RCT 490 late stage (>65% lung change chest radiography at baseline) hospitalized patients in Malaysia, showing no significant differences.
Mortality was 1.2% for ivermectin vs. 4% for control. If the same event rates continue, the trial would need to add ~13% more patients to reach statistical significance.
i.e., by continuing the trial for ~2 weeks, there is a reasonable chance of the result being a statistically significant ~69% reduction in mortality, which would equate to ~4 million lives saved if adopted at the start of the pandemic.
The mortality reduction is consistent with the results from all trials to date. While not reaching the significance threshold with the specified test, Bayesian analysis shows a 97% probability that ivermectin reduces mortality normanfenton.com
Authors describe the mortality results as "similar" and they are not mentioned in the visual abstract or the conclusion, suggesting substantial investigator bias with a preference for a null result.
The primary outcome is based on SpO2
<95%, however baseline SpO2
is not provided. This outcome is of limited use in evaluating treatment because it occurred before the end of treatment for > ~80% of patients. The trial was open label and the primary outcome is subject to investigator bias - clinicians could easily bias the results by altering how they monitor SpO2
, how precisely they enforced the threshold, or other aspects of SOC such as propensity to use prone positioning. Authors indicate the 95% value is from clinical stage 4, however the Malaysian government defines 94% as the threshold for stage 4 covid-19.moh.gov.my
, as per the NIH definition covid19treatmentguidelines.nih.gov
. Using death/IMV/NIV/high flow for severe (as per WHO) also shows more favorable results
The mortality rate among all patients is too low to detect a 69% benefit with statistical significance, however the primary outcome gives us a subset of patients with severe cases that had progressed to SpO2
<95% shortly after randomization (and mostly before treatment ended). This result is statistically significant. For more discussion see: twitter.com (B),
The trial started May 31, 2021 and outcomes were changed in the trial record on June 16, 2021 clinicaltrials.gov
. Previously the only clinical outcomes listed (under secondary outcomes) were mortality and clinical response, both at 28 days. Clinical response at 28 days would be more informative than complete recovery at day 5 as reported.
Contact information was deleted in the trial record on November 3, 2021 clinicaltrials.gov (B)
The ivermectin arm had higher incidence of chronic cardiac disease (15% vs. 8%, p
=0.02) and higher use of antibiotics prior to enrollment (8% vs. 3%, p
= 0.01), which may indicate that randomization resulted in more patients with higher risk/severity in the treatment arm.
Data sharing: authors report that the data is available, send requests to: email@example.com. NCT04920942 (history)
This is the 31st of 46 COVID-19 RCTs
for ivermectin, which collectively show efficacy with p=0.00000014
This is the 66th of 99 COVID-19 controlled studies
for ivermectin, which collectively show efficacy with p<0.0000000001 (1 in 2 sextillion)
risk of death, 69.0% lower, RR 0.31, p = 0.09, treatment 3 of 241 (1.2%), control 10 of 249 (4.0%), NNT 36.
risk of death, 75.2% lower, RR 0.25, p = 0.02, treatment 3 of 52 (5.8%), control 10 of 43 (23.3%), NNT 5.7, among patients progressing to severe cases (mostly before treatment ended).
risk of mechanical ventilation, 59.0% lower, RR 0.41, p = 0.17, treatment 4 of 241 (1.7%), control 10 of 249 (4.0%), NNT 42.
risk of ICU admission, 22.0% lower, RR 0.78, p = 0.79, treatment 6 of 241 (2.5%), control 8 of 249 (3.2%), NNT 138.
risk of progression, 31.1% lower, RR 0.69, p = 0.29, treatment 14 of 241 (5.8%), control 21 of 249 (8.4%), NNT 38, death/IMV/NIV/high flow (WHO severe cases).
risk of progression, 25.0% higher, RR 1.25, p = 0.25, treatment 52 of 241 (21.6%), control 43 of 249 (17.3%), primary outcome.
hospitalization time, 5.5% higher, relative time 1.05, p = 0.38, treatment 241, control 249.
risk of no recovery, 2.5% higher, RR 1.02, p = 0.86, treatment 116 of 241 (48.1%), control 116 of 247 (47.0%), day 5.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Lim et al., 3 Nov 2021, Randomized Controlled Trial, Malaysia, peer-reviewed, 26 authors, study period 31 May, 2021 - 9 October, 2021, average treatment delay 5.1 days, dosage 400μg/kg days 1-5, trial NCT04920942 (history)
Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities
JAMA Internal Medicine, doi:10.1001/jamainternmed.2022.0189
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.
Conflict of Interest
Additional Contributions: The authors thank all the investigators at the 21 study sites and the Institute for Clinical Research, Ministry of Health Malaysia, for their immense contribution and support. In addition, we are grateful for the participation of the patients enrolled in this study. We also thank the members of the independent Data and Safety Monitoring Board, namely Petrick Periyasamy, MMed, National University Medical Centre, Malaysia; Lai Hui Pang, BPharm, Institute for Clinical Research, Malaysia; Mohamad Adam Bujang, PhD, Institute for Clinical Research, Malaysia; Wei Hong Lai, PhD, Institute for Clinical Research, Malaysia; and Nurakmal Baharum, BSc, Institute for Clinical Research, Malaysia. They did not receive compensation for their contribution to this study. We also thank Noor Hisham Abdullah, M Surg, Director-General of Health Malaysia, for his permission to publish this study.
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