COVID-19 Update: Ivermectin

Background: Throughout the COVID-19 pandemic, numerous therapeutic agents have been repurposed and applied empirically and within clinical trials. Prophylactic medications for COVID-19 could have a huge benefit, but studies to date haven’t panned out. Initially many therapeutic medications were used late in illness, and one of the criticisms of these negative studies was that the drugs were applied too late in the disease and therefore did not show any benefit. There were also numerous studies showing associations of benefit, but subsequent randomized clinical trials have failed to prove effectiveness in reducing mortality (i.e. Remdesivir, hydroxychloroquine, lopinavir/ritonavir, convalescent plasma, monoclonal antibody therapy).

Ivermectin is an interesting medication that had fallen off my radar until recently. It is an anti-parasitic medication, with potential anti-viral, and anti-inflammatory properties against SARS-CoV-2 and COVID-19. In this post we will review some of the current evidence in using Ivermectin as a prophylactic and therapeutic agent in COVID-19.

Clinical Question: Does Ivermectin demonstrate efficacy in prophylaxis and treatment of COVID-19?

In Vitro Evidence [2]

  • Cells infected with SARS-CoV-2 RNA
  • Added Ivermectin or nothing (control) to cells and analyzed RT-PCR for replication of SARS-CoV-2 RNA at days 0 to 3
  • 24h = 93% reduction in viral RNA present
  • 48h = 99.8% reduction in viral RNA present
  • By 48hrs there was an ≈5000-fold reduction in viral RNA in Ivermectin treated cells compared to control samples
  • With a single dose of Ivermectin viral replication was controlled effectively eliminating all viral material by 48hrs
  • No toxicity observed at anytime
  • Proposed anti-viral mechanism of action

Evidence from Egypt [3]

  • RCT of 600 patients (400 symptomatic confirmed COVID-19 & 200 healthcare and household contacts)
    • Group 1: 100 pts with mild/moderate COVID-19 infection + 4d course of 400ug/kg Ivermectin qD (max dose 24mg) + standard of care
    • Group 2: 100 pts with mild/moderate COVID-19 infection + 400mg hydroxychloroquine BID x1d, then 200mg BID for 5d + standard of care
    • Group 3: 100 pts with severe COVID-19 + 4d course of 400ug/kg Ivermectin qD (max dose 24mg) + standard of care
    • Group 4: 100 pts with severe COVID-19 + 400mg hydroxychloroquine BID x1d, then 200mg BID for 5d + standard of care
    • Group 5: 100 healthcare and/or household contacts PPE + ivermectin 400mcg/kg x1 and repeated in 1 week
    • Group 6: 100 healthcare and/or household contacts PPE only
  • Excluded pregnant, lactating, and critical cases (respiratory failure requiring mechanical ventilation, presence of shock, other organ failure)
  • Mild Cases = Mild symptoms such as anosmia, loss of taste, fever, respiratory or GI tract symptoms
  • Moderate Cases = Symptoms such as fever, respiratory tract or GI symptoms + pneumonia manifestations on chest imaging
  • Severe Cases =
    • RR >30/min
    • O2 sat <93%
    • PaO2/FiO2 < 200
    • Lung infiltrates >50% of lung fields or rapid progression within 24 – 48hrs
    • Respiratory support (i.e. HFNC or NIV or IMV)
  • Primary Endpoint: Improvement in clinical/laboratory investigations and/or 2 consecutive negative PCR tests taken at least 48hours apart, and hospital LOS
  • Results:
    • In mild, moderate and severe COVID-19 patients there was improvement in lymphocyte count, CRP, ferritin, d-dimer and RT-PCR conversion days in Ivermectin group compared to hydroxychloroquine group after one week of treatment
    • Mortality:
      • Ivermectin Group 1: 0%
      • Hydroxychloroquine Group 2: 4%
      • Ivermectin Group 3: 2%
      • Hydroxychloroquine Group 4: 20%
    • Mean Hospital LOS:
      • Ivermectin Group 1: 5 +/- 1d
      • Hydroxychloroquine Group 2: 15 +/- 8d
      • Ivermectin Group 3: 6 +/- 1d
      • Hydroxychloroquine Group 4: 18 +/- 8d
    • Prevention of COVID-19 Infection in Healthcare or Household Contacts of COVID-19:
      • Ivermectin Group 5: 2%
      • No Ivermectin Group 6: 10%
    • Limitations:
      • Multiple primary endpoints with many being subjective/soft
      • Trial not registered at clinicaltrials.gov so can’t really check on what outcomes were originally set as primary outcomes and what was added or found through analysis
    • Conclusion: Ivermectin in addition to standard care was more effective in treatment and prophylaxis compared to hydroxychloroquine in addition to standard care according to the authors. Without a placebo arm, we do not know if ivermectin is superior to standard care alone. Additionally, the methodology has concerning issues including multiple primary outcomes.

Evidence from Countries Using Prophylactic Ivermectin vs Those not Using Prophylactic Ivermectin [4]

  • Grouped countries into three different categories:
    • Include ivermectin in prophylaxis
    • Do not include ivermectin in prophylaxis
    • Do not do prophylaxis
  • Compared COVID-19 incidence between these three groups:

  • The fact that prophylaxis without ivermectin also showed a strong and statistically significant association with COVID-19 incidence suggests that other drugs could include additional candidates for the treatment and/or prevention of COVID-19
  • Conclusion: There seems to be an association rather than a causation of ivermectin use reducing COVID-19 incidence. However, we don’t know the rates of COVID-19 in these countries, crowding, testing availability, etc. There’s simply too much unknown information to make anything of this paper other than a hypothesis to study.

Evidence from Iraq [5 ]

  • Randomized controlled trial of 140 patients:
    • 70 COVID-19 patients (48 mild-moderate, 11 severe, and 11 critical patients) treated with 200ug/kg PO of ivermectin qD for 2 to 3 days + 100mg PO doxycycline BID for 5 to 10 days + standard of care
    • 70 COVID-19 patients (48 mild-moderate and 22 severe and zero critical patients) treated with standard of care alone
    • Mild to moderate disease = outpatients
    • Severe/Critical disease = inpatients
  • Results:

  • Ivermectin-Doxycycline reduced mean time to recovery from 17.9 to 10.61d in all recruited patients
    • In mild to moderate patients this reduction was from 13.66d to 6.34d
    • In severe patients this reduction was from 24d to 20d
    • This can have a tremendous effect on lowering the burden of disease and quickly freeing up hospital beds to other patients
  • Limitations:
    • Convenience sample: We have no idea how many patients total could have gotten treatment
    • Unclear what earlier means as there were no critical patients in the SOC arm
    • Non-blinded: Everyone knew what they were taking
    • Randomization method is flawed
    • Small study
    • No clear definition of recovery making this a subjective outcome that can bias the study
    • No idea if it’s the ivermectin or the doxycycline making the difference if you believe the difference
    • No information on patients to see if groups were balanced (i.e. demographics, underlying disease, etc.)
  • Conclusion: On the surface it seems Ivermectin with doxycycline reduced the time to recovery, percentage of patients who progress to more advanced stages of disease and reduced mortality. However, there were so many methodological issues I would not put any weight in these conclusions.

The ICON Study [7 ]

  • Retrospective observational cohort trial of consecutive patients hospitalized with COVID-19 from 4 hospitals in Florida
  • Reviewed charts of patients with COVID-19 treated with and without Ivermectin
  • This is the study that got everyone’s attention on Ivermectin as it was published in CHEST
  • Primary: All-cause in-hospital mortality
  • Results:
    • 280 patients (173 treated with Ivermectin and 107 without)
    • Patients received at least one dose of Ivermectin 200mcg/kg + standard care vs standard care alone
    • A second dose of 200mcg/kg of Ivermectin could be given on day 7 at the discretion of the treating clinician
    • Univariate analysis showed lower mortality in ivermectin group (15.0%vs 25.2%; OR 0.52; 95% CI 0.29 to 0.96; p = 0.03)
    • Mortality also lower in patients with severe pulmonary involvement (need for FiO2 ≥50%, NIV, or IMV)
      • 8% vs 80.7%; OR 0.15; 95% CI 0.05 to 0.47; p = 0.001
    • No difference in extubation rates or length of state
    • After multivariate adjustment for confounders, mortality difference remained significant (OR 0.27; 95% CI 0.09 to 0.80; p = 0.03)
    • Propensity matching was also used and found mortality to be significantly lower in ivermectin group (13.3% vs 24.5%; OR 0.47; 95% CI 0.22 to 0.99; p < 0.05) an 11.2% absolute risk reduction with a NNT of 8.9
  • Limitations:
    • Biggest limitation of this study is that patients in the Ivermectin group got steroids far more commonly than those who didn’t:
      • Unmatched Cohort: 39.8% vs 19.6%
      • Matched Cohort: 25.5% vs 21.4%
    • More of the control group was enrolled in the 1st weeks of the study suggesting a timing bias. We get better at caring for a new disease as time goes on
  • Conclusion: According to the authors, Ivermectin treatment was associated with lower mortality during treatment of COVID-19, especially in patients with severe pulmonary involvement. However more patients in the Ivermectin arm received corticosteroids than those who didn’t and the benefits seen in this trial may simply be due to this fact.

Summary of Clinical Evidence for Ivermectin Against COVID-19 [1]

Again, on the surface this looks promising, however going through the individual trials is essential, as the conclusions of any meta-analysis are only as good as the individual trials that go into it. Many of these individual trials have methodological flaws that limit the utility of this analysis.

Poorly Done Trial + Poorly Done Trial + Poorly Done Trial = Poor Conclusion

Discussion:

  • All of these trials discuss the efficacy of Ivermectin in the treatment of COVID-19 at various time points in illness, but very little was mentioned about safety
    • Due to its massive global use in low- and middle-income countries, the knowledge base establishing a high margin of safety and low rate of adverse effects is nearly unparalleled
    • Most common adverse events are mild and transient
    • Adverse effects are likely attributed to bodies inflammatory response and include itching, rash, swollen lymph nodes, joint pain, fever, and headache
    • In one trial of 17,877 patients treated with ivermectin 150mcg/kg for Loa loa in Cameroon. Only 20 patients (0.11%) developed serious reactions without neurological signs lasting for more than a week
  • The definition of insanity: Doing the same thing over and over again and expecting different results

  • ADDENDUM (12/21/2020):

    • I want to be clear about what I am saying in this post. I am not against using ivermectin but not sold on it based on the available data thus far…lots of issues that bias the results to favor ivermectin. Maybe it works or maybe it doesn’t, but I think the jury is still out at this point in time.
  • ADDENDUM (01/21/2021) – Two More Trials Sent My Way for Review

Evidence from Spain [8]

What They Did:

  • Pilot, randomized, double-blind, single-center, parallel-arm, superiority placebo-controlled trial performed in Spain
  • Evaluating single dose of ivermectin to reduce transmission of SARS-CoV-2 when administered early after disease onset
  • Consecutive patients with non-severe COVID-19 and no risk factors for complicated disease presenting to the ED
  • All enrollments occurred within 72hrs of onset of fever or cough
  • Patients randomized 1:1 to receive:
    • Ivermectin 400mcg/kg single dose
    • Placebo single doseOutcomes:
  • Primary: Proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day 7 post treatment
  • Secondary:
    • Viral load at days 4, 7, 14, and 21 post treatment
    • Proportion of patients with symptoms (fever and cough) at days 4, 7, 14, and 21 post treatment
    • Proportion of patients progressing to severe disease or death during the trial
    • Proportion of patients with seroconversion at day 21 post treatment
    • Proportion of drug-related adverse eventsInclusion:
  • Patients presenting to the ED
  • Symptoms compatible with COVID-19
  • No more than 72hrs of fever or cough
  • Positive PCR for SARS-CoV-2Exclusion:
  • Positive IgG against SARS-CoV-2
  • Comorbidities considered risk factors for severe disease
  • COVID-19 pneumonia at baselineResults:
  • 24 total patients
    • 100% had symptoms at recruitment
  • Proportion of patients with Detectable SARS-CoV-2 at Day 7 Post Treatment:
    • Ivermectin:
      • Gene N: 100%
      • Gene E: 91%
    • Placebo:
      • Gene N: 100%
      • Gene E: 100%
    • RR 0.92; 95% CI 0.77 – 1.09; p = 1.0
  • Ivermectin group had significantly lower viral loads at day 4 (3-fold lower) and day 7 (18-fold lower)
    • Confidence intervals crossed at all time points making this not statistically significant
  • Symptoms
    • Fewer days of any symptoms, however driven by anosmia/hyposmia (50% less) and cough (30% less)
    • No patients from either group progressed to severe disease
  • IgG Titers:
    • All patients in both groups seroconverted by day 21 post treatment
    • Lower IgG titers at day 21 post treatment in the ivermectin group (4.7 vs 7.5)
      • Not statistically significant
    • Safety:
      • No severe adverse events in either group
      • More dizziness and blurred vision with IvermectinStrengths:
  • Asks a clinically relevant question
  • Randomized, double-blind, placebo-controlled trial
  • All patients recruited completed the trial
  • No difference in vital signs, inflammatory markers or blood counts between groupsLimitations:
  • Small trial (n = 24 patients)
  • Surrogate soft outcomes without any patient oriented outcomes (i.e. mortality)
  • Placebo tablets did not match Ivermectin tablets which could lead to unblinding
  • Slow recruitment (24 patients over 10 weeks)
  • 94 patients assessed however many excluded due to not wanting to participate, or asymptomatic (70 patients excluded)
  • Trial too small to make any conclusions about adverse effects
  • Only included healthy patients with no comorbid diseaseDiscussion:
  • Authors were looking for a 50% reduction in the proportion of positive SARS-CoV-2. This large reduction was due to the small size of the trial.
  • Endpoint of negative PCR is not reflective of disease as patient can be fully recovered but still have enough viral material to be amplified by PCR (ie irrelevant viral material)Author Conclusion: “Among patients with non-severe COVID-19 and no risk factors for severe disease receiving a single 400mcg/kg dose of ivermectin within 72 hours of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers which warrants assessment in larger trials.”Bottom Line: Like many of the other studies reviewed on this post, the findings are interesting, however a RCT of 24 healthy patients, without comorbid disease, with no improvements in patient-oriented outcomes (i.e. mortality, progression of disease) does not justify early adoption of Ivermectin.

Evidence from India [9]

What They Did:

  • Observational study of 118 healthcare providers in Bangladesh
  • Subjects divided into:
    • Experimental: Monthly Ivermectin 12mg x4months
    • Control: No treatmentOutcomes:
  • Acquiring COVID-19Inclusion:
  • Healthcare workers working in COVID-19 isolation wards
  • Age 21 to 60 years
  • No treatment with any antiviral drugsExclusion:
  • ≥60 years of age and <21 years of age
  • Pregnant women or lactating mothers
  • Chronic liver disease
  • Symptomatically illResults:
  • 118 healthcare workers
  • COVID-19 Diagnosis:
    • Experimental: 4/58 (6.9%)
    • Control: 44/60 (73.3%)
    • P <0.05Strengths:
  • Asks a clinically important question
  • Included healthcare workers which are at high risk of COVID-19 infectionLimitations:
  • Observational not RCT, which means confounders could affect the results. For example, it is unclear what PPE was used during this study
  • Only subjects who became symptomatic were tested. It is unclear what these results would be if asymptomatic subjects were included (i.e. knowing infection rate is not clear from this data)
  • Excluded highest risk groups: age >60, liver disease, pregnant/lactating womenDiscussion:
  • INTERESTING FACT: Ivermectin has a plasma half-life of ≈16 to 18hrs with time-length ranging from 4 to 12days. The reason this is interesting is that if Ivermectin is only given 1x/month you wouldn’t have effective drug in your system after 12 days. This makes a 1x/month dosing scheme pharmacologically irrelevant for the finding
  • A 70% conversion rate is ridiculously high. This makes me question how good PPE use and availability were during this trialAuthor Conclusion: “Ivermectin, an FDA-approved, safe, cheap and widely available drug, should be subjected to large-scale trials all over the world to ascertain its effectiveness as pre-exposure prophylaxis for COVID-19.”Bottom Line: Of all the studies reviewed in this post, this is the most promising. However it’s a single center study, observational and there are a number of factors that are unknown. Given the high conversion rate in the control group, it would be important to know what level of PPE was being used and if it was different between groups. Additionally, there was no patient oriented outcomes relegating the results of this study to promising and hypothesis generating requiring larger RCTs to confirm the results.

ADDENDUM 02/05/2021 – Statement From Merck (Maker of Ivermectin) [Link is HERE]

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.

Clinical Take Home Point:

  • Evidence for the use of Ivermectin is based on in vitro, prophylaxis, clinical, safety, and large-scale epidemiologic studies (heterogenous populations in multiple different settings) BUT…
  • Many of the trials thus far are methodologically flawed without enough information about baseline demographics, multiple primary outcomes, soft/subjective outcomes, convenience samples, and unclear definitions, just to name a few
  • Additionally, a valid concern in evaluating the literature is that many of the trials have not yet passed the peer review process and are in pre-print format
  • Although Ivermectin is cheap, readily available, with a fairly safe side effect profile, based on the evaluation of the literature above, at this time, Ivermectin should not be recommended outside of a clinical trial to ensure we get a true answer of effect
  • Ivermectin is interesting, there is certainly signal to evaluate further, but in our desire to want a treatment option, let’s not continue to do the same thing over and over again, as we saw play out with Hydroxychloroquine

References:

  1. Kory P et al. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. FLCCC Alliance 2020. [Link is HERE]
  2. Caly L et al. The FDA-Approved Drug Ivermectin Inhibits the Replication of SARS-CoV-2 in Vitro. Antiviral Res 2020. PMID: 32251768
  3. Elgazzar A et al. Efficacy and Safety of Ivermectin for Treatment and Prophylaxis of COVID-19 Pandemic. Research Square 2020 Pre-Print [Link is HERE]
  4. Hellwig MD et al. A COVID-19 Prophylaxis? Lower Incidence Associated with Prophylactic Administration of Ivermectin, International Journal of Antibcrobial Agents 2020. PMID: 33259913
  5. Hashim A et al. Controlled Randomized Clinical Trial on Using Ivermectin with Doxycycline for Treating COVID-19 Patients in Baghdad, Iraq. medRxiv PrePrint 2020 [Link is HERE]
  6. Gardon J et al. Serious Reactions After Mass Treatment of Onchocerciasis with Ivermectin in an Area Endemic for Loa Loa Infection. Lancet 1997. PMID: 9217715
  7. Rajter JC et al. Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with Coronavirus Disease 2019: The ICON Study. CHEST 2020. PMID: 33065103
  8. Chaccour C et al. The Effect of Early Treatment with Ivermectin on Viral Load, Symptoms and Humoral Response in Patients with Non-Severe COVID-19: A Pilot, Double-Blind, Placebo Controlled, Randomized Clinical Trial. Lancet 2021 [Link is HERE]
  9. Alam MT et al. Ivermectin as Pre-Exposure Prophylaxis for COVID-19 Among Healthcare Providers in a Selected Tertiary Hospital in Dhaka – An Observational Study. EJMED 2020. [Link is HERE]
  10. Lopez-Medina E et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults with Mild COVID-19: A Randomized Clinical Trial. JAMA 2021. PMID: 33662102