Dear Editor,
A letter doesn’t permit a comprehensive review, however, health authorities from South Africa to the US FDA to the WHO have already done so. This is a follow up to my letter on June 13 as commentary points to exclusion of specific references to clinical trials that indicate limitations with existing work claiming Ivermectin works. Apparently references to detailed reviews by a huge body of scientific and medical experts across the globe from regulatory bodies is not good enough.
Most of the fervent advocates for this drug usually reference the Front Line COVID-19 Critical Care (FLCCC) Alliance (a group not without controversy themselves) so I’ve selected 3 papers (as much as the letter allows) from their website for summary, indicating limitations:
Rajter JC et al. Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with Coronavirus Disease 2019, Chest. 2021, 159:85-92
This study was a retrospective observational cohort trial of 280 consecutive patients hospitalized with COVID-19 in 4 hospitals in Florida. 173 patients were given Ivermectin (one dose of Ivermectin 200mcg/kg + standard care; a second dose of 200mcg/kg could be given on day 7 at the discretion of the treating clinician). As a negative control 107 patients were not given Ivermectin. The results with univariate analysis showed lower mortality in Ivermectin group (see paper for numbers).
Limitations: The authors concluded that Ivermectin treatment was associated with lower mortality in COVID-19 however more patients in the Ivermectin group received corticosteroids than those who didn’t and the results in this trial may simply be due to this fact; can also be interpreted as patients need more steroids. This is a huge limitation as steroids themselves reduce mortality in COVID-19 patients. This is widely known and published.
A trial with more properly designed negative controls is needed to clear up any ambiguity.
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, 2:1-6
This was an observational study of 118 healthcare workers where Ivermectin was given monthly (12mg for 4 months). The control group was not given Ivermectin. The results show that 4/58 people given the drug got COVID-19 while 44/60 people not given the drug got COVID-19.
Limitations: It’s an observational study not randomized control trial and the study group is small. Only symptomatic subjects tested so it’s unclear if asymptomatic subjects were included (so infection rate is not clear).
What the authors said: “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.”
Note: Ivermectin has a plasma half-life of ~16 to 18hrs with time-length 4 to 12 days. If it was given after 1 month there wouldn’t be an effective drug in your system after 12 days. So, 1 month dosing is not pharmacologically relevant.
Hashim A et al. Controlled Randomized Clinical Trial on Using Ivermectin with Doxycycline for Treating COVID-19 Patients in Baghdad, Iraq. medRxiv PrePrint 2020 doi: https://doi.org/10.1101/2020.10.26.20219345
Note – this is a non-peer reviewed paper.
This study was a randomized controlled trial of 140 patients at different stages of COVID-19. The experimental group comprised 70 COVID-19 patients (48 mild-moderate, 11 severe, and 11 critical patients) that were treated with 200ug/kg PO of Ivermectin for 2 to 3 days + 100mg PO doxycycline BID for 5 to 10 days + standard of care. The control group also had 70 patients (48 mild-moderate and 22 severe and zero critical patients) but they were treated with standard of care alone. The results say that Ivermectin + Doxycycline reduced mean recovery time in all recruited patients
Limitations: It’s not clear whether Ivermectin or Doxycycline is making the difference as they were given together. The study is not blinded as everyone knew what they were taking so there is room for bias here. There is no clear definition of what ‘recovery’ means making this a subjective outcome that can bias the study. Small study size.
Although I’ve only summarized three studies, this issue in controls not properly being defined is seen in many studies with Ivermectin and is emphasized by regulatory bodies and scientific advisory committees who have done comprehensive reviews. Further, data interpretation is confounded as in many instances multiple treatments are given to people infected with COVID-19. This simplified summary (see paper for more details) is written to support my point in my June 13 letter – Ivermectin is unproven, to date, for COVID-19. To be clear on my position, I work in drug and vaccine research and development and therefore am not opposed to drugs in treatment. I believe they both have a role to play, however there must be large-scale studies with very defined negative controls to show without ambiguity that this drug works at safe levels before approved for use. Large trials will also allow evaluation of the extent of adverse events. It may be proven for parasitic infections but it’s still being tested for COVID-19 a very different disease. For vaccines, although the modification to target a new variant may be fast, the modified form needs to go through Phase 1,2, 3 clinical trials all over again and data reviewed at each stage by regulatory bodies, before approval for use.
The hallmark of proof, for safety and efficacy, lies with the double-blinded placebo control phase 3 clinical trials at a large scale (Placebo-Controlled Trials of Covid-19 Vaccines — Why We Still Need Them, N Engl J Med 2021; 384:e2). For comparison, the Sputnik V and Oxford AstraZeneca vaccines’ blinded placebo-controlled phase three trials, published in peer reviewed journals, had 19866 and 11636 participants respectively in safety and efficacy testing; WHO’s review of the Sinopharm phase 3 results had 16671 participants. These vaccines are now in Phase 4 where there is a significant amount of real time data available, as millions have been vaccinated, showing safety and effectiveness and the continuous monitoring for adverse events post use. Until this standard is met for Ivermectin, it remains unproven. The same for other unproven drugs.
Sincerely,
Jacquelyn Jhingree, PhD
