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0 0.5 1 1.5 2+ Hospitalization 67% Improvement Relative Risk Progression 86% Clearance rate -9% primary c19ivermectin.com Schilling et al. NCT05041907 PLATCOV Ivermectin RCT EARLY Favors ivermectin Favors control
Schilling, 90 patient ivermectin early treatment RCT: 86% lower progression [p=0.24] and 9% worse viral clearance [p=0.36] https://c19p.org/schilling
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Pharmacometric assessment of the in-vivo antiviral activity of ivermectin in early symptomatic COVID-19
Schilling et al., medRxiv, doi:10.1101/2022.07.15.22277570 (Preprint), NCT05041907 (history)
19 Jul 2022    Source   PDF   Share   Tweet
Very high conflict of interest RCT with design optimized for a null result: very low risk patients, high existing immunity, post-hoc change to exclude patients more likely to benefit. There was no significant difference in viral clearance among low risk patients with high viral load at baseline. All 3 progression events occured in the control arm (one hospitalization, two COVID-19 related rhabdomyolysis). Patients in both arms cleared the virus quickly with a viral clearance half-life of 21.1 hours vs. 19.2 hours, which may be in part due to prior immunity.
Hypothetically, if we want to design a trial to produce a null effect on viral clearance we can:
Choose very low risk patients that typically recover quickly without any treatment.
Choose patients with high existing levels of immunity from prior infection or vaccination.
Make sure we do not test culture viability and we do not distinguish between live/inactive virus.
While we do not comment on the reason for the design, this trial does all of these and more with a post-hoc change to exclude patients from being treated early prior to high viral load:
Very low risk patients: median age 27, range 18-45, all patients recovered, no major comorbidities, control arm viral clearance half-life 0.8 days. This leaves little room for improvement, especially with an oral treatment. Results with this population have minimal relevance to real-world usage in patients at higher risk.
Patients had high existing immunity with very high vaccination levels and very high baseline antibody positive results (notably favoring the control arm with 2.2 times as many baseline antibody negative patients in the ivermectin arm).
Authors do not test culture viability, using PCR which does not distinguish between live and disabled virus.
Authors have made an additional post-hoc change in favor of finding null results. Specifically, inclusion criteria were changed from the pre-specified criteria [clinicaltrials.gov] to only include patients with very high viral load. Authors added a restriction to require PCR Ct <25 or a specific antigen test positive within 2 minutes at baseline. This minimizes the chance of including patients that may be caught early before peak viral load, i.e., patients more likely to have benefit from antiviral mechanisms of action. As shown in Figure S7, almost all patients including control patients were enrolled at peak viral load and had declining viral load from baseline. i.e., the selection criteria and population largely prevented enrolling patients earlier than the point where their immune system was already efficiently handling the virus.
Note that these methods are synergistic - for example restricting to high viral load implies greater chance of the virus spreading to more tissues, requiring longer treatment for oral ivermectin to reach therapeutic levels in those tissues, thereby reducing the chance of reaching therapeutic levels before recovery with the population of very fast recovering patients.
Notably, authors are aware that the post-hoc change favors a null result — in the discussion they note that results do not apply to prophylaxis because less potent viral suppression is needed. Similarly, the required therapeutic level may be much lower as treatment occurs earlier in the viral cycle when viral load is lower and spread to other tissues is lower.
Authors provide very little baseline information, however very large differences are seen - 10, 22, and 50% antibody negative for each arm, maximum age 31, 45, and 43. Baseline mean viral load was 1.6 times higher in the ivermectin arm vs. control arm before log conversion.
Figure 2b shows that control patients were enrolled at peak viral load, while ivermectin patients had peak load one day later. From Figure S7, this is driven by a small percentage of patients, and may be related to the 2.2x difference in baseline antibody negative results. These differences suggest a significant randomization failure in favor of the control group.
Authors provide results for only 10 of the 40 casirivimab/imdevimab patients, which do not match the other arms in terms of variants, have a much lower maximum age (31 vs. 45), and much lower antibody negative at baseline (50% versus 22%/10%).
risk of hospitalization, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 45 (0.0%), control 1 of 45 (2.2%), NNT 45, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of progression, 85.7% lower, RR 0.14, p = 0.24, treatment 0 of 45 (0.0%), control 3 of 45 (6.7%), NNT 15, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), hospitalization or progression to COVID-19 rhabdomyolysis.
relative clearance rate, 9.1% worse, RR 1.09, p = 0.36, treatment 45, control 45, primary outcome.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
This study is excluded in the after exclusion results of meta analysis: post-hoc change to exclude patients treated before high viral load, population very low risk, recovering quickly without treatment, high baseline immunity, 2.2x greater baseline antibody negative for the treatment arm.
Schilling et al., 7/19/2022, Randomized Controlled Trial, Thailand, preprint, median age 27.0, 38 authors, study period 30 September, 2021 - 18 April, 2022, average treatment delay 2.0 days, dosage 600μg/kg days 1-7, trial NCT05041907 (history) (PLATCOV).
Contact: william@tropmedres.ac, nickw@tropmedres.ac.
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