Pharmacometric assessment of the <i>in vivo</i> antiviral activity of ivermectin in early symptomatic COVID-19

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

doi:10.1101/2022.07.15.22277570

Cited by 4 publications

(8 citation statements)

References 19 publications

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“…Due to the lack of early-phase studies or animal-model studies to determine optimal dosing for a therapeutic drug, the appropriate dosing of ivermectin for COVID-19 was never determined. Modeling studies and a proof-of-concept clinical study have suggested that doses up to 600 μg/kg daily may achieve levels sufficient for in vitro antiviral activity; however, a phase 2 trial testing ivermectin, 600 μg/kg daily for 7 days, and assessing a virologic end point of oropharyngeal SARS-CoV-2 polymerase chain reaction test result did not show measurable antiviral activity and was stopped for futility . With weight-based dosing, there is additional variability in the range for dosing and, in this study, the dosing per weight strata was targeted to a maximum dose of 600 μg/kg; thus, the median dose across the study population of approximately 500 μg/kg is meaningfully higher than that achieved in studies that targeted a maximum dose of 400 μg/kg.…”

Section: Discussionmentioning

confidence: 99%

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19

Naggie

Boulware

Lindsell

et al. 2023

JAMA

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ImportanceIt is unknown whether ivermectin, with a maximum targeted dose of 600 μg/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate COVID-19.ObjectiveTo evaluate the effectiveness of ivermectin at a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo, for the treatment of early mild to moderate COVID-19.Design, Setting, and ParticipantsThe ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial was designed to evaluate repurposed therapies among outpatients with mild to moderate COVID-19. A total of 1206 participants older than 30 years with confirmed COVID-19 experiencing at least 2 symptoms of acute infection for less than or equal to 7 days were enrolled at 93 sites in the US from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022.InterventionsParticipants were randomly assigned to receive ivermectin, with a maximum targeted dose of 600 μg/kg (n = 602) daily, or placebo (n = 604) for 6 days.Main Outcomes and MeasuresThe primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28.ResultsAmong 1206 randomized participants who received study medication or placebo, the median (IQR) age was 48 (38-58) years, 713 (59.1%) were women, and 1008 (83.5%) reported receiving at least 2 SARS-CoV-2 vaccine doses. The median (IQR) time to sustained recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group. The hazard ratio (posterior probability of benefit) for improvement in time to recovery was 1.02 (95% credible interval, 0.92-1.13; P = .68). Among those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (hazard ratio, 1.0 [95% credible interval, 0.6-1.5]; P = .53). In the ivermectin group, 1 participant died and 4 were hospitalized (0.8%); 2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. Adverse events were uncommon in both groups.Conclusions and RelevanceAmong outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo did not improve time to sustained recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19.Trial RegistrationClinicalTrials.gov Identifier: NCT04885530

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Section: Discussionmentioning

confidence: 99%

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19

Naggie

Boulware

Lindsell

et al. 2023

JAMA

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“…PLATCOV is an ongoing phase 2 open label, randomized, controlled adaptive platform trial (ClinicalTrials.gov: NCT05041907) designed to provide a standardized quantitative comparative method for in vivo assessment of potential antiviral treatments in low-risk adults with early symptomatic COVID-19. The primary outcome measure is the viral clearance rate derived from the slope of the log 10 oropharyngeal viral clearance curve over the first 7 days following randomization 27,28 . The treatment effect is defined as the multiplicative change in viral clearance rate relative to the no study drug arm.…”

Section: Methodsmentioning

confidence: 99%

“…The primary outcome measure was the rate of viral clearance, expressed as a slope coefficient (28), and estimated under a Bayesian hierarchical linear model fitted to the daily log 10 viral load measurements between days 0 and 7 (18 measurements per patient). The viral clearance rate (i.e.…”

Section: Outcome Measures and Statistical Analysismentioning

confidence: 99%

Clinical antiviral efficacy of remdesivir and casirivimab/imdevimab against the SARS-CoV-2 Delta and Omicron variants

Jittamala

Schilling

Watson

et al. 2022

Preprint

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Background: Uncertainty over the therapeutic benefit provided by parenteral remdesivir in COVID-19 has resulted in varying treatment guidelines. Early in the pandemic the monoclonal antibody cocktail, casirivimab/imdevimab, proved highly effective in clinical trials but because of weak or absent in vitro activity against the SARS-CoV-2 Omicron BA.1 subvariant, it is no longer recommended. Methods: In a multicenter open label, randomized, controlled adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to one of eight treatment arms including intravenous remdesivir (200mg followed by 100mg daily for five days), casirivimab/imdevimab (600mg/600mg), and no study drug. The primary outcome was the viral clearance rate in the modified intention-to-treat population derived from daily log10 viral densities (days 0-7) in standardized duplicate oropharyngeal swab eluates. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907). Results: Acceleration in mean estimated SARS-CoV-2 viral clearance, compared with the contemporaneous no study drug arm (n=64), was 42% (95%CI 18 to 73%) for remdesivir (n=67). Acceleration with casirivimab/imdevimab was 58% (95%CI: 10 to 120) in Delta (n=13), and 20% (95%CI: 3 to 43) in Omicron variant (n=61) infections compared with contemporaneous no study drug arm (n=84). In a post hoc subgroup analysis viral clearance was accelerated by 8% in BA.1 (95%CI: -21 to 59) and 23% (95%CI: 3 to 49) in BA.2 and BA.5 Omicron subvariants. Conclusions: Parenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Despite substantially reduced in vitro activities, casirivimab/imdevimab retains in vivo antiviral activity against COVID-19 infections caused by currently prevalent Omicron subvariants.

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“…17,18 Although a phase 2 trial testing ivermectin 600 µg/kg daily for 7 days and assessing a virologic endpoint of oropharyngeal SARS-CoV-2 PCR did not show measurable antiviral activity and was stopped for futility. 21 This dose was safe and generally well tolerated, with a higher prevalence of the known self-resolving visual disturbances in the intervention arm previously reported with similar doses of ivermectin for parasitic infections. 17,18 Recent results from the current platform trial reported participants receiving ivermectin, with a 400 µg/kg, daily for 3 days had a an average ~12-hour shorter time spent unwell when compared with placebo, a secondary outcome for the trial.…”

Section: Discussionmentioning

confidence: 65%

Effect of Ivermectin 600 μg/kg for 6 days vs Placebo on Time to Sustained Recovery in Outpatients with Mild to Moderate COVID-19: A Randomized Clinical Trial

Naggie¹,

Boulware²,

Lindsell³

et al. 2022

Preprint

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Background: Whether ivermectin, with a maximum targeted dose of 600 mcg/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) remains unknown. Our objective was to evaluate the effectiveness of ivermectin, dosed at 600 mcg/kg, daily for 6 days compared with placebo for the treatment of early mild to moderate COVID-19. Methods: ACTIV-6, an ongoing, decentralized, randomized, double-blind, placebo-controlled, platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1206 participants age >=30 years with confirmed COVID-19, experiencing >=2 symptoms of acute infection for <=7 days, were enrolled from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022, at 93 sites in the US. Participants were randomized to ivermectin, with a maximum targeted dose of 600 mcg/kg (n=602), daily vs. placebo daily (n=604) for 6 days. The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28. Results: Among 1206 randomized participants who received study medication or placebo, median (interquartile range) age was 48 (38-58) years; 713 (59%) were women; and 1008 (84%) reported 2 or more SARS-CoV-2 vaccine doses. Median time to recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group. The hazard ratio (HR) (95% credible interval [CrI], posterior probability of benefit) for improvement in time to recovery was 1.02 (0.92-1.13; P[HR>1]=0.68). In those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (HR 1.0, 0.6-1.5; P[HR<1]=0.53). In the ivermectin group, 1 participant died and 4 were hospitalized (0.8%); 2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. Adverse events were uncommon in both groups. Conclusions: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 mcg/kg daily for 6 days, compared with placebo did not improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19. Trial registration: ClinicalTrials.gov Identifier:NCT04885530.

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Pharmacometric assessment of the in vivo antiviral activity of ivermectin in early symptomatic COVID-19

Cited by 4 publications

References 19 publications

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19

Clinical antiviral efficacy of remdesivir and casirivimab/imdevimab against the SARS-CoV-2 Delta and Omicron variants

Effect of Ivermectin 600 μg/kg for 6 days vs Placebo on Time to Sustained Recovery in Outpatients with Mild to Moderate COVID-19: A Randomized Clinical Trial

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