Inhaled Laninamivir Octanoate as Prophylaxis for Influenza in Children Takashi Nakano, MD, PhD,a Naruhiko Ishiwada, MD, PhD, b Tokuhito Sumitani, MSc, c Mitsutoshi Uemori, MSc,d Koji Isobe, MSc, c for the Laninamivir Prophylaxis Study Group

BACKGROUND: A single 20-mg dose of inhaled laninamivir octanoate is an effective treatment of abstract influenza. However, the efficacy of laninamivir octanoate for the prevention of influenza in children <10 years of age has not yet been established. METHODS: We conducted a double-blind, multicenter, randomized, placebo-controlled study to determine whether the efficacy of a single 20-mg dose of inhaled laninamivir octanoate to prevent the development of influenza was superior to that of placebo as prophylaxis for influenza in pediatric (<10 years) household members of index cases. Eligible subjects without influenza, in contact with an influenza-infected index case living in the same household, were blindly randomly assigned in a 1:1 ratio to receive 20 mg of laninamivir octanoate or placebo. The primary end point was the proportion of subjects who developed clinical influenza during a 10-day period. RESULTS: A total of 343 subjects were randomly assigned, with 341 subjects included in the full analysis set for the primary analysis. The proportions of subjects who developed clinical influenza were 11% (18/171) in the laninamivir octanoate group and 19% (33/170) in the placebo group (P = .02). The relative risk reduction was 45.8% (95% confidence interval, 7.5% to 68.2%). The incidence of adverse events was similar in both groups. CONCLUSIONS: A single 20-mg dose of inhaled laninamivir octanoate was effective and well tolerated as prophylaxis for influenza.

a Department of Pediatrics, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan; bDepartment WHAT’S KNOWN ON THIS SUBJECT: Neuraminidase of Infectious Diseases Medical Mycology Research Center, Chiba University, Chiba, Japan; and cClinical inhibitors (NAIs) are recommended for d Development Department and Clinical Data and Biostatistics Department, Daiichi Sankyo Co, Ltd, Tokyo, Japan chemoprophylaxis of infl uenza. But only a few Drs Nakano and Ishiwada conceptualized and designed the study, interpreted the data, and clinical data are available on the prophylactic reviewed and revised the manuscript; Mr Isobe and Mr Sumitani conceptualized and designed the effi cacy of NAIs in children <10 years of age. study, designed the data collection instruments, supervised data collection and interpreted the WHAT THIS STUDY ADDS: This study demonstrates data, and drafted the initial manuscript; Mr Uemori performed the statistical analysis, interpreted the effi cacy of laninamivir as prophylaxis for the data, and drafted the initial manuscript; and all authors approved the fi nal manuscript as submitted. infl uenza in children aged ≥2 and <10 years with a single 20-mg dose of inhaled laninamivir octanoate. DOI: 10.1542/peds.2016-0109 Accepted for publication Sep 1, 2016 Address correspondence to Laninamivir Prophylaxis Study Group, Clinical Development Department, Daiichi Sankyo Co, Ltd, Hiromachi 1-2-58, Shinagawa-ku, Tokyo 140-8710, Japan. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2016 by the American Academy of Pediatrics To cite: Nakano T, Ishiwada N, Sumitani T, et al. Inhaled Laninamivir Octanoate as Prophylaxis for Infl uenza in FINANCIAL DISCLOSURE: Drs Nakano and Ishiwada were consultants of this study for Daiichi Children. Pediatrics. 2016;138(6):e20160109 Sankyo; the other authors have indicated they have no fi nancial relationships relevant to this article to disclose.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 138 , number 6 , December 2016 :e 20160109 ARTICLE Influenza is a common viral members of the household infected the index case was present within respiratory illness that could by influenza A or B virus in the the household, had a history of increase risks of hospitalization, 2011/2012 influenza season) has abnormal behavior accompanied by severe morbidity, and death 1 – 3 in been demonstrated. 16 influenza or pyrexia, hypersensitivity young children, elderly, and others However, the efficacy of laninamivir to neuraminidase inhibitors (NAIs), with underlying medical conditions. octanoate as prophylaxis for being treated with corticosteroid Additionally, abnormal behavior influenza in children <10 years of or other immunosuppressant, in children has been reported in age has not yet been evaluated. We or had been treated with a NAI 4–6 patients with influenza. It is conducted a randomized controlled within 4 weeks before informed highly important to take preventive study to determine whether consent. Influenza inactivated- measures against seasonal influenza, laninamivir octanoate is efficaciously vaccine recipients in the 2014/2015 particularly in the pediatric superior compared with placebo, season were considered eligible population. Prophylactic vaccination in pediatric (<10 years of age) because prophylaxis for influenza against influenza has been generally household members of an index case is particularly indicated for groups recommended for children, and as a prophylaxis of influenza. at risk for complications, and hence vaccination rates among children for whom influenza vaccination is had reached 40% to 60% during recommended. the 6 seasons of 2005/2006 to METHODS 2010/2011.7 However, despite the increasing rates in influenza Study Design Study Procedure vaccination, an outbreak of 2009 This study was a randomized, pandemic influenza A (H1N1) double-blind, placebo-controlled trial Participants were blindly randomly [A(H1N1)pdm09] virus occurred, and conducted from November 2014 to assigned in a 1:1 ratio to receive oseltamivir-resistant strains emerged March 2015 at 50 pediatric clinics in 20 mg of inhaled laninamivir in the years after the pandemics. 8 Japan. The study was approved by octanoate or placebo through an Furthermore, during the 2013/2014 the ethics committee at each center inhaler on day 1. The study used season in Japan, influenza A(H1N1) and complied with the provisions random allocation through an pdm09 virus cross-resistant to of Good Clinical Practice and the interactive Web response system oseltamivir and peramivir was Declaration of Helsinki. 17 All index that centrally assigned subjects on detected. 9 Such circumstances cases, subjects, and their legally the basis of computer-generated suggest the emergence and outbreak acceptable representatives provided permuted-block randomization by of new drug-resistant strains of written or oral informed consent Bell Medical Solutions, Inc (Tokyo, influenza virus. Given the limitations in accordance with their age before Japan). Stratification factors for of vaccination, extensive variations enrollment in the study. 18 randomization were virus types in the option for antiinfluenza for the index cases and influenza prophylaxis are desirable as an Subjects vaccination status of the 2014/2015 adjunct to influenza vaccine. Eligible subjects were aged <10 influenza season for the subjects. years, had an axillary temperature After confirming eligibility, the Laninamivir potently inhibits of ≤36.9°C, had no influenzalike investigator enrolled the subjects neuraminidase activities of various symptoms at the time of receiving through the Web system, which influenza A and B viruses, including consent, and were determined by generated allocation numbers subtypes N1 to N9, influenza the investigator of having sufficient for the drug. The subjects, index A(H1N1)pdm09 viruses, highly inhalation capability for using an cases, investigators, and trial pathogenic avian influenza H5N1 inhaler (evaluated by a test using personnel were blinded to the viruses, and oseltamivir-resistant training whistles 19). Eligible index group assignment throughout the viruses.10, 11 The efficacy of a single cases were the first members trial. If the subjects were deemed 20-mg dose of laninamivir octanoate infected with influenza A or B virus ineligible after obtaining informed for influenza treatment in adults and in the 2014/2015 influenza season consent, they were not enrolled. children has been demonstrated. 12 – 15 within the household, tested positive The investigator recorded whether In addition, the efficacy of a single for influenza by the rapid diagnostic subjects inhaled the drug well or not. 20-mg dose of laninamivir octanoate test. The study excluded subjects who The index cases were treated with once daily for 2 days as postexposure were unable to start the treatment oseltamivir or zanamivir. Participants prophylaxis of influenza in household within 48 hours of the onset of were not allowed to use any other members (adults and children ≥10 influenza symptom in the index case, antiinfluenza agents before the years of age) of index cases (first infected family members other than diagnosis of influenza infection.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 NAKANO et al Clinical and Virological Monitoring end points included the proportions after enrollment. All analyses were of subjects with symptomatic performed by using SAS System The legal representatives influenza (laboratory-confirmed Release 9.2 (SAS Institute, Inc, Cary, observed and recorded the axillary influenza with either an axillary NC). The planned sample size was temperature and the presence or temperature of ≥37.5°C or ≥1 300 subjects on the basis of the absence of any of the 7 influenza influenza symptom present), assumptions that the relative risk symptoms (headache, myalgia/ asymptomatic influenza (laboratory- reduction would be at least 70% arthralgia, fatigue, chills/sweats, confirmed influenza without an and the proportion of subjects with nasal symptoms, sore throat, and axillary temperature of ≥37.5°C and clinical influenza in the placebo cough) of subjects twice daily over a no influenza symptoms present), group would be 15% as in previous 10-day period on diary cards. and influenza infection (laboratory- studies, 22, 23 corresponding to a rate For viral detection, anterior nose and confirmed influenza, excluding of 4.5% in the laninamivir octanoate posterior pharyngeal throat swabs participants with confirmed influenza group. We estimated that 150 were taken from the index cases at virus at baseline). subjects in each group would provide the initial visit and from the subjects 80% power to detect superior on days 1, 3, and 11. Samples were Safety and Tolerability efficacy. also taken from the subjects during an outpatient visit within 3 days if For safety assessments, all adverse axillary temperature of ≥37.5°C or events were assessed to determine the onset of influenza symptoms whether they corresponded to RESULTS were confirmed. If the subjects abnormal behavior on the basis of were diagnosed with influenza virus the definition of Ministry of Health, Study Population 21 infection by a rapid diagnostic test at Labor, and Welfare, regardless of infection. Blood and urine the visits, they were provided with A total of 343 subjects were samples were taken on days 1 and appropriate treatment. randomly assigned. Of these, 2 11 to perform hematology, blood subjects were excluded from the Viral isolation was performed by chemistry, and urinalysis as part of analyses due to discontinuation local laboratories for all samples safety evaluation. collected in a tube. before administration, because they were unable to start study treatment Statistical Analyses Viral RNA was extracted from within 48 hours after the initial supernatant fluids using QIAamp The primary population for onset of influenza symptom in the viral RNA minikit (Qiagen, Inc, evaluating efficacy was defined as index case. A total of 341 subjects Hilden, Germany) and virus was the full analysis set (FAS). FAS in were included in the FAS and were confirmed by determining the virus the current study is defined as a assigned to the laninamivir octanoate type and subtype, based on a reverse population excluding subjects in group (N = 171) and in the placebo transcription polymerase chain which the study drug has not been group (N = 170; Fig 1). 20 reaction with specific primers administered, from population designed from the hemagglutinin on the basis of the intention-to- The demographic characteristics sequence of the influenza A(H1N1) treat principle. Between-group of subjects and index cases were pdm09, seasonal influenza A(H1N1), comparisons were made by 2-sided comparable in the FAS ( Table 1). influenza A(H3N2), or influenza B Fisher’s exact test with a significance Most of the index cases were children viruses. All laboratory virological level of 5%. For protective efficacy, ≤15 years of age (all cases were procedures were performed by relative risk reduction compared ≥2 years of age), and subjects were LSI Medience Corporation (Tokyo, with placebo and the 95% mostly siblings of the index case. Of Japan). confidence interval (CI) on the basis all index cases, 333 (98%; 165 [97%] of normal approximation were and 168 [99%] cases of household Effi cacy End Points estimated. Symptomatic influenza, contacts in the laninamivir octanoate The primary efficacy end point, asymptomatic influenza, and group and in the placebo group, clinical influenza, was the proportion influenza infection were analyzed respectively) were infected with of subjects who developed clinical as the secondary end points in the influenza A(H3N2) virus. Among all influenza, defined as laboratory- same manner as for the primary end subjects, 140 (41%) had received confirmed influenza with an axillary point. The safety analysis population the 2014/2015 seasonal influenza temperature of ≥37.5°C and ≥2 included all subjects except for vaccination ( Table 1). All index cases influenza symptoms present from those who received no treatment or were treated with either oseltamivir days 1 through 11. The secondary could not be investigated for safety or zanamivir in the current study.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 138 , number 6 , December 2016 3 and 27% (45/170) in the placebo group (P = .01). The proportions of subjects with influenza infection in laninamivir octanoate group and placebo groups were 13% (20/153) and 30% (46/155), respectively, showing significant reduction in the incidence of infected cases (P < .001). The proportion of subjects with asymptomatic influenza appeared to be lower but was not significant (Table 2). In the subpopulation of subjects who were the household members of index cases who had tested virus- FIGURE 1 positive at baseline (18/168 and Subjects fl owchart. A total of 341 subjects were included in the safety analysis set (171 subjects in 33/168 clinical influenza cases in the laninamivir group and 170 in the placebo group). laninamivir octanoate and placebo groups, respectively), the relative Effi cacy Outcomes and placebo group, respectively risk reduction was 45.5% (95% CI, (Table 2; P = .02). The relative risk 7.1% to 68.0%), and the relative risk In the FAS, the proportion of reduction was 45.8% (95% CI, 7.5% reduced to 64.5% (95% CI, 26.7% subjects with clinical influenza, to 68.2%; Table 2). The proportion to 82.8%) when that subpopulation the primary end point, were 11% of subjects with symptomatic only included subjects who were (18/171) and 19% (33/170) in influenza was 15% (26/171) in virus-negative at baseline (9/150 the laninamivir octanoate group the laninamivir octanoate group and 26/154 clinical influenza cases

TABLE 1 Demographic and Baseline Characteristics of Subjects (FAS) and Index Cases Subjects (Household Contacts) Index Casesa Characteristic Laninamivir 20 mg Placebo Characteristic Household Contacts, Household Contacts, Placebo Laninamivir 20 mg No. N = 171 N = 170 No. N = 171 N = 170 Age Age Mean ± SD, y 6.7 ± 1.7 6.8 ± 1.7 Mean ± SD, year 8.9 ± 7.5 8.9 ± 7.4 Group, no. (%), y Group, No. (%), y −4 19 (11) 17 (10) −4 49 (29) 40 (24) 5 to 6 54 (32) 53 (31) 5 to 9 61 (36) 74 (44) 7 to 9 98 (57) 100 (59) 10 to 14 50 (29) 45 (26) 15 11 (6) 11 (6) Sex, no. (%) Sex, no. (%) Girls 81 (47) 90 (53) Girls 85 (50) 83 (49) Infl uenza virus negative at baseline, no. (%) Yes 153 (90) 155 (91) Time from onset of infl uenza in index case to completion of study Rapid diagnostic test, no. (%) treatment Mean ± SD, h 24.43 ± 11.26 22.75 ± 10.73 Positive 168 (98) 168 (99) Group, No. (%) Laboratory-confi rmed infl uenza infection, no. (%) <24 hrs 88 (51) 89 (52) Virus type and subtype, No. (%) A/H1N1pdm09 1 (1) 0 (0) Vaccinated for 2014/2015 season, no.(%) A/H1N1 0 (0) 0( 0) Yes 71 (42) 69 (41) A/H3N2 165 (97) 168 (99) Relationship to the index case, no. (%) B 2 (1) 0 (0) Sibling 161 (94) 161 (95) Mixed 0 (0) 0 (0) Child 10 (6) 9 (5) Negative 3 (2) 2 (1) 2009H1N1, infl uenza A(H1N1)pdm09; A/H3N2, infl uenza A(H3N2); B, infl uenza B. a More than 1 subject could be enrolled for each index case. In this case, the index case was counted once for each household member who was enrolled. Of the 304 index cases (FAS) enrolled, 269 were associated with 1 subject, 33 with 2 subjects, and 2 with 3 subjects. In this table, the number “N” of household members and index cases in each treatment group is identical.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 4 NAKANO et al TABLE 2 Protective Effects of Laninamivir Against Infl uenza Infection Outcome Laninamivir 20 mg, no./total Placebo, no./total Pa RRRb (95% CI) (%) (%) Primary end point Clinical infl uenza (FAS) 18/171 (11) 33/170 (19) .02 45.8 (7.5 to 68.2) Secondary end points Symptomatic infl uenza (FAS) 26/171 (15) 45/170 (27) .01 42.6 (11.4 to 62.8) Asymptomatic infl uenza (FAS) 12/171 (7) 16/170 (9) .44 25.4 (−52.8 to 63.6) Infl uenza infectionc 20/153 (13) 46/155 (30) <.001 56.0 (29.2 to 72.6) RRR, relative risk reduction. a Analyzed by using Fisher’s exact test. b 100 × (1 − Laninamivir/Placebo) c Denominators are subpopulation of subjects in the FAS who had tested negative for infl uenza virus at baseline for each group.

TABLE 3 Subgroup Analyses for Clinical Infl uenza (FAS) Subgroup Laninamivir 20 mg, no./total (%) Placebo, no./total (%) Pa RRRb (95% CI) Age, y <7 y 6/73 (8) 16/70 (23) .02 64.0 (13.4 to 85.1) ≥7 y 12/98 (12) 17/100 (17) .42 28.0 (−42.8 to 63.7) Sex Girls 9/81 (11) 18/90 (20) .14 44.4 (-16.6 to 73.5) Boys 9/90 (10) 15/80 (19) .12 46.7 (−15.1 to 75.3) Time from onset of infl uenza in index case to completion of study treatment <24 h 10/88 (11) 18/89 (20) .15 43.8 (−14.8 to 72.5) ≥24 h 8/83 (10) 15/81 (19) .12 48.0 (−16.0 to 76.7) Vaccinated for 2014/2015 season No 14/100 (14) 22/101 (22) .20 35.7 (−18.3 to 65.1) Yes 4/71 (6) 11/69 (16) .06 64.7 (−5.7 to 88.2) Infection in previous seasonal infl uenza No 14/121 (12) 31/137 (23) .02 48.9 (8.5 to 71.4) Yes 4/50 (8) 2/33 (6) 1.0 −32.0 (−580.1 to 74.4) Relationship to index case Sibling 18/161 (11) 33/161 (21) .03 45.5 (7.2 to 67.9) Child 0/10 (0) 0/9 (0) — — RRR, relative risk reduction a Analyzed by using Fisher’s exact test. b 100 × (1 − Laninamivir/Placebo). in laninamivir octanoate and placebo also effective. The study revealed adverse events were considered groups, respectively). equivocal significance between mild or moderate, and few were placebo and laninamivir octanoate considered to be related to the Subgroup analyses ( Table 3) groups in the vaccination subgroups revealed that in the population study drug (1% in both laninamivir (P = .06). <7 years the proportion of subjects and placebo groups). No deaths, who developed clinical influenza serious adverse events, or abnormal Safety and Tolerability was significantly reduced by a behavior were reported. Although single 20-mg dose of laninamivir A single 20-mg dose of laninamivir the subjects were limited (2% and octanoate (P = .02), whereas in the octanoate was well tolerated. No 5% in the laninamivir and placebo population ≥7 years the proportion subjects withdrew from the study groups, respectively), the incidence in the laninamivir octanoate group after administration. In the safety of adverse events among the appeared to be lower without analysis set (341 subjects), the subgroup of high risk subjects (such statistical significance. Among incidence of adverse events was as those with chronic respiratory contacts whose index cases were 15% (25/171) in the laninamivir diseases) was similar to the overall infected with the influenza A(H3N2) octanoate group and 13% (22/170) result (data not shown). No abnormal virus, laninamivir octanoate was in the placebo group ( Table 4). All hematology and blood chemistry

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 138 , number 6 , December 2016 5 TABLE 4 Incidence of Adverse Events (P = .02). For age category ≥7 Laninamivir 20 mg (N = 171), Placebo (N = 170), no. years, the significance level was no. (%) (%) not achieved. This age group was Adverse events 25 (15) 22 (13) inclusive of 9 out of 12 subjects who Drug-related adverse event 2 (1) 1 (1) were household members of index Serious adverse events 0 0 cases who had tested influenza Adverse event leading to discontinuation 00virus-negative and subjects who had of study drug Abnormal behavior 0 0 tested virus-positive at baseline. As Adverse events by MedDRAa preferred term, stated above, there is a tendency of reported by ≥ 2 subjects reduced efficacy in such subjects. Bronchitis 1 (1) 2 (1) In the evaluation of population Gastroenteritis 1 (1) 3 (2) excluding such cases, the incidence Nasopharyngitis 7 (4) 2 (1) Pharyngitis 2 (1) 2 (1) was 4% (3/84) in the laninamivir Upper respiratory tract infl ammation 5 (3) 6 (4) octanoate group and 14% (12/88) Blood urine present 0 2 (1) in placebo (P = .03; data not shown). Protein urine present 0 2 (1) In the subgroup of subjects who MedDRA, Medical Dictionary for Regulatory Activities. were infected with the previous a MedDRA/J Version: 17.1. seasonal influenza virus, the efficacy of the regimen was similar to that of placebo. A possible explanation for values were observed in ≥2 subjects 2 groups in the current study this result could be the preventive in the laninamivir octanoate group was 11. effect against the development (Table 4). No abnormal behavior was of influenza caused by acquired observed. The FAS included subjects who had tested virus positive at registration, immunity via infection with the and subjects with household index previous seasonal influenza affecting DISCUSSION cases who had tested virus negative the results regardless of prophylactic at registration. In the analysis of treatment. However, because the Household members are at great population excluding such subjects, proportions of clinical influenza risk of secondary infection when the relative risk reduction revealed cases were as low as 4/50 (8%) and an index member is infected greater reduction (64.5%), compared 2/33 (6%) in the respective groups, by the influenza virus. The risk with the results for the FAS. This possibility of the protective effect of complications of influenza- finding indicates that laninamivir of this regimen in this subgroup associated encephalitis/ octanoate prevents transmission of cannot be denied ( Table 3). Statistical encephalopathy and abnormal influenza to noninfected individuals significance was not reached for behavior are high, particularly in within the household as an effective both groups treated and untreated young Japanese children. Therefore, prophylaxis. Laninamivir potently with 2014/2015 season vaccination. influenza prophylaxis in pediatric inhibits the neuraminidase activities Therefore, the effect of vaccination patients is of particular importance. of various influenza A and B viruses. on the efficacy of laninamivir octanoate is inconclusive in the In this study, a single 20-mg dose of Neuraminidase activity is vital for current study. Studies have revealed laninamivir octanoate significantly viral release from host cells and viral that vaccines containing formerly lowered the risk of developing spread. Because viral multiplication prevalent strains are expected to be clinical influenza, the primary end had already initiated in the host less effective against virus variants point, in children ≤10 years of age, cells for subjects infected with 24 revealing antigenic drift. Prediction compared with placebo in the FAS of influenza virus, the regimen of the of future variations is not possible the primary population. current study may be insufficient for preventing the development of because the mechanism related to Since a single 20-mg dose of influenza illness in patients who have antigenicity still remains 25 laninamivir octanoate revealed been already infected with influenza a mystery. Given such prophylactic effect, the regimen before prophylaxis. circumstances, antiinfluenza in the current study is a highly prophylaxis could be useful as an user-friendly option. Although Regarding age category adjunct to influenza vaccine. the numbers of infected individuals (<7 years), the proportion of may differ by season, the number subjects who developed clinical Single 20-mg dose of laninamivir needed to treat based on the influenza was significantly reduced octanoate was well tolerated incidence of clinical influenza for the in the laninamivir octanoate group without the incidence of associated

Downloaded from www.aappublications.org/news by guest on September 30, 2021 6 NAKANO et al safety concerns. Survey was 98.5% (336/341). The value was Project Steering Committee: performed prospectively between comparable with the value described Takashi Nakano (Department of the 2007/2008 and 2012/2013 in the previous meta-analytic study Pediatrics, Kawasaki Medical School, seasons, and retrospectively for (98.2%).26 The specificity might have Okayama, Japan); Naruhiko Ishiwada the 2006/2007 season regarding been high because all index cases (Laboratory of Infection Control and abnormal behavior associated in this study were tested within 48 Prevention, Department of Infectious with influenza. As the result of hours from onset, when influenza Diseases, Medical Mycology Research the investigation, 858 cases were activity was high 27 and also because Center, Chiba University, Chiba, reported and among of them 95.7% rapid diagnostic test is a ubiquitous Japan); Katsuyasu Ishida, Koji Isobe, were positive by the influenza technique used for prescribing NAIs Tokuhito Sumitani, Shinichiro rapid diagnosis test. 4 As in these in Japan. Awamura, Satoshi Nishioka, and findings, children with influenza Another limitation is that very few Mitsutoshi Uemori (Daiichi Sankyo, virus infection often show abnormal subjects considered being at high Tokyo, Japan). behavior during the febrile period risk, such as patients with chronic Clinical investigators who enrolled at regardless of antiinfluenza drug respiratory disease, were enrolled least 1 subject: Toshiko Yamaguchi, 3–5 exposure. In this study, the in the study. Generally, antiviral Yutaka Igarashi, Hideki Sato, Kouta association of laninamivir octanoate chemoprophylaxis is considered for Saito, Tomoyuki Shibuya, Shinya with abnormal behavior was persons at high risk of developing Enomoto, Eiki Oshika, Yasuko investigated because it was also complications from influenza, Murakawa, Haruo Kuroki, Koji administered to subjects who had including persons with chronic Maehara, Yuko Miyazono, Yoshihiro not developed influenza. No respiratory illness, metabolic Umezawa, Ryuta Ono, Kenji Saito, abnormal behavior was observed disorders including diabetes Jiro Takei, Mikiko Takano, Hideki in all 153 subjects who had not mellitus, chronic heart disease, Amemiya, Kazuo Arakawa, Shigenori developed influenza in the current or immunodeficiency. 28 Further Matsubara, Kazumasa Sugimoto, study. Hence, the proposed regimen studies regarding the prophylactic Hiroshi Kikumori, Toshihiko Sunami, does not appear to induce abnormal administration of laninamivir Ryota Yoshimura, Toshikazu behavior. octanoate in such subjects are Takahashi, Yutaka Nakamura Keiichi A limitation of this study is that we necessary. Tsuboi, Hidehisa Shinohara, Shigeru were unable to evaluate efficacy Onari, Michiko Tanabe, Hiroshi Taniguchi, Mikio Kihara, Tatsuo by subgrouping the subjects on the CONCLUSIONS basis of virus types of the index- Yoshimitsu, Takato Yokoyama, infected cases. This was because Single 20-mg dose of inhaled Yoshio Takasaki, Yuji Yamashita, the vast majority of the index laninamivir octanoate was sufficient Hiroshi Harada, Katsumaro Aida, cases were infected with influenza to protect against influenza in Shizuo Shindo, Kunihisa Shimomura, ≥ A(H3N2; 98%). In a nonclinical study, pediatric ( 2 years and <10 years Yumi Kiyomatsu, Toru Umezu, laninamivir octanoate has been of age) household members of index Motohisa Ikeda, Minako Iwaya, shown to exhibit neuraminidase cases for prophylaxis of influenza, Masaki Higashikawa, Takeshi inhibitory activity against both and laninamivir octanoate can be Inamitsu, Yasuyuki Tokunaga, Satoru influenza A(H1N1)pdm09 and recommended as an option for Okazaki, Yoichi Tokunaga, Tetsunari influenza B viruses. 10, 11 In addition, prevention of influenza. Additionally, Maeda, and Hirofumi Tahara. this regimen was well tolerated. the influenza A(H1N1)pdm09 virus Daiichi Sankyo Co, Ltd was involved This suggests that laninamivir cross-resistant to oseltamivir and in the study design, data collection, octanoate should be a safe and peramivir detected during the and statistical analyses. Assistance useful agent as chemoprophylaxis. 2013/2014 season in Japan for editing of the manuscript was These results may provide some remained sensitive to laninamivir. 9 provided by SunFlare Co, Ltd (Tokyo, evidence that this regimen could Therefore, this regimen may Japan), funded by Daiichi Sankyo, Co, be effective for preventing the be effective for preventing the Ltd. development of influenza against development of influenza in pediatric these virus types, and further household members of index cases evaluation is necessary. for 10 days. ABBREVIATIONS Although the diagnostic kits used CI: confidence interval were unspecified, the specificity ACKNOWLEDGMENTS FAS: full analysis set of the rapid diagnostic test Laninamivir Prophylaxis Study NAI: neuraminidase inhibitor performed on the index cases was Group

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 138 , number 6 , December 2016 7 FUNDING: All phases of this study were supported by Daiichi Sankyo Co, Ltd. No external funding was secured for this study. POTENTIAL CONFLICT OF INTEREST: This study was sponsored by Daiichi Sankyo Co, Ltd; Dr Nakano has received consulting fees and payment for lectures from Daiichi Sankyo, Takeda Pharmaceutical, Tanabe-Mitsubishi, Japan Vaccine, MSD, Denka Seiken, Astellas Pharma, and Glaxo Smith Kline; Dr Ishiwada has received consulting fees and payment for lectures from Daiichi Sankyo, Astellas Pharma, Japan Vaccine, Kyorin Pharmaceutical, Abbvie, Pfi zer, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical, and Sanofi ; all other authors are employees of Daiichi Sankyo Co, Ltd.

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Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 138 , number 6 , December 2016 9 Inhaled Laninamivir Octanoate as Prophylaxis for Influenza in Children Takashi Nakano, Naruhiko Ishiwada, Tokuhito Sumitani, Mitsutoshi Uemori, Koji Isobe and for the Laninamivir Prophylaxis Study Group Pediatrics originally published online November 2, 2016;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2016/10/31/peds.2 016-0109 References This article cites 23 articles, 5 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2016/10/31/peds.2 016-0109#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Influenza http://www.aappublications.org/cgi/collection/influenza_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 30, 2021 Inhaled Laninamivir Octanoate as Prophylaxis for Influenza in Children Takashi Nakano, Naruhiko Ishiwada, Tokuhito Sumitani, Mitsutoshi Uemori, Koji Isobe and for the Laninamivir Prophylaxis Study Group Pediatrics originally published online November 2, 2016;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2016/10/31/peds.2016-0109

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2016 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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