ADDENDUM 02/05/2021 – Statement From Merck (Maker of Ivermectin)

ADDENDUM 05/03/2021 – The EPIC Trial – RCT in Colombia [10]

Clinical Question: What is the effect of ivermectin on duration of symptoms in adults with mild COVID-19?

What They Did:

  • EPIC Trial: Estudio Para Evaluar la Ivermectina en COVID-19

  • Double-blind, randomized trial conducted at a single center in Colombia

  • Patients were identified by random sampling from the state’s health department electronic database

  • Patients randomized 1:1 to:

  • Ivermectin 300ug/kg per day x5d

  • Matching placebo per day x5d


Outcomes:

  • Primary: Time to resolution of symptoms within 21d

  • Secondary:

  • Proportion of patients with clinical deterioration (Worsening by 2 points from baseline score on the 8-category ordinal scale) since randomization

  • Proportion of patients with new onset hospitalization + New onset oxygen requirement for >24hrs


  • Adverse Events:

  • Solicited adverse events

  • Serious adverse events


Inclusion:

  • Adult patients

  • Laboratory confirmed COVID-19

  • Mild disease (not receiving high-flow nasal oxygen or mechanical ventilation (invasive or noninvasive)

  • Symptoms for ≤7d (at home or hospitalized)

Exclusion:

  • Pregnant or breastfeeding

  • Asymptomatic

  • Severe pneumonia

  • Received ivermectin within previous 5d

  • Hepatic dysfunction

  • LFTs >1.5x upper limit of normal

Results:

  • 476 adult patients with mild disease included

  • 400 patients randomized in the primary analysis

  • Median age = 37 years

  • 79% did not have comorbid conditions at baseline

  • 398 (99.5%) completed the trial


  • No difference in adverse events or serious adverse events between groups


ADDENDUM 02/05/2021 – Statement From Merck (Maker of Ivermectin)

Discussion:

  • Young patient population without comorbid disease does not allow for extrapolation of results to older patients and/or patients with comorbid conditions

  • Up to August 26th, 2020 placebo was a mixture of 5% dextrose in saline and dextrose in distilled water. Due to potential for unblinding due to different taste and smell of ivermectin vs saline/dextrose placebo only 1 patient per household was included in the study to minimize chances of unblinding

  • Collected bottles at the end of study to certify adherence to the assigned regimen

  • Original primary outcome was defined as the time from randomization until worsening 2 points on the 8-category ordinal scale. Before the interim analysis, it became apparent that the pooled event rate of worsening by 2 points was substantially lower than the expected 18%, creating an unattainable sample size.Therefore, on Aug 31st, 2020 the primary outcome was changed to time from randomization to complete resolution of symptoms within 21d

  • On Oct. 20th, 2020 it was realized that a labeling error occurred between Sept 29th and Oct 15th, 2020 resulting in all patients receiving ivermectin and none receiving placebo during this time frame. Study blinding was not unmasked due to this error and these patients were excluded from the primary analysis

  • Authors used daily instead of intermittent dosing of ivermectin based on pharmacokinetic models showing higher lung concentrations with daily dosing

  • Although there was a numerically smaller group of patients in the ivermectin arm that required escalation of care vs placebo (2.0% vs 5.0%), this difference was not statistically significant and after removing 4 patients that were hospitalized within 3.25hrs after randomization this finding was further diminished

  • Additionally, ivermectin did not reduce ED visits or telephone consultations compared to placebo in this trial

Author Conclusion: “Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.”

Bottom Line: This randomized, double-blinded, placebo-controlled trial showed no benefit to the use of ivermectin compared to placebo in resolution of symptoms by 21 days. The methodology of this trial is certainly of better quality than previous trials, however there are some clear short comings with errors and potential for unblinding. Also, the relatively young and healthy study population included in this trial makes it difficult to extrapolate conclusions to older patient populations and/or patients with comorbid disease. We will just have to wait and see what future trials in different patient populations show.


credited to rebelem


 


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