severe disease (RR, 1.92; 95% CI, 0.99-3.71; P = .06). Post hoc analyses on clinical outcomes by vaccination status showed that fully vaccinated patients in the control group had a significantly lower rate of severe disease (P = .002; supporting data in eTable 6 in Supplement 2).Adverse Events

A total of 55 AEs occurred in 44 patients (9.0%) (Table 4). Among them, 33 were from the ivermectin group, with diarrhea being the most common AE (14 [5.8%]). Five events were classified as SAEs, with 4 in the ivermectin group (2 patients had myocardial infarction, 1 had severe anemia, and 1 developed hypovolemic shock secondary to severe diarrhea), and 1 in the control group had inferior epigastric arterial bleeding. Six patients discontinued ivermectin, and 3 withdrew from the study owing to AEs. The majority of AEs were grade 1 and resolved within the study period.

Among the 13 deaths, severe COVID-19 pneumonia was the principal direct cause (9 deaths [69.2%]). Four patients in the control group died from nosocomial sepsis. None of the deaths were attributed to ivermectin treatment.Discussion

In this randomized clinical trial of early ivermectin treatment for adults with mild to moderate COVID-19 and comorbidities, we found no evidence that ivermectin was efficacious in reducing the risk of severe disease. Our findings are consistent with the results of the IVERCOR-COVID19 trial,17 which found that ivermectin was ineffective in reducing the risk of hospitalization.

Prior randomized clinical trials of ivermectin treatment for patients with COVID-19 and with 400 or more patients enrolled focused on outpatients.16,17 In contrast, the patients in our trial were hospitalized, which permitted the observed administration of ivermectin with a high adherence rate. Furthermore, we used clearly defined criteria for ascertaining progression to severe disease.

Before the trial started, the case fatality rate in Malaysia from COVID-19 was about 1%,25 a rate too low for mortality to be the primary end point in our study. Even in a high-risk cohort, there were 13 deaths (2.7%). A recent meta-analysis of 8 randomized clinical trials of ivermectin to treat SARS-CoV-2 infection, involving 1848 patients with 71 deaths (3.8%), showed that treatment with the drug had no significant effect on survival.26

The pharmacokinetics of ivermectin for treating COVID-19 has been a contentious issue. The plasma inhibitory concentrations of ivermectin for SARS-CoV-2 are high; thus, establishing an effective ivermectin dose regimen without causing toxic effects in patients is difficult.27,28 The dose regimens that produced favorable results against COVID-19 ranged from a 0.2-mg/kg single dose to 0.6 mg/kg/d for 5 days2932; a concentration-dependent antiviral effect was demonstrated by Krolewiecki et al.29 Pharmacokinetic studies have suggested that a single dose of up to 120 mg of ivermectin can be safe and well tolerated.33 Considering the peak of SARS-CoV-2 viral load during the first week of illness and its prolongation in severe disease,34 our trial used an ivermectin dose of 0.4 mg/kg of body weight daily for 5 days. The notably higher incidence of AEs in the ivermectin group raises concerns about the use of this drug outside of trial settings and without medical supervision.Limitations

Our study has limitations. First, the open-label trial design might contribute to the underreporting of adverse events in the control group while overestimating the drug effects of ivermectin. Second, our study was not designed to assess the effects of ivermectin on mortality from COVID-19. Finally, the generalizability of our findings may be limited by the older study population, although younger and healthier individuals with low risk of severe disease are less likely to benefit from specific COVID-19 treatments.Conclusions

In this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study findings do not support the use of ivermectin for patients with COVID-19.Back to topArticle Information

Accepted for Publication: January 22, 2022.

Published Online: February 18, 2022. doi:10.1001/jamainternmed.2022.0189

Corresponding Author: Steven Chee Loon Lim, MRCP, Department of Medicine, Raja Permaisuri Bainun Hospital, Jalan Raja Ashman Shah, 30450 Ipoh, Perak, Malaysia (stevenlimcl@gmail.com).

Author Contributions: Dr S. Lim and Mr King had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: S. Lim, Tan, Chow, Cheah, Cheng, An, Low, Song, Chidambaram, Peariasamy.

Acquisition, analysis, or interpretation of data: S. Lim, Hor, Tay, Mat Jelani, Tan, Ker, Zaid, Cheah, H. Lim, Khalid, Mohd Unit, An, Nasruddin, Khoo, Loh, Zaidan, Ab Wahab, Koh, King, Lai.

Drafting of the manuscript: S. Lim, Hor, Tay, Mat Jelani, Tan, Zaid, H. Lim, An, Low, Ab Wahab, King, Peariasamy.

Critical revision of the manuscript for important intellectual content: S. Lim, Hor, Tan, Ker, Chow, Cheah, Khalid, Cheng, Mohd Unit, An, Nasruddin, Khoo, Loh, Zaidan, Song, Koh, King, Lai, Chidambaram.

Statistical analysis: S. Lim, Hor, Tan, King, Lai.

Administrative, technical, or material support: S. Lim, Hor, Tay, Mat Jelani, Tan, Ker, Chow, Zaid, Cheah, H. Lim, Khalid, Low, Khoo, Loh, Zaidan, Ab Wahab, Song, Koh, Chidambaram.

Supervision: S. Lim, Tan, Ker, Chow, Zaid, Cheng, Khoo, Loh, Song, Peariasamy.

Conflict of Interest Disclosures: None reported.

Ivermectin disinformation leads to new kinds of chaos

BY JUSTINE COLEMAN – 09/29/21 06:00 AM EDT

An avalanche of misinformation about the antiparasitic drug ivermectin’s ability to treat COVID-19 has caused a series of national problems, from increased calls to poisoning centers to a shortage of the medicine itself. 

Patients have become desperate for a treatment that’s most commonly used for livestock and have taken their disputes over ivermectin with hospitals to court. 

Disinformation has flooded the internet, where dozens of Facebook groups centered around ivermectin remain active despite insufficient evidence that the medicine works in treating people for COVID-19. 

It’s also gone well beyond the internet to popular podcast hosts like Joe Rogan, who has touted the medicine to his millions of listeners. 

The Food and Drug Administration (FDA), other state health departments and even Merck, the drug’s main manufacturer, have all warned against using ivermectin for COVID-19. 

Still, online influences supporting the controversial COVID-19 treatment endure. 

It’s all raising questions about whether the government needs to do more to step in. 

“The promise that there are miracle solutions to an illness is really persuasive,” Jennifer Reich, a professor of sociology at the University of Colorado Denver. “And the idea that individuals can manage their own health, if they read a lot, gather information and make their own decisions is really powerful.”

Media Matters for America found 60 public and private Facebook groups dedicated to ivermectin last month, before the social media giant removed 25 of them after the liberal watchdog’s report. But the other groups still involve more than 70,000 combined users. 

Media Matters released a report on Tuesday concluding that Facebook users are getting around the platform’s moderation strategies by posting links and screenshots of misinformation in the comments of posts and by purposely misspelling keywords such as ivermectin and vaccines. 

“Unfortunately, due to Facebook’s lax moderation of the content on its platform, these evasion techniques are working, and misinformation is thriving on the social media site,” the report reads.

Kayla Gogarty, the associate research director for Media Matters, criticized Facebook for not adequately responding to such misinformation in groups.

“The fact that Facebook has not taken much action against these groups is definitely problematic,” she said.

A Facebook spokesperson told The Hill that the company has removed 20 million pieces of content from Facebook and Instagram for violating COVID-19 misinformation policies.  

“As we enforce our policies against COVID misinformation, we know people will keep trying new tactics to get around our policies and we are constantly evolving to stay ahead of them,” the spokesperson said. 

“We will continue to enforce against any account or group that violates our COVID-19 and vaccine policies,” the statement continued. 

A spokesperson also told The New York Times that the platform removes “content that attempts to buy, sell or donate for ivermectin” and any claims that the drug is “a guaranteed cure or guaranteed prevention.”

Ivermectin is not the first drug to gain traction online as a possible COVID-19 treatment despite lacking evidence. Several experts compared the dewormer’s popularity to that of antimalarial hydroxychloroquine that former President Trump promoted last year.

Yunkang Yang, a postdoctoral research scientist at the Institute for Data, Democracy and Politics at George Washington University, said that influential figures, including Republican politicians, have contributed to the discourse of ivermectin as a “miracle cure.”

For instance, Rogan declared to his millions of listeners that he was taking ivermectin following his COVID-19 diagnosis.

“It would be hard to imagine this information gaining any traction without [their] participation,” he said. 

Misinformation surrounding ivermectin specifically is also not new, as the drug was proposed as a possible treatment earlier in the pandemic, including in some studies retracted due to flawed or fabricated data.

But ivermectin-related calls to poison control centers this year have more than tripled compared to the same period last year, with 1,440 calls through Sept. 20, according to the American Association of Poison Control Centers. 

July, in particular, saw a five-fold increase in ivermectin calls compared to the “pre-pandemic baseline,” according to the Centers for Disease Control and Prevention. Some cases have been fatal, with New Mexico reporting this week two deaths from misusing ivermectin as a COVID-19 medication.

The spikes in ivermectin misuse sparked the FDA to issue an advisory against using the drug for the virus earlier this month. 

“You are not a horse. You are not a cow. Seriously, y’all. Stop it,” the agency said on Twitter. 

While the FDA has approved ivermectin to treat parasitic worms, lice and skin conditions like rosacea among humans, the drug is more often used to treat animals, including cattle and horses. 

In addition to taking unprescribed ivermectin, several cases have emerged where people have been using these animal products. 

“The issue happens when you have inappropriate use where you have a non-human product, for example, that is meant for cattle that has a different formulation composition,” said Ziad Kazzi, a professor of medical toxicology at Emory University.

“The strength of the formulation is different than what you would use in a human,” said Kazzi, who is also the secretary treasurer of the American College of Medical Toxicology,.

Tara Kirk Sell, a senior scholar at the Johns Hopkins Center for Health Security, said the government can always counter specific COVID-19 rumors such as ivermectin’s effectiveness, but it may not be perceived as a “trusted messenger.”

Instead, she said the government needs to develop a national strategy to fight against misinformation in general so Americans are “more resilient to future misinformation.”

“That can kind of be more of a role for government, rather than deciding what’s true, helping people have the tools to figure it out for themselves,” she said.  

“We’ll see this again with something else,” she added. “And we have to realize that we’re going to have to be pushing back against these rumors for a long time to come.”

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

Authors: Bryant, Andrew MSc1,*; Lawrie, Theresa A. MBBCh, PhD2; Dowswell, Therese PhD2; Fordham, Edmund J. PhD2; Mitchell, Scott MBChB, MRCS3; Hill, Sarah R. PhD1; Tham, Tony C. MD, FRCP4 American Journal of Therapeutics: July/August 2021 – Volume 28 – Issue 4 – p e434-e460doi: 10.1097/MJT.0000000000001402

Abstract

Background: 

Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials.

Areas of uncertainty: 

We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection.

Data sources: 

We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion.

Therapeutic Advances: 

Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19–0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian–Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff–Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%–91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for “need for mechanical ventilation,” whereas effect estimates for “improvement” and “deterioration” clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty.

Conclusions: 

Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.

For More Information:https://journals.lww.com/americantherapeutics/Fulltext/2021/08000/Ivermectin_for_Prevention_and_Treatment_of.7.aspx

Prophylaxis against covid-19: living systematic review and network meta-analysis

Authors: Jessica J Bartoszko, methodologist,1 ,*Reed A C Siemieniuk, methodologist, internist,1 ,*Elena Kum, methodologist,1 ,*Anila Qasim, methodologist,1 ,*Dena Zeraatkar, methodologist,1 ,*Long Ge, methodologist,2 ,*Mi Ah Han, methodologist,3Behnam Sadeghirad, assistant professor,1,4Arnav Agarwal, methodologist, internist,1,5Thomas Agoritsas, methodologist, internist,1,6Derek K Chu, methodologist, immunologist,1,7Rachel Couban, librarian,4Andrea J Darzi, methodologist,1Tahira Devji, methodologist,1Maryam Ghadimi, methodologist,1Kimia Honarmand, methodologist, critical care physician,8Ariel Izcovich, methodologist, internist,9Assem Khamis, data analyst,10Francois Lamontagne, methodologist, critical care physician,11Mark Loeb, methodologist, infectious disease physician,1,7Maura Marcucci, methodologist, internist,1,7Shelley L McLeod, methodologist, assistant professor,12,13Sharhzad Motaghi, methodologist,1Srinivas Murthy, clinical associate professor, paediatric critical care, infectious diseases physician,14Reem A Mustafa, methodologist, nephrologist,15John D Neary, methodologist, internist,7Hector Pardo-Hernandez, methodologist,16,17Gabriel Rada, methodologist,18,19Bram Rochwerg, methodologist, critical care physician,1,7Charlotte Switzer, methodologist,1Britta Tendal, methodologist,20Lehana Thabane, professor,1Per O Vandvik, methodologist, internist,21Robin W M Vernooij, methodologist,22,23Andrés Viteri-García, methodologist,18,24Ying Wang, methodologist, pharmacist,1Liang Yao, methodologist,1Zhikang Ye, methodologist, pharmacist,1Gordon H Guyatt, methodologist, internist,1,7 and Romina Brignardello-Petersen, methodologist1

BMJ. 2021; 373: n949.Published online 2021 Apr 26. doi: 10.1136/bmj.n949

Abstract

Objective

To determine and compare the effects of drug prophylaxis on SARS-CoV-2 infection and covid-19.

Design

Living systematic review and network meta-analysis.

Data sources

World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 25 March 2021, and six additional Chinese databases to 20 February 2021.

Study selection

Randomized trials of people at risk of covid-19 who were assigned to receive prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles.

Methods

Random effects Bayesian network meta-analysis was performed after duplicate data abstraction. Included studies were assessed for risk of bias using a modification of the Cochrane risk of bias 2.0 tool, and certainty of evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach.

Results

The first iteration of this living network meta-analysis includes nine randomised trials—six of hydroxychloroquine (n=6059 participants), one of ivermectin combined with iota-carrageenan (n=234), and two of ivermectin alone (n=540), all compared with standard care or placebo. Two trials (one of ramipril and one of bromhexine hydrochloride) did not meet the sample size requirements for network meta-analysis. Hydroxychloroquine has trivial to no effect on admission to hospital (risk difference 1 fewer per 1000 participants, 95% credible interval 3 fewer to 4 more; high certainty evidence) or mortality (1 fewer per 1000, 2 fewer to 3 more; high certainty). Hydroxychloroquine probably does not reduce the risk of laboratory confirmed SARS-CoV-2 infection (2 more per 1000, 18 fewer to 28 more; moderate certainty), probably increases adverse effects leading to drug discontinuation (19 more per 1000, 1 fewer to 70 more; moderate certainty), and may have trivial to no effect on suspected, probable, or laboratory confirmed SARS-CoV-2 infection (15 fewer per 1000, 64 fewer to 41 more; low certainty). Owing to serious risk of bias and very serious imprecision, and thus very low certainty of evidence, the effects of ivermectin combined with iota-carrageenan on laboratory confirmed covid-19 (52 fewer per 1000, 58 fewer to 37 fewer), ivermectin alone on laboratory confirmed infection (50 fewer per 1000, 59 fewer to 16 fewer) and suspected, probable, or laboratory confirmed infection (159 fewer per 1000, 165 fewer to 144 fewer) remain very uncertain.

Conclusions

Hydroxychloroquine prophylaxis has trivial to no effect on hospital admission and mortality, probably increases adverse effects, and probably does not reduce the risk of SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, it is highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073806/

Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial

Abstract

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has changed our lives. The scientific community has been investigating re-purposed treatments to prevent disease progression in coronavirus disease (COVID-19) patients.

Objective

To determine whether ivermectin treatment can prevent hospitalization in individuals with early COVID-19.

Design, setting and participants: A randomized, double-blind, placebo-controlled study was conducted in non-hospitalized individuals with COVID-19 in Corrientes, Argentina. Patients with SARS-CoV-2 positive nasal swabs were contacted within 48 h by telephone to invite them to participate. The trial randomized 501 patients between August 19th 2020 and February 22nd 2021.

Intervention

Patients were randomized to ivermectin (N = 250) or placebo (N = 251) arms in a staggered dose, according to the patient’s weight, for 2 days.

Main outcomes and measures

The efficacy of ivermectin to prevent hospitalizations was evaluated as primary outcome. We evaluated secondary outcomes in relationship to safety and other efficacy end points.

Results

The mean age was 42 years (SD ± 15.5) and the median time since symptom onset to the inclusion was 4 days [interquartile range 3–6]. The primary outcome of hospitalization was met in 14/250 (5.6%) individuals in ivermectin group and 21/251 (8.4%) in placebo group (odds ratio 0.65; 95% confidence interval, 0.32–1.31; p = 0.227). Time to hospitalization was not statistically different between groups. The mean time from study enrollment to invasive mechanical ventilatory support (MVS) was 5.25 days (SD ± 1.71) in ivermectin group and 10 days (SD ± 2) in placebo group, (p = 0.019). There were no statistically significant differences in the other secondary outcomes including polymerase chain reaction test negativity and safety outcomes.

Limitations

Low percentage of hospitalization events, dose of ivermectin and not including only high-risk population.

Conclusion

Ivermectin had no significant effect on preventing hospitalization of patients with COVID-19. Patients who received ivermectin required invasive MVS earlier in their treatment. No significant differences were observed in any of the other secondary outcomes.

Trial registration

ClinicalTrials.gov NCT04529525.

For More Information: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06348-5

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

Authors: Pierre Kory, MD,1,*Gianfranco Umberto Meduri, MD,2Joseph Varon, MD,3Jose Iglesias, DO,4 and Paul E. Marik, MD5

Background:

After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials.

Areas of Uncertainty:

The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses.

Data Sources:

Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns.

Therapeutic Advances:

A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large “natural experiments” occurred in regions that initiated “ivermectin distribution” campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns.

Conclusions:

Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088823/

India’s Ivermectin Blackout

Authors: Authored by Justus R Hope, MD. via TheDesertReview.com,

Ivermectin Wins in India

News of India’s defeat of the Delta variant should be common knowledge. It is just about as obvious as the nose on one’s face. It is so clear when one looks at the graphs that no one can deny it.

Yet, for some reason, we are not allowed to talk about it. Thus, for example, Wikipedia cannot mention the peer-reviewed meta-analyses by Dr. Tess Lawrie or Dr. Pierre Kory published in the American Journal of Therapeutics

Wikipedia is not allowed to publish the recent meta-analysis on Ivermectin authored by Dr. Andrew Hill.

Furthermore, it is not allowed to say anything concerning www.ivmmeta.com showing the 61 studies comprising 23,000 patients which reveal up to a 96% reduction in death [prophylaxis] with Ivermectin.

One can see the bias in Wikipedia by going on the “talk” pages for each subject and reading about the fierce attempts of editors to add these facts and the stone wall refusals by the “senior” editors who have an agenda. And that agenda is not loyalty to your health.

The easy way to read the “talk” page on any Wikipedia subject is to click the top left “talk” button. Anyone can then review the editors’ discussions.

There is a blackout on any conversation about how Ivermectin beat COVID-19 in India. When I discussed the dire straits that India found itself in early this year with 414,000 cases per day, and over 4,000 deaths per day, and how that evaporated within five weeks of the addition of Ivermectin, I am often asked, “But why is there no mention of that in the news?”

Yes, exactly. Ask yourself why India’s success against the Delta variant with Ivermectin is such a closely guarded secret by the NIH and CDC. Second, ask yourself why no major media outlets reported this fact, but instead, tried to confuse you with false information by saying the deaths in India are 10 times greater than official reports.

Perhaps NPR is trying so hard because NPR is essentially a government mouthpiece. The US government is “all-in” with vaccines with the enthusiasm of a 17th century Catholic Church “all-in” with a Geocentric Model of the Universe disputing Galileo. Claiming that India’s numbers are inaccurate might distract from the overwhelming success of Ivermectin.

But in the end, the truth matters. It mattered in 1616, and it matters in 2021.

The graphs and data from the Johns Hopkins University CSSE database do not lie.

On the contrary, they provide a compelling trail of truth that no one can dispute, not even the NIH, CDC, FDA, and WHO.

For More Information: https://www.zerohedge.com/covid-19/indias-ivermectin-blackout

Ivermectin for COVID-19: real-time meta analysis of 63 studies

Authors: Covid AnalysisAug 12, 2021Version 109 — twitter personality response, added Together Trial (V1 Nov 26, 2020)

•Meta analysis using the most serious outcome reported shows 73% and 86% improvement for early treatment and prophylaxis (RR 0.27 [0.16-0.44] and 0.14 [0.08-0.25]), with similar results after exclusion based sensitivity analysis, restriction to peer-reviewed studies, restriction to serious outcomes, and restriction to Randomized Controlled Trials.•61% and 96% lower mortality is observed for early treatment and prophylaxis (RR 0.39 [0.17-0.90] and 0.04 [0.00-0.59]). Statistically significant improvements are seen for mortalityhospitalizationrecoverycases, and viral clearance. 27 studies show statistically significant improvements in isolation.

StudiesProphylaxisEarly treatmentLate treatmentPatientsAuthors
All studies6386% [75‑92%]73% [56‑84%]40% [24‑52%]26,422613
With exclusions5188% [76‑94%]76% [66‑83%]50% [28‑65%]18,907525
Peer-reviewed4286% [73‑93%]75% [61‑84%]43% [21‑59%]16,455436
Randomized Controlled Trials3184% [25‑96%]67% [54‑76%]30% [2‑50%]6,561359
Mortality results2596% [41‑100%]61% [10‑83%]53% [32‑67%]13,911263
Percentage improvement with ivermectin treatment
Meta-Analysis of Studies for Ivermectin Effectiveness Against COVID-19

•The probability that an ineffective treatment generated results as positive as the 63 studies to date is estimated to be 1 in 1 trillion (p = 0.00000000000083).

Heterogeneity arises from many factors including treatment delay, population, dose, and effect measured, and is low in specific cases, e.g., early treatment mortality.

•While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 29% of ivermectin studies show zero events in the treatment arm.

•Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. All practical, effective, and safe means should be used. Those denying the efficacy of treatments share responsibility for the increased risk of COVID-19 becoming endemic; and the increased mortality, morbidity, and collateral damage.

•The evidence base is much larger and has much lower conflict of interest than typically used to approve drugs.•All data to reproduce this paper and sources are in the appendix.

See [BryantHariyantoHillKoryLawrieNardelli] for other meta analyses with similar results confirming effectiveness. 00.250.50.7511.251.51.752+Kory et al.69%0.31 [0.20-0.47]Improvement, RR [CI]Hill et al.75%0.25 [0.12-0.52]Bryant et al.62%0.38 [0.19-0.73]Lawrie et al.83%0.17 [0.08-0.35]Nardelli et al.79%0.21 [0.11-0.36]Hariyanto et al.69%0.31 [0.15-0.62]WHO (OR)81%0.19 [0.09-0.36]ivmmeta61%0.39 [0.28-0.56]Ivermectin meta analysis mortality resultsivmmeta.com 8/14/21Lower RiskIncreased Risk

Global adoption: 30%
Evidence base used for other COVID-19 approvals
MedicationStudiesPatientsImprovement
Budesonide (UK)11,77917%
Remdesivir (USA)11,06331%
Casiri/imdevimab (USA)179966%
Ivermectin evidence6326,39869% [60‑75%]
Effectiveness of Other Medications Against COVID-19

For More Information: https://ivmmeta.com/

Huge study supporting ivermectin as Covid treatment withdrawn over ethical concerns

The preprint endorsing ivermectin as a coronavirus therapy has been widely cited, but independent researchers find glaring discrepancies in the data

Authors: Melissa Davey

The efficacy of a drug being promoted by rightwing figures worldwide for treating Covid-19 is in serious doubt after a major study suggesting the treatment is effective against the virus was withdrawn due to “ethical concerns”.

The preprint study on the efficacy and safety of ivermectin – a drug used against parasites such as worms and headlice – in treating Covid-19, led by Dr Ahmed Elgazzar from Benha University in Egypt, was published on the Research Square website in November.

It claimed to be a randomised control trial, a type of study crucial in medicine because it is considered to provide the most reliable evidence on the effectiveness of interventions due to the minimal risk of confounding factors influencing the results. Elgazzar is listed as chief editor of the Benha Medical Journal, and is an editorial board member.

The study found that patients with Covid-19 treated in hospital who “received ivermectin early reported substantial recovery” and that there was “a substantial improvement and reduction in mortality rate in ivermectin treated groups” by 90%.

But the drug’s promise as a treatment for the virus is in serious doubt after the Elgazzar study was pulled from the Research Square website on Thursday “due to ethical concerns”. Research Square did not outline what those concerns were.

For More Information: https://www.theguardian.com/science/2021/jul/16/huge-study-supporting-ivermectin-as-covid-treatment-withdrawn-over-ethical-concerns