Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents
BACKGROUND: Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.
METHODS: We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.
RESULTS: In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.
CONCLUSIONS: Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354 .).
| Errataetall: |
CommentIn: N Engl J Med. 2018 Sep 6;379(10):975-977. - PMID 30184452 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:379 |
|---|---|
| Enthalten in: |
The New England journal of medicine - 379(2018), 10 vom: 06. Sept., Seite 913-923 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hayden, Frederick G [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.10.2018 Date Revised 08.04.2022 published: Print ClinicalTrials.gov: NCT02954354 CommentIn: N Engl J Med. 2018 Sep 6;379(10):975-977. - PMID 30184452 Citation Status MEDLINE |
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| doi: |
10.1056/NEJMoa1716197 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents |
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| 500 | |a Date Revised 08.04.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT02954354 | ||
| 500 | |a CommentIn: N Engl J Med. 2018 Sep 6;379(10):975-977. - PMID 30184452 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents | ||
| 520 | |a METHODS: We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population | ||
| 520 | |a RESULTS: In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively | ||
| 520 | |a CONCLUSIONS: Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354 .) | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Clinical Trial, Phase III | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Dibenzothiepins |2 NLM | |
| 650 | 7 | |a Morpholines |2 NLM | |
| 650 | 7 | |a Oxazines |2 NLM | |
| 650 | 7 | |a Pyridines |2 NLM | |
| 650 | 7 | |a Pyridones |2 NLM | |
| 650 | 7 | |a Thiepins |2 NLM | |
| 650 | 7 | |a Triazines |2 NLM | |
| 650 | 7 | |a Oseltamivir |2 NLM | |
| 650 | 7 | |a 20O93L6F9H |2 NLM | |
| 650 | 7 | |a baloxavir |2 NLM | |
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| 650 | 7 | |a Endonucleases |2 NLM | |
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| 700 | 1 | |a Sugaya, Norio |e verfasserin |4 aut | |
| 700 | 1 | |a Hirotsu, Nobuo |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Nelson |e verfasserin |4 aut | |
| 700 | 1 | |a de Jong, Menno D |e verfasserin |4 aut | |
| 700 | 1 | |a Hurt, Aeron C |e verfasserin |4 aut | |
| 700 | 1 | |a Ishida, Tadashi |e verfasserin |4 aut | |
| 700 | 1 | |a Sekino, Hisakuni |e verfasserin |4 aut | |
| 700 | 1 | |a Yamada, Kota |e verfasserin |4 aut | |
| 700 | 1 | |a Portsmouth, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Kawaguchi, Keiko |e verfasserin |4 aut | |
| 700 | 1 | |a Shishido, Takao |e verfasserin |4 aut | |
| 700 | 1 | |a Arai, Masatsugu |e verfasserin |4 aut | |
| 700 | 1 | |a Tsuchiya, Kenji |e verfasserin |4 aut | |
| 700 | 1 | |a Uehara, Takeki |e verfasserin |4 aut | |
| 700 | 1 | |a Watanabe, Akira |e verfasserin |4 aut | |
| 700 | 0 | |a Baloxavir Marboxil Investigators Group |e verfasserin |4 aut | |
| 700 | 1 | |a Arahata, Masahisa |e investigator |4 oth | |
| 700 | 1 | |a Doi, Takahito |e investigator |4 oth | |
| 700 | 1 | |a Fujishima, Hiromitsu |e investigator |4 oth | |
| 700 | 1 | |a Fukuyo, Kensuke |e investigator |4 oth | |
| 700 | 1 | |a Hachinohe, Hiroshi |e investigator |4 oth | |
| 700 | 1 | |a Harada, Hiroshi |e investigator |4 oth | |
| 700 | 1 | |a Harada, Yuji |e investigator |4 oth | |
| 700 | 1 | |a Hatakeyama, Sadamune |e investigator |4 oth | |
| 700 | 1 | |a Hisadome, Tetsuo |e investigator |4 oth | |
| 700 | 1 | |a Horikawa, Isao |e investigator |4 oth | |
| 700 | 1 | |a Ikeda, Mitsumi |e investigator |4 oth | |
| 700 | 1 | |a Ishikawa, Takayuki |e investigator |4 oth | |
| 700 | 1 | |a Ito, Junichi |e investigator |4 oth | |
| 700 | 1 | |a Iwaki, Norio |e investigator |4 oth | |
| 700 | 1 | |a Kanemitsu, Hiroyoshi |e investigator |4 oth | |
| 700 | 1 | |a Kinoshita, Masaharu |e investigator |4 oth | |
| 700 | 1 | |a Kitada, Hirokazu |e investigator |4 oth | |
| 700 | 1 | |a Kokubun, Takehiko |e investigator |4 oth | |
| 700 | 1 | |a Komo, Tomoyuki |e investigator |4 oth | |
| 700 | 1 | |a Kuroki, Haruo |e investigator |4 oth | |
| 700 | 1 | |a Matsunaga, Atsushi |e investigator |4 oth | |
| 700 | 1 | |a Mitani, Ikuo |e investigator |4 oth | |
| 700 | 1 | |a Miyazono, Hirotaka |e investigator |4 oth | |
| 700 | 1 | |a Morizono, Shigeaki |e investigator |4 oth | |
| 700 | 1 | |a Murakawa, Hisashi |e investigator |4 oth | |
| 700 | 1 | |a Nagumo, Akihiko |e investigator |4 oth | |
| 700 | 1 | |a Nakama, Seitaro |e investigator |4 oth | |
| 700 | 1 | |a Nakazato, Hidehisa |e investigator |4 oth | |
| 700 | 1 | |a Nemoto, Satohiko |e investigator |4 oth | |
| 700 | 1 | |a Noguchi, Yoshimasa |e investigator |4 oth | |
| 700 | 1 | |a Ogasawara, Tadahiko |e investigator |4 oth | |
| 700 | 1 | |a Ogawa, Jun |e investigator |4 oth | |
| 700 | 1 | |a Okawa, Hiroji |e investigator |4 oth | |
| 700 | 1 | |a Okumura, Haruhiko |e investigator |4 oth | |
| 700 | 1 | |a Owada, Yasuko |e investigator |4 oth | |
| 700 | 1 | |a Sadanaga, Yasuaki |e investigator |4 oth | |
| 700 | 1 | |a Sasaki, Ryotaro |e investigator |4 oth | |
| 700 | 1 | |a Sasho, Hideyuki |e investigator |4 oth | |
| 700 | 1 | |a Satake, Kazuo |e investigator |4 oth | |
| 700 | 1 | |a Seki, Masahiko |e investigator |4 oth | |
| 700 | 1 | |a Shudo, Hiroshi |e investigator |4 oth | |
| 700 | 1 | |a Sugimoto, Masayuki |e investigator |4 oth | |
| 700 | 1 | |a Taguchi, Fumihiro |e investigator |4 oth | |
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| 700 | 1 | |a Takei, Jiro |e investigator |4 oth | |
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| 700 | 1 | |a Tanaka, Hiroaki |e investigator |4 oth | |
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| 700 | 1 | |a Tanaka, Shinichi |e investigator |4 oth | |
| 700 | 1 | |a Tomori, Hiroaki |e investigator |4 oth | |
| 700 | 1 | |a Uehara, Akira |e investigator |4 oth | |
| 700 | 1 | |a Ueyama, Sigehiro |e investigator |4 oth | |
| 700 | 1 | |a Umezawa, Yoshihiro |e investigator |4 oth | |
| 700 | 1 | |a Umezu, Toru |e investigator |4 oth | |
| 700 | 1 | |a Wakasa, Yutaka |e investigator |4 oth | |
| 700 | 1 | |a Yamada, Katsumi |e investigator |4 oth | |
| 700 | 1 | |a Yamagata, Toshiharu |e investigator |4 oth | |
| 700 | 1 | |a Yamamoto, Munemitsu |e investigator |4 oth | |
| 700 | 1 | |a Yasuda, Kenji |e investigator |4 oth | |
| 700 | 1 | |a Yokoyama, Takahiro |e investigator |4 oth | |
| 700 | 1 | |a Yoshida, Riko |e investigator |4 oth | |
| 700 | 1 | |a Yamaguchi, Tsuyoshi |e investigator |4 oth | |
| 700 | 1 | |a Yamato, Tsuyoshi |e investigator |4 oth | |
| 700 | 1 | |a Ahiko, Tomoaki |e investigator |4 oth | |
| 700 | 1 | |a Aida, Katsumaro |e investigator |4 oth | |
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| 700 | 1 | |a Fukushima, Yasushi |e investigator |4 oth | |
| 700 | 1 | |a Funato, Akitoshi |e investigator |4 oth | |
| 700 | 1 | |a Gushiken, Masamichi |e investigator |4 oth | |
| 700 | 1 | |a Haji, Yoichiro |e investigator |4 oth | |
| 700 | 1 | |a Hashiguchi, Kazuhiro |e investigator |4 oth | |
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| 700 | 1 | |a Honda, Kazuyuki |e investigator |4 oth | |
| 700 | 1 | |a Igarashi, Tadayuki |e investigator |4 oth | |
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| 700 | 1 | |a Irahara, Minoru |e investigator |4 oth | |
| 700 | 1 | |a Irie, Takashi |e investigator |4 oth | |
| 700 | 1 | |a Ishida, Kiyotaka |e investigator |4 oth | |
| 700 | 1 | |a Ishii, Hajime |e investigator |4 oth | |
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| 700 | 1 | |a Karimata, Yoichi |e investigator |4 oth | |
| 700 | 1 | |a Kato, Masaki |e investigator |4 oth | |
| 700 | 1 | |a Katsura, Fumihiro |e investigator |4 oth | |
| 700 | 1 | |a Kawada, Toshio |e investigator |4 oth | |
| 700 | 1 | |a Kawamoto, Kenji |e investigator |4 oth | |
| 700 | 1 | |a Kikuchi, Koki |e investigator |4 oth | |
| 700 | 1 | |a Kikumori, Hiroshi |e investigator |4 oth | |
| 700 | 1 | |a Kimura, Shiro |e investigator |4 oth | |
| 700 | 1 | |a Kin, Heido |e investigator |4 oth | |
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