The I-TECH Randomized Clinical Trial February 18, 2022
Authors:
Steven Chee Loon Lim, MRCP1; Chee Peng Hor, MSc2,3; Kim Heng Tay, MRCP4; et alAnilawati Mat Jelani, MMed5; Wen Hao Tan, MMed6; Hong Bee Ker, MRCP1; Ting Soo Chow, MRCP7; Masliza Zaid, MMed8; Wee Kooi Cheah, MRCP6; Han Hua Lim, MRCP9; Khairil Erwan Khalid, MRCP10; Joo Thye Cheng, MRCP2; Hazfadzila Mohd Unit, MRCP11; Noralfazita An, MMed12; Azraai Bahari Nasruddin, MRCP13; Lee Lee Low, MRCP14; Song Weng Ryan Khoo, MRCP15; Jia Hui Loh, MRCP16; Nor Zaila Zaidan, MMed17; Suhaila Ab Wahab, MMed18; Li Herng Song, MD19; Hui Moon Koh, MClinPharm20; Teck Long King, BPharm21; Nai Ming Lai, MRCPCH22; Suresh Kumar Chidambaram, MRCP4; Kalaiarasu 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),1–3 monoclonal antibodies,4–6 and antivirals (remdesivir, molnupiravir, and nirmatrelvir/ritonavir)7–9 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 days29–32; 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.
Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384(8):693-704. doi:10.1056/NEJMoa2021436PubMedGoogle Scholar2.Gordon AC, Mouncey PR, Al-Beidh F, et al;
REMAP-CAP Investigators. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021;384(16):1491-1502. doi:10.1056/NEJMoa2100433PubMedGoogle Scholar
3.RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-1645. doi:10.1016/S0140-6736(21)00676-0PubMedGoogle ScholarCrossref
4.Weinreich DM, Sivapalasingam S, Norton T, et al; Trial Investigators. REGN-COV2, a neutralizing antibody cocktail, in outpatients with COVID-19. N Engl J Med. 2021;384(3):238-251. doi:10.1056/NEJMoa2035002PubMedGoogle ScholarCrossref
5.Dougan M, Nirula A, Azizad M, et al; BLAZE-1 Investigators. Bamlanivimab plus etesevimab in mild or moderate COVID-19. N Engl J Med. 2021;385(15):1382-1392. doi:10.1056/NEJMoa2102685PubMedGoogle ScholarCrossref
6.Gupta A, Gonzalez-Rojas Y, Juarez E, et al; COMET-ICE Investigators. Early treatment for COVID-19 with SARS-CoV-2 neutralizing antibody sotrovimab. N Engl J Med. 2021;385(21):1941-1950. doi:10.1056/NEJMoa2107934PubMedGoogle ScholarCrossref
7.Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group Members. Remdesivir for the treatment of COVID-19—final report. N Engl J Med. 2020;383(19):1813-1826. doi:10.1056/NEJMoa2007764PubMedGoogle ScholarCrossref
8.Mahase E. COVID-19: molnupiravir reduces risk of hospital admission or death by 50% in patients at risk, MSD reports. BMJ. 2021;375(n2422):n2422. doi:10.1136/bmj.n2422PubMedGoogle Scholar
9.Mahase E. COVID-19: Pfizer’s paxlovid is 89% effective in patients at risk of serious illness, company reports. BMJ. 2021;375(n2713):n2713. doi:
10.1136/bmj.n2713PubMedGoogle Scholar10.Drożdżal S, Rosik J, Lechowicz K, et al. An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment. Drug Resist Updat. 2021;59:100794. doi:10.1016/j.drup.2021.100794PubMedGoogle Scholar
11.Sim BLH, Chidambaram SK, Wong XC, et al. Clinical characteristics and risk factors for severe COVID-19 infections in Malaysia: A nationwide observational study. Lancet Reg Health West Pac. 2020;4:100055. doi:10.1016/j.lanwpc.2020.100055PubMedGoogle Scholar
12.Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. doi:10.1016/j.antiviral.2020.104787PubMedGoogle Scholar
13.Bryant A, Lawrie TA, Dowswell T, et al. Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. Am J Ther. 2021;28(4):e434-e460. doi:10.1097/MJT.0000000000001402PubMedGoogle ScholarCrossref
14.Kory P, Meduri GU, Varon J, Iglesias J, Marik PE. Review of the emerging evidence demonstrating the efficacy of ivermectin in the prophylaxis and treatment of COVID-19. Am J Ther. 2021;28(3):e299-e318. doi:10.1097/MJT.0000000000001377PubMedGoogle ScholarCrossref
15.Garegnani LI, Madrid E, Meza N. Misleading clinical evidence and systematic reviews on ivermectin for COVID-19. BMJ Evid Based Med. Published online April 22, 2021. doi:10.1136/bmjebm-2021-111678PubMedGoogle Scholar
16.López-Medina E, López P, Hurtado IC, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial. JAMA. 2021;325(14):1426-1435. doi:10.1001/jama.2021.3071 ArticlePubMedGoogle ScholarCrossref
17.Vallejos J, Zoni R, Bangher M, et al. Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19): a randomized, double-blind, placebo-controlled trial. BMC Infect Dis. 2021;21(1):635. doi:10.1186/s12879-021-06348-5PubMedGoogle ScholarCrossref
18.Popp M, Stegemann M, Metzendorf MI, et al. Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev. 2021;7(7):CD015017.PubMedGoogle Scholar
19.World Health Organization. WHO advises that ivermectin only be used to treat COVID-19 within clinical trials. Accessed March 31, 2021. https://www.who.int/news-room/feature-stories/detail/who-advises-that-ivermectin-only-be-used-to-treat-covid-19-within-clinical-trials
20.COVID-19 management guidelines in Malaysia. Ministry of Health, Malaysia. Accessed February 2, 2022. https://covid-19.moh.gov.my/garis-panduan/garis-panduan-kkm
21.Marshall JC, Murthy S, Diaz J, et al; WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020;20(8):e192-e197. doi:10.1016/S1473-3099(20)30483-7PubMedGoogle ScholarCrossref
22.Harris PA, Taylor R, Minor BL, et al; REDCap Consortium. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208. doi:10.1016/j.jbi.2019.103208PubMedGoogle Scholar
23.Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377-381. doi:10.1016/j.jbi.2008.08.010PubMedGoogle ScholarCrossref
24.National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. US Department of Health and Human Services; 2017.
25.COVIDNOW in Malaysia. Ministry of Health, Malaysia. Accessed February 2, 2022. https://covidnow.moh.gov.my/deaths
26.Hill A, Garratt A, Levi J, et al. Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection. Open Forum Infect Dis. 2021;8(11):ofab358. doi:10.1093/ofid/ofab358PubMedGoogle Scholar
27.Schmith VD, Zhou JJ, Lohmer LRL. The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19. Clin Pharmacol Ther. 2020;108(4):762-765. doi:10.1002/cpt.1889PubMedGoogle Scholar
28.Momekov G, Momekova D. Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: antiviral levels are not likely attainable with known dosing regimens. Biotechnology & Biotechnological Equipment. 2020;34(1):469-474. doi:10.1080/13102818.2020.1775118Google Scholar
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
33.Guzzo CA, Furtek CI, Porras AG, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42(10):1122-1133. doi:10.1177/009127002401382731PubMedGoogle Scholar
34.Magleby R, Westblade LF, Trzebucki A, et al. Impact of Severe Acute Respiratory Syndrome Coronavirus 2 viral load on risk of intubation and mortality among hospitalized patients with coronavirus disease 2019. Clin Infect Dis. 2021;73(11):e4197-e4205. doi:10.1093/cid/ciaa851PubMedGoogle Scholar