Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial
Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in out...
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| Veröffentlicht in: | The Lancet infectious diseases 2020-10, Vol.20 (10), p.1204-1214 |
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| creator | Ison, Michael G Portsmouth, Simon Yoshida, Yuki Shishido, Takao Mitchener, Melissa Tsuchiya, Kenji Uehara, Takeki Hayden, Frederick G |
| description | Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications.
We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight ( |
| doi_str_mv | 10.1016/S1473-3099(20)30004-9 |
| format | Article |
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We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (<80 kg vs ≥80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011.
2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73·2 h [95% CI 67·2 to 85·1]) than in the placebo group (102·3 h [92·7 to 113·1]; difference 29·1 h [95% CI 14·6 to 42·8]; p<0·0001). The median TTIIS in the oseltamivir group was 81·0 h (95% CI 69·4 to 91·5), with a difference from the baloxavir group of 7·7 h (−7·9 to 22·7). Adverse events were reported in 183 (25%) of 730 patients in the baloxavir group, 216 (30%) of 727 in the placebo group, and 202 (28%) of 721 in the oseltamivir group. Serious adverse events were noted in five patients in the baloxavir group, nine patients in the placebo group, and eight patients in the oseltamivir group; one case each of hypertension and nausea in the placebo group and two cases of transaminase elevation in the oseltamivir group were considered to be treatment related. Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus.
Single-dose baloxavir has superior efficacy to placebo and similar efficacy to oseltamivir for ameliorating influenza symptoms in high-risk outpatients. The safety of baloxavir was comparable to placebo. This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications.
Shionogi.</description><identifier>ISSN: 1473-3099</identifier><identifier>EISSN: 1474-4457</identifier><identifier>DOI: 10.1016/S1473-3099(20)30004-9</identifier><language>eng</language><publisher>London: Elsevier Ltd</publisher><subject>Amino acids ; Antiviral drugs ; Bacterial infections ; Clinical trials ; Drug dosages ; Endonuclease ; Hypertension ; Illnesses ; Infections ; Infectious diseases ; Influenza ; Influenza A ; Influenza B ; Interactive systems ; Mixed infection ; Mortality ; Nausea ; Oseltamivir ; Patients ; Polymerase chain reaction ; Risk analysis ; Risk factors ; Safety ; Skin cancer ; Southern Hemisphere ; Transaminase ; Viruses ; Weighing ; Weight</subject><ispartof>The Lancet infectious diseases, 2020-10, Vol.20 (10), p.1204-1214</ispartof><rights>2020 Elsevier Ltd</rights><rights>2020. Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c368t-c1f0814575054ba14bd98cf6d00d1e2f92d1f98eda5881a277a13fc1d411afb03</citedby><cites>FETCH-LOGICAL-c368t-c1f0814575054ba14bd98cf6d00d1e2f92d1f98eda5881a277a13fc1d411afb03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1473309920300049$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids></links><search><creatorcontrib>Ison, Michael G</creatorcontrib><creatorcontrib>Portsmouth, Simon</creatorcontrib><creatorcontrib>Yoshida, Yuki</creatorcontrib><creatorcontrib>Shishido, Takao</creatorcontrib><creatorcontrib>Mitchener, Melissa</creatorcontrib><creatorcontrib>Tsuchiya, Kenji</creatorcontrib><creatorcontrib>Uehara, Takeki</creatorcontrib><creatorcontrib>Hayden, Frederick G</creatorcontrib><title>Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial</title><title>The Lancet infectious diseases</title><description>Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications.
We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (<80 kg vs ≥80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011.
2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73·2 h [95% CI 67·2 to 85·1]) than in the placebo group (102·3 h [92·7 to 113·1]; difference 29·1 h [95% CI 14·6 to 42·8]; p<0·0001). The median TTIIS in the oseltamivir group was 81·0 h (95% CI 69·4 to 91·5), with a difference from the baloxavir group of 7·7 h (−7·9 to 22·7). Adverse events were reported in 183 (25%) of 730 patients in the baloxavir group, 216 (30%) of 727 in the placebo group, and 202 (28%) of 721 in the oseltamivir group. Serious adverse events were noted in five patients in the baloxavir group, nine patients in the placebo group, and eight patients in the oseltamivir group; one case each of hypertension and nausea in the placebo group and two cases of transaminase elevation in the oseltamivir group were considered to be treatment related. Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus.
Single-dose baloxavir has superior efficacy to placebo and similar efficacy to oseltamivir for ameliorating influenza symptoms in high-risk outpatients. The safety of baloxavir was comparable to placebo. This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications.
Shionogi.</description><subject>Amino acids</subject><subject>Antiviral drugs</subject><subject>Bacterial infections</subject><subject>Clinical trials</subject><subject>Drug dosages</subject><subject>Endonuclease</subject><subject>Hypertension</subject><subject>Illnesses</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Influenza</subject><subject>Influenza A</subject><subject>Influenza B</subject><subject>Interactive systems</subject><subject>Mixed infection</subject><subject>Mortality</subject><subject>Nausea</subject><subject>Oseltamivir</subject><subject>Patients</subject><subject>Polymerase chain reaction</subject><subject>Risk analysis</subject><subject>Risk factors</subject><subject>Safety</subject><subject>Skin cancer</subject><subject>Southern Hemisphere</subject><subject>Transaminase</subject><subject>Viruses</subject><subject>Weighing</subject><subject>Weight</subject><issn>1473-3099</issn><issn>1474-4457</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>BENPR</sourceid><recordid>eNqFkc2KFDEUhQtRcBx9BCEgSA9YmqRSf26kadofGBxhxnW4ldzqzpiu1CSpscen8hFNdbly4yrJ4buHc3Oy7CWjbxll1btrJuoiL2jbrji9KCilIm8fZWdJFrkQZf34dF-Qp9mzEG4pZTWj4iz7vQVvH0j0CPGAQyQ_TdyTDqw7wr3x5AC-c0djiRnI3uz2uTfhBwHtLAY18zDo9JxsJG6KI0STxLC4TINyh9EaBRF1MujthMMvIKvN-tv1zdXXbc4v3hMgPnm4gwmo35DRgsLO5coN0TtrT9oeApIihTRgn2dPerABX_w9z7PvH7c3m8_55dWnL5v1Za6Kqom5Yj1tWNq9pKXogIlOt43qK02pZsj7lmvWtw1qKJuGAa9rYEWvmBaMQd_R4jxbLb6jd3cThihTQoXWwoBuCpILxtumKWuR0Ff_oLdu8kNKlyhRFowWoknU64XagUVphnlDPMYdTCFIua4E5SVn1QyWC6i8C8FjL0dvUg8PklE5Fy5Phcu5TcmpPBUu2zT3YZnD9C33Br0MKrWhUBuPKkrtzH8c_gAt6bOj</recordid><startdate>202010</startdate><enddate>202010</enddate><creator>Ison, Michael G</creator><creator>Portsmouth, Simon</creator><creator>Yoshida, Yuki</creator><creator>Shishido, Takao</creator><creator>Mitchener, Melissa</creator><creator>Tsuchiya, Kenji</creator><creator>Uehara, Takeki</creator><creator>Hayden, Frederick G</creator><general>Elsevier Ltd</general><general>Elsevier B.V</general><general>Elsevier Limited</general><scope>AAYXX</scope><scope>CITATION</scope><scope>0TZ</scope><scope>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8C2</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope></search><sort><creationdate>202010</creationdate><title>Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial</title><author>Ison, Michael G ; Portsmouth, Simon ; Yoshida, Yuki ; Shishido, Takao ; Mitchener, Melissa ; Tsuchiya, Kenji ; Uehara, Takeki ; Hayden, Frederick G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c368t-c1f0814575054ba14bd98cf6d00d1e2f92d1f98eda5881a277a13fc1d411afb03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Amino acids</topic><topic>Antiviral drugs</topic><topic>Bacterial infections</topic><topic>Clinical trials</topic><topic>Drug dosages</topic><topic>Endonuclease</topic><topic>Hypertension</topic><topic>Illnesses</topic><topic>Infections</topic><topic>Infectious diseases</topic><topic>Influenza</topic><topic>Influenza A</topic><topic>Influenza B</topic><topic>Interactive systems</topic><topic>Mixed infection</topic><topic>Mortality</topic><topic>Nausea</topic><topic>Oseltamivir</topic><topic>Patients</topic><topic>Polymerase chain reaction</topic><topic>Risk analysis</topic><topic>Risk factors</topic><topic>Safety</topic><topic>Skin cancer</topic><topic>Southern Hemisphere</topic><topic>Transaminase</topic><topic>Viruses</topic><topic>Weighing</topic><topic>Weight</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ison, Michael G</creatorcontrib><creatorcontrib>Portsmouth, Simon</creatorcontrib><creatorcontrib>Yoshida, Yuki</creatorcontrib><creatorcontrib>Shishido, Takao</creatorcontrib><creatorcontrib>Mitchener, Melissa</creatorcontrib><creatorcontrib>Tsuchiya, Kenji</creatorcontrib><creatorcontrib>Uehara, Takeki</creatorcontrib><creatorcontrib>Hayden, Frederick G</creatorcontrib><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Lancet Titles</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><jtitle>The Lancet infectious diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ison, Michael G</au><au>Portsmouth, Simon</au><au>Yoshida, Yuki</au><au>Shishido, Takao</au><au>Mitchener, Melissa</au><au>Tsuchiya, Kenji</au><au>Uehara, Takeki</au><au>Hayden, Frederick G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial</atitle><jtitle>The Lancet infectious diseases</jtitle><date>2020-10</date><risdate>2020</risdate><volume>20</volume><issue>10</issue><spage>1204</spage><epage>1214</epage><pages>1204-1214</pages><issn>1473-3099</issn><eissn>1474-4457</eissn><abstract>Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications.
We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (<80 kg vs ≥80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011.
2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73·2 h [95% CI 67·2 to 85·1]) than in the placebo group (102·3 h [92·7 to 113·1]; difference 29·1 h [95% CI 14·6 to 42·8]; p<0·0001). The median TTIIS in the oseltamivir group was 81·0 h (95% CI 69·4 to 91·5), with a difference from the baloxavir group of 7·7 h (−7·9 to 22·7). Adverse events were reported in 183 (25%) of 730 patients in the baloxavir group, 216 (30%) of 727 in the placebo group, and 202 (28%) of 721 in the oseltamivir group. Serious adverse events were noted in five patients in the baloxavir group, nine patients in the placebo group, and eight patients in the oseltamivir group; one case each of hypertension and nausea in the placebo group and two cases of transaminase elevation in the oseltamivir group were considered to be treatment related. Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus.
Single-dose baloxavir has superior efficacy to placebo and similar efficacy to oseltamivir for ameliorating influenza symptoms in high-risk outpatients. The safety of baloxavir was comparable to placebo. This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications.
Shionogi.</abstract><cop>London</cop><pub>Elsevier Ltd</pub><doi>10.1016/S1473-3099(20)30004-9</doi><tpages>11</tpages></addata></record> |
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| source | Elsevier ScienceDirect Journals |
| subjects | Amino acids Antiviral drugs Bacterial infections Clinical trials Drug dosages Endonuclease Hypertension Illnesses Infections Infectious diseases Influenza Influenza A Influenza B Interactive systems Mixed infection Mortality Nausea Oseltamivir Patients Polymerase chain reaction Risk analysis Risk factors Safety Skin cancer Southern Hemisphere Transaminase Viruses Weighing Weight |
| title | Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial |
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