Pub Date : 2021-11-01DOI: 10.1136/thorax-2021-btsabstracts.55
Z. Temesgen, C. Burger, J. Baker, C. Polk, C. Libertin, C. Kelley, VC Marconi, R. Orenstein, VM Catterson, W. Aronstein, C. Durrant, D. Chappell, O. Ahmed, G. Chappell, A. Badley
BackgroundThe hyperinflammatory cytokine storm (CS) of COVID-19 is mediated by GM-CSF leading to release of downstream inflammatory chemokines, cytokines, and markers of systemic inflammation (C-reactive protein, CRP). The LIVE-AIR study demonstrated that lenzilumab, an anti-GM-CSF monoclonal antibody in patients hospitalized with COVID-19, safely improved the likelihood of achieving the primary endpoint, survival without ventilation (SWOV) by 1.54-fold (HR: 1.54;95%CI: 1.02–2.32, p=0.0403) compared with placebo. An exploratory analysis in patients with CRP<150 mg/L and age<85 years was conducted to determine lenzilumab efficacy when administered prior to advanced inflammation.MethodsLIVE-AIR was a phase 3 randomized, double-blind, placebo-controlled trial. Patients with COVID-19 (n=520), >18 years, and ≤94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation (IMV), were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Participants were followed through Day 28 following treatment.ResultsOverall, baseline demographics were comparable between treatment groups: male, 64.7%;mean age, 60.5 years;mean BMI, 32.5 kg/m2;median CRP, 79 mg/L;CRP was <150 mg/L in 78% of participants. Participants received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab (n=159) improved the likelihood of SWOV by 3.04-fold in participants with CRP<150 mg/L and age<85 years (3.04;1.68–5.51, nominal p=0.0003) compared with placebo (n=178). Response to lenzilumab was observed in the first through third quartiles of baseline CRP (<41 mg/L, HR:8.33;41<79 mg/L, HR:1.60;79<137 mg/L, HR: 2.12;>137 mg/L, HR: 1.17). The incidence of IMV, ECMO, or death was reduced (OR: 0.31;95%CI: 0.15–0.63, p=0.002) and mortality was improved by 2.22-fold (OR: 2.22;95%CI: 1.07–4.67, p=0.034). In these participants, lenzilumab decreased CRP as early as Day 2 following treatment, compared with placebo which was further decreased by 38% on Day 28 compared with placebo (24.4±3.4 mg/L vs 39.1±4.9 mg/L).ConclusionLenzilumab significantly improved SWOV in hospitalized, hypoxic participants with COVID-19 pneumonia with the greatest benefits in SWOV and survival in patients with CRP<150 mg/L and age <85 years. Inhibition of GM-CSF, an orchestrator of CS, early in the hyperinflammatory response improved outcomes in COVID-19. NCT04351152
{"title":"S49 C-reactive protein as a biomarker for improved efficacy of lenzilumab in Covid-19 patients: results from the LIVE-AIR trial","authors":"Z. Temesgen, C. Burger, J. Baker, C. Polk, C. Libertin, C. Kelley, VC Marconi, R. Orenstein, VM Catterson, W. Aronstein, C. Durrant, D. Chappell, O. Ahmed, G. Chappell, A. Badley","doi":"10.1136/thorax-2021-btsabstracts.55","DOIUrl":"https://doi.org/10.1136/thorax-2021-btsabstracts.55","url":null,"abstract":"BackgroundThe hyperinflammatory cytokine storm (CS) of COVID-19 is mediated by GM-CSF leading to release of downstream inflammatory chemokines, cytokines, and markers of systemic inflammation (C-reactive protein, CRP). The LIVE-AIR study demonstrated that lenzilumab, an anti-GM-CSF monoclonal antibody in patients hospitalized with COVID-19, safely improved the likelihood of achieving the primary endpoint, survival without ventilation (SWOV) by 1.54-fold (HR: 1.54;95%CI: 1.02–2.32, p=0.0403) compared with placebo. An exploratory analysis in patients with CRP<150 mg/L and age<85 years was conducted to determine lenzilumab efficacy when administered prior to advanced inflammation.MethodsLIVE-AIR was a phase 3 randomized, double-blind, placebo-controlled trial. Patients with COVID-19 (n=520), >18 years, and ≤94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation (IMV), were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Participants were followed through Day 28 following treatment.ResultsOverall, baseline demographics were comparable between treatment groups: male, 64.7%;mean age, 60.5 years;mean BMI, 32.5 kg/m2;median CRP, 79 mg/L;CRP was <150 mg/L in 78% of participants. Participants received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab (n=159) improved the likelihood of SWOV by 3.04-fold in participants with CRP<150 mg/L and age<85 years (3.04;1.68–5.51, nominal p=0.0003) compared with placebo (n=178). Response to lenzilumab was observed in the first through third quartiles of baseline CRP (<41 mg/L, HR:8.33;41<79 mg/L, HR:1.60;79<137 mg/L, HR: 2.12;>137 mg/L, HR: 1.17). The incidence of IMV, ECMO, or death was reduced (OR: 0.31;95%CI: 0.15–0.63, p=0.002) and mortality was improved by 2.22-fold (OR: 2.22;95%CI: 1.07–4.67, p=0.034). In these participants, lenzilumab decreased CRP as early as Day 2 following treatment, compared with placebo which was further decreased by 38% on Day 28 compared with placebo (24.4±3.4 mg/L vs 39.1±4.9 mg/L).ConclusionLenzilumab significantly improved SWOV in hospitalized, hypoxic participants with COVID-19 pneumonia with the greatest benefits in SWOV and survival in patients with CRP<150 mg/L and age <85 years. Inhibition of GM-CSF, an orchestrator of CS, early in the hyperinflammatory response improved outcomes in COVID-19. NCT04351152","PeriodicalId":114929,"journal":{"name":"Developing treatments for COVID-19","volume":"20 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126497629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-11-01DOI: 10.1136/thorax-2021-btsabstracts.59
S. Waring, G. Gamtkitsulashvili, S. Kumar, Y. Narayan, A. D'Souza, S. Jiwani, O. Taylor, G. Collins, K. Patrick, A. Sethuraman, S. Naik, S. Kuckreja, R. Ragatha, M. Anwar, U. Ekeowa, P. Russell
S53 Figure 1Rates of mortality against cumulative number of antibiotics received per patient during inpatient spell.[Figure omitted. See PDF]ConclusionIn both COVID-19 waves, antibiotic administration correlated to increased inpatient morbidity and mortality. Given a near-linear relationship of mortality and cumulative antibiotic numbers, antimicrobial stewardship is essential, and tapering an appropriate therapy for likely responsible pathogens will yield lower mortality compared to overlapping coverage and inappropriate escalation. We strongly discourage the use of empirical antibiotics without supporting biochemical evidence of bacterial co-infection for possible future COVID-19 waves.ReferenceRussell C, et al. Lancet Microbe. 2021 Jun 2. https://doi.org/10.1016/S2666-5247(21)00090-2
{"title":"S53 Impact of empirical antibiotic use in patients with COVID-19 on morbidity and mortality during the first and second UK SARS-CoV-2 waves","authors":"S. Waring, G. Gamtkitsulashvili, S. Kumar, Y. Narayan, A. D'Souza, S. Jiwani, O. Taylor, G. Collins, K. Patrick, A. Sethuraman, S. Naik, S. Kuckreja, R. Ragatha, M. Anwar, U. Ekeowa, P. Russell","doi":"10.1136/thorax-2021-btsabstracts.59","DOIUrl":"https://doi.org/10.1136/thorax-2021-btsabstracts.59","url":null,"abstract":"S53 Figure 1Rates of mortality against cumulative number of antibiotics received per patient during inpatient spell.[Figure omitted. See PDF]ConclusionIn both COVID-19 waves, antibiotic administration correlated to increased inpatient morbidity and mortality. Given a near-linear relationship of mortality and cumulative antibiotic numbers, antimicrobial stewardship is essential, and tapering an appropriate therapy for likely responsible pathogens will yield lower mortality compared to overlapping coverage and inappropriate escalation. We strongly discourage the use of empirical antibiotics without supporting biochemical evidence of bacterial co-infection for possible future COVID-19 waves.ReferenceRussell C, et al. Lancet Microbe. 2021 Jun 2. https://doi.org/10.1016/S2666-5247(21)00090-2","PeriodicalId":114929,"journal":{"name":"Developing treatments for COVID-19","volume":"3 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133943797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-11-01DOI: 10.1136/thorax-2021-btsabstracts.56
T. Hinks, L. Cureton, R. Knight, A. Wang, J. Cane, VS Barber, J. Black, SJ Dutton, J. Melhorn, M. Jabeen, P. Moss, R. Garlapati, T. Baron, G. Johnson, F. Cantle, D. Clarke, S. Elkhodair, J. Underwood, D. Lasserson, I. Pavord, SB Morgan, D. Richards
{"title":"S50 A randomised clinical trial of azithromycin versus standard care in ambulatory COVID-19 – the ATOMIC2 trial","authors":"T. Hinks, L. Cureton, R. Knight, A. Wang, J. Cane, VS Barber, J. Black, SJ Dutton, J. Melhorn, M. Jabeen, P. Moss, R. Garlapati, T. Baron, G. Johnson, F. Cantle, D. Clarke, S. Elkhodair, J. Underwood, D. Lasserson, I. Pavord, SB Morgan, D. Richards","doi":"10.1136/thorax-2021-btsabstracts.56","DOIUrl":"https://doi.org/10.1136/thorax-2021-btsabstracts.56","url":null,"abstract":"","PeriodicalId":114929,"journal":{"name":"Developing treatments for COVID-19","volume":"69 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125066057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-11-01DOI: 10.1136/thorax-2021-btsabstracts.54
Z. Temesgen, C. Burger, J. Baker, C. Polk, C. Libertin, C. Kelley, VC Marconi, R. Orenstein, VM Catterson, W. Aronstein, C. Durrant, D. Chappell, O. Ahmed, G. Chappell, A. Badley
{"title":"S48 Lenzilumab efficacy and safety in newly hospitalized Covid-19 subjects: results from the LIVE-AIR phase 3 randomized double-blind placebo-controlled trial","authors":"Z. Temesgen, C. Burger, J. Baker, C. Polk, C. Libertin, C. Kelley, VC Marconi, R. Orenstein, VM Catterson, W. Aronstein, C. Durrant, D. Chappell, O. Ahmed, G. Chappell, A. Badley","doi":"10.1136/thorax-2021-btsabstracts.54","DOIUrl":"https://doi.org/10.1136/thorax-2021-btsabstracts.54","url":null,"abstract":"","PeriodicalId":114929,"journal":{"name":"Developing treatments for COVID-19","volume":"12 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114184976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-11-01DOI: 10.1136/thorax-2021-btsabstracts.57
A. Kilcoyne, E. Jordan, C. Durrant, D. Chappell, O. Ahmed
BackgroundCOVID-19 has driven innovation leading to emergency use authorization of treatments that address its urgent healthcare needs. However, physicians, payers and healthcare systems are challenged to select among these novel treatments for both effectiveness and value. Reliance on change in relative, rather than absolute, risk often makes discrimination of treatment effects between medications impractical, with potentially misleading conclusions. Number Needed to Treat (NNT), the reciprocal of the Absolute Risk Reduction, can be a valuable alternative in assessing benefit:risk. The objective of the current analysis was to calculate NNT for reported endpoints of COVID-19 treatments.MethodsClinical information was captured from published literature and pre-prints from investigations of COVID-19 treatments. NNTs were calculated for reported endpoints. Outpatient treatments to reduce viral load included neutralizing antibody ‘cocktails’ REGN-COV21 and bamlanivimab/etesevimab.2 Inpatient treatments included the anti-viral: remdesivir 3,4;and immune modulators: baricitinib5, and lenzilumab.6ResultsREGN-COV2 reduced the number of medically attended visits with NNT of 33.3. The NNT for hospitalization or death was 20 for bamlanivimab/etesevimab. NNTs for 28-day mortality with inpatient treatment were 37 for baricitinib, 26.3 for remdesivir alone, and 22.7 for lenzilumab. Additional analyses of lenzilumab resulted in NNT of 14.7 when combined with remdesivir and corticosteroids, 15.4 when combined with remdesivir, and 13.9 in patients with baseline CRP<150mg/L and age<85 years. The NNT for lenzilumab to prevent survival without ventilation (SWOV) was 15.4 which, decreased to 6.4 in patients with baseline CRP<150mg/L and age<85 years. The number needed to prevent a serious adverse event was 20 for baricitinib, 15 for remdesivir, and 20.4 for lenzilumab.ConclusionThe NNT for COVID-19 treatments varied with setting, endpoint, and mechanism. The NNT for lenzilumab improved with refinement of concomitant medications and patient phenotype. NNT provides a simple measure for comparative analyses that helps inform clinical decision-making and resource allocation.ReferencesWeinreich, et al. N Engl J Med 2021;384:238–51.Gottlieb, et al. JAMA 2021;325:632–44.Garibaldi, et al. JAMA NetwOpen 2021;4:e213071.Beigel, et al. N Engl J Med 2020;383:1813–26.Kalil, et al. N Engl J Med 2020.Temesgen, et al. medRxiv 2021.
{"title":"S51 Evaluation of treatment approaches for hospitalized Covid-19 patients","authors":"A. Kilcoyne, E. Jordan, C. Durrant, D. Chappell, O. Ahmed","doi":"10.1136/thorax-2021-btsabstracts.57","DOIUrl":"https://doi.org/10.1136/thorax-2021-btsabstracts.57","url":null,"abstract":"BackgroundCOVID-19 has driven innovation leading to emergency use authorization of treatments that address its urgent healthcare needs. However, physicians, payers and healthcare systems are challenged to select among these novel treatments for both effectiveness and value. Reliance on change in relative, rather than absolute, risk often makes discrimination of treatment effects between medications impractical, with potentially misleading conclusions. Number Needed to Treat (NNT), the reciprocal of the Absolute Risk Reduction, can be a valuable alternative in assessing benefit:risk. The objective of the current analysis was to calculate NNT for reported endpoints of COVID-19 treatments.MethodsClinical information was captured from published literature and pre-prints from investigations of COVID-19 treatments. NNTs were calculated for reported endpoints. Outpatient treatments to reduce viral load included neutralizing antibody ‘cocktails’ REGN-COV21 and bamlanivimab/etesevimab.2 Inpatient treatments included the anti-viral: remdesivir 3,4;and immune modulators: baricitinib5, and lenzilumab.6ResultsREGN-COV2 reduced the number of medically attended visits with NNT of 33.3. The NNT for hospitalization or death was 20 for bamlanivimab/etesevimab. NNTs for 28-day mortality with inpatient treatment were 37 for baricitinib, 26.3 for remdesivir alone, and 22.7 for lenzilumab. Additional analyses of lenzilumab resulted in NNT of 14.7 when combined with remdesivir and corticosteroids, 15.4 when combined with remdesivir, and 13.9 in patients with baseline CRP<150mg/L and age<85 years. The NNT for lenzilumab to prevent survival without ventilation (SWOV) was 15.4 which, decreased to 6.4 in patients with baseline CRP<150mg/L and age<85 years. The number needed to prevent a serious adverse event was 20 for baricitinib, 15 for remdesivir, and 20.4 for lenzilumab.ConclusionThe NNT for COVID-19 treatments varied with setting, endpoint, and mechanism. The NNT for lenzilumab improved with refinement of concomitant medications and patient phenotype. NNT provides a simple measure for comparative analyses that helps inform clinical decision-making and resource allocation.ReferencesWeinreich, et al. N Engl J Med 2021;384:238–51.Gottlieb, et al. JAMA 2021;325:632–44.Garibaldi, et al. JAMA NetwOpen 2021;4:e213071.Beigel, et al. N Engl J Med 2020;383:1813–26.Kalil, et al. N Engl J Med 2020.Temesgen, et al. medRxiv 2021.","PeriodicalId":114929,"journal":{"name":"Developing treatments for COVID-19","volume":"2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132978789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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