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
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