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Pharmacometrics of high dose ivermectin in early COVID-19: an open label, randomized, controlled adaptive platform trial (PLATCOV)

Schilling et al., eLife, doi:10.7554/eLife.83201 (date from preprint), PLATCOV, NCT05041907

Jul 2022

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Ivermectin for COVID-19

4th treatment shown to reduce risk in August 2020, now with p < 0.00000000001 from 105 studies, recognized in 23 countries.

Lower risk for mortality, ventilation, ICU admission, hospitalization, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 109 treatments. c19ivm.org

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 and two cases of 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.

With rapid viral clearance and very low risk patients, infection is less likely to spread to other tissues. Systemic treatment is less applicable, and has less time to reach therapeutic concentrations before self-recovery.

Treatment administered directly to the respiratory tract, e.g. as in1-8, may be more effective for COVID-19 in general, and extend applicability to fast-resolving cases with infection primarily localized to the respiratory tract.

The following sentence in the results section, reporting on the secondary endpoint, was deleted in the journal version: "One patient in the no study drug arm was hospitalized for clinical reasons before day 28".

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 criteria9 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%).

This is the 40th of 52 COVID-19 RCTs for ivermectin, which collectively show efficacy with p=0.00000021.

This is the 89th of 105 COVID-19 controlled studies for ivermectin, which collectively show efficacy with p<0.0000000001 (1 in 774 quintillion).

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.

Important missing comments or errors? Let us know.

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

1. Albariqi et al., Pharmacokinetics and Safety of Inhaled Ivermectin in Mice as a Potential COVID-19 Treatment, International Journal of Pharmaceutics, doi:10.1016/j.ijpharm.2022.121688.sciencedirect.com, doi.org.

2. Albariqi (B) et al., Preparation and Characterization of Inhalable Ivermectin Powders as a Potential COVID-19 Therapy, Journal of Aerosol Medicine and Pulmonary Drug Delivery, doi:10.1089/jamp.2021.0059.liebertpub.com, doi.org.

3. Chaccour et al., Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats, Scientific Reports, doi:10.1038/s41598-020-74084-y.nature.com, doi.org.

4. Francés-Monerris et al., Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent, ChemRxiv, doi:10.26434/chemrxiv.12782258.v1.chemrxiv.org, doi.org.

5. Mansour et al., Safety of inhaled ivermectin as a repurposed direct drug for treatment of COVID-19: A preclinical tolerance study, International Immunopharmacology, doi:10.1016/j.intimp.2021.108004.sciencedirect.com, doi.org.

6. Elkholy et al., Ivermectin: A Closer Look at a Potential Remedy, Cureus, doi:10.7759/cureus.10378.cureus.com, doi.org.

7. Errecalde et al., Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model, Journal of Pharmaceutical Sciences, doi:10.1016/j.xphs.2021.01.017.sciencedirect.com, doi.org.

8. Aref et al., Possible Role of Ivermectin Mucoadhesive Nanosuspension Nasal Spray in Recovery of Post-COVID-19 Anosmia, Infection and Drug Resistance, doi:10.2147/IDR.S381715.dovepress.com, doi.org.

9. clinicaltrials.gov, clinicaltrials.gov/ct2/show/NCT05041907.clinicaltrials.gov/ct2/show/NCT05041907.

Schilling et al., 19 Jul 2022, Randomized Controlled Trial, Thailand, peer-reviewed, 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.

This Paper Ivermectin All

Pharmacometrics of high dose ivermectin in early COVID-19: an open label, randomized, controlled adaptive platform trial (PLATCOV)

William Hk Schilling, Podjanee Jittamala, James A Watson, Maneerat Ekkapongpisit, Tanaya Siripoon, Thundon Ngamprasertchai, Viravarn Luvira, Sasithorn Pongwilai, Cintia Cruz, James J Callery, Simon Boyd, Varaporn Kruabkontho, Thatsanun Ngernseng, Jaruwan Tubprasert, Mohammad Yazid Abdad, Nattaporn Piaraksa, Kanokon Suwannasin, Pongtorn Hanboonkunupakarn, Borimas Hanboonkunupakarn, Sakol Sookprome, Kittiyod Poovorawan, Janjira Thaipadungpanit, Stuart Blacksell, Mallika Imwong, Joel Tarning, Walter Rj Taylor, Vasin Chotivanich, Chunlanee Sangketchon, Wiroj Ruksakul, Kesinee Chotivanich, Mauro M Teixeira, Sasithon Pukrittayakamee, Arjen M Dondorp, Nicholas Pj Day, Watcharapong Piyaphanee, Weerapong Phumratanaprapin, Nicholas J White

High dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Pharmacometric evaluation of viral clearance rates based on frequent oropharyngeal sampling is a highly efficient and well-tolerated method of assessing and comparing SARS CoV-2 antiviral therapeutics in vivo.

Identifications were confirmed using Whole Genome Sequencing as below: The sequencing method carried out in this experiment follows the "PCR tiling of SARS-CoV-2 virus with rapid barcoding and Midnight RT PCR Expansion" provided by Oxford Nanopore Technology (Oxford, UK) developed based on a protocol by ARTIC network group 1 . Library preparation process started with reverse transcription, which consists of mixing the purified viral RNA with LunaScript RT SuperMix and incubating the mixtures in a thermal cycler. DNA fragments to be used in the assembly process were amplified by PCR using Midnight primer set (V3) and attached with barcodes from Rapid Barcode Plate (RB96). The mixtures from each sample were pooled together, cleaned with AMPure XP Beads (AXP) and attached with Rapid Adapter F (RAP F). The prepared DNA fragments were then loaded into a primed flow cell (FLO-MIN106) and sequenced on GridION MK1 system. Viral genome assembly and classification The output sequencing data (.fast5) from MinKNOW software was base-called with Guppy software using the High Accuracy (HAC) model to generate nucleotide sequence data for each fragment (reads) in the fastq format. These base-called data were then processed through the established workflow wf-artic on EPI2ME software to be assembled into consensus sequences. Only reads with average Phred Quality (Q) score above 9 and Adverse events (AE) and Serious Adverse Events See supplementary files for: Supplementary file..

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{ 'indexed': {'date-parts': [[2023, 2, 21]], 'date-time': '2023-02-21T05:35:51Z', 'timestamp': 1676957751211}, 'reference-count': 0, 'publisher': 'eLife Sciences Publications, Ltd', 'license': [ { 'start': { 'date-parts': [[2023, 2, 21]], 'date-time': '2023-02-21T00:00:00Z', 'timestamp': 1676937600000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'http://creativecommons.org/licenses/by/4.0/'}, { 'start': { 'date-parts': [[2023, 2, 21]], 'date-time': '2023-02-21T00:00:00Z', 'timestamp': 1676937600000}, 'content-version': 'am', 'delay-in-days': 0, 'URL': 'http://creativecommons.org/licenses/by/4.0/'}, { 'start': { 'date-parts': [[2023, 2, 21]], 'date-time': '2023-02-21T00:00:00Z', 'timestamp': 1676937600000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'http://creativecommons.org/licenses/by/4.0/'}], 'funder': [ { 'DOI': '10.13039/100010269', 'name': 'Wellcome Trust', 'doi-asserted-by': 'publisher', 'award': ['223195/Z/21/Z']}, { 'DOI': '10.13039/100010269', 'name': 'Wellcome Trust', 'doi-asserted-by': 'publisher', 'award': ['223195/Z/21/Z']}, { 'DOI': '10.13039/100010269', 'name': 'Wellcome Trust', 'doi-asserted-by': 'publisher', 'award': ['223195/Z/21/Z']}], 'content-domain': {'domain': ['elifesciences.org'], 'crossmark-restriction': False}, 'accepted': {'date-parts': [[2023, 2, 3]]}, 'abstract': 'Background: There is no generally accepted methodology for ' 'in vivo assessment of antiviral activity in SARS-CoV-2 infections. ' 'Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has ' 'clinically significant antiviral activity in vivo is ' 'uncertain.Methods: In a multicentre open label, ' 'randomized, controlled adaptive platform trial, adult patients with early symptomatic ' 'COVID-19 were randomized to one of six treatment arms including high dose oral ivermectin ' '(600µg/kg daily for seven days), the monoclonal antibodies casirivimab and imdevimab ' '(600mg/600mg), and no study drug. The primary outcome was the comparison of viral clearance ' 'rates in the modified intention-to-treat population (mITT). This was derived from daily ' 'log10 viral densities in standardized duplicate oropharyngeal swab ' 'eluates. This ongoing trial is registered at ClinicalTrials.gov ' '(NCT05041907).Results: Randomization to the ' 'ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified ' 'futility threshold was reached. Following ivermectin the mean estimated rate of SARS-CoV-2 ' 'viral clearance was 9.1% slower [95%CI -27.2% to +11.8%; n=45] than in the no drug arm ' '[n=41], whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% ' 'faster [95%CI +7.0% to +115.1%; n=10 (Delta variant) versus ' 'n=41].Conclusions: High dose ivermectin did not have ' 'measurable antiviral activity in early symptomatic COVID-19. Pharmacometric evaluation of ' 'viral clearance rate from frequent serial oropharyngeal qPCR viral density estimates is a ' 'highly efficient and well tolerated method of assessing SARS CoV-2 antiviral therapeutics ' "in vivo.Funding: 'Finding " 'treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral ' "pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)' is supported by the Wellcome Trust " 'Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics ' 'Accelerator.Clinical trial number: ClinicalTrials.gov ' '(NCT05041907).', 'DOI': '10.7554/elife.83201', 'type': 'journal-article', 'created': {'date-parts': [[2023, 2, 21]], 'date-time': '2023-02-21T00:00:54Z', 'timestamp': 1676937654000}, 'update-policy': 'http://dx.doi.org/10.7554/elife.83201', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Pharmacometrics of high dose ivermectin in early COVID-19: an open label, randomized, controlled ' 'adaptive platform trial (PLATCOV)', 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