Ivermectin-Doxycycline reduced mean time to recovery from 17.9 to 10.61d in all recruited patientsI


Ivermectin-Doxycycline reduced mean time to recovery from 17.9 to 10.61d in all recruited patientsI

gain, 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

  • We have seen the adoption of therapeutics too early during this pandemic with many of them not panning out with subsequent RCTs

  • Hydroxychloroquine is a perfect example of this:

  • In vitro studies showing decrease in viral load

  • REBEL EM: COVID-19: Clinical/Therapeutic Staging Proposal and Treatment


  • Subsequent observational trials showing associations of benefit

  • REBEL EM: COVID-19 Treatment Update: Can We Just Stop Wasting Time on Hydroxychloroquine


  • Later randomized clinical trials showing no benefit and potential harms

  • REBEL EM: Hydroxychloroquine is Ineffective for Post-Exposure Prophylaxis


  • If you believe the evidence thus far, which are severely flawed: Dosing of Ivermectin Used in Trials

  • Prophylaxis: 0.2 mg/kg on day 1 and day 3 followed by one dose/month

  • Treatment 0.2mg/kg o day 1 and day 3 followed by Days 6 and 8 if not recovered



Ivermectin-Doxycycline reduced mean time to recovery from 17.9 to 10.61d in all recruited patientsI
  • 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 dose


Outcomes:

  • 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 events


Inclusion:

  • Patients presenting to the ED

  • Symptoms compatible with COVID-19

  • No more than 72hrs of fever or cough

  • Positive PCR for SARS-CoV-2

Exclusion:

  • Positive IgG against SARS-CoV-2

  • Comorbidities considered risk factors for severe disease

  • COVID-19 pneumonia at baseline

Results:

  • 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 Ivermectin



Strengths:

  • 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 groups

Limitations:

  • 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 disease

Discussion:

  • 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)

credited to rebelem


 

 


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