Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: a double-blind, randomized, noninferiority clinical trial

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M A J O R A R T I C L E

Long-Acting Neuraminidase Inhibitor Laninamivir

Octanoate versus Oseltamivir for Treatment

of Inﬂuenza: A Double-Blind, Randomized,

Noninferiority Clinical Trial

Akira Watanabe,1_{Shan-Chwen Chang,}3_{Min Ja Kim,}4_{Daniel Wai-sing Chu,}5_{and Yasuo Ohashi}2_{; for the MARVEL}

Study Groupa

1_{Research Division for Development of Anti-Infective Agents, Institute of Development, Aging and Cancer, Tohoku University, Sendai,}2_Department of Biostatistics, School of Public Health Science, University of Tokyo, Tokyo, Japan;3_{Department of Internal Medicine, National Taiwan University} Hospital, Taipei, Taiwan;4_{Division of Infectious Diseases, Korea University Medical Center, Anam Hospital, Seoul, Korea; and}5_Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China

Background. A single administration of laninamivir octanoate, a long-acting neuraminidase inhibitor, against influenza infection has been proven effective in nonclinical studies. This study evaluated the clinical efficacy of laninamivir octanoate for the treatment of adult influenza patients.

Methods. A double-blind, randomized controlled trial examined whether laninamivir octanoate was noninferior

to oseltamivir. A total of 1003 patients aged⭓20 years with febrile inﬂuenza symptoms for no more than 36 h

were randomized to receive either 40 mg of laninamivir octanoate, 20 mg of laninamivir octanoate, or oseltamivir. Laninamivir octanoate was inhaled once on day 1, and oseltamivir (75 mg) was administered orally twice daily for 5 days. The primary end point was the time to illness alleviation.

Results. A total of 996 patients were included in the primary analysis (40-mg laninamivir octanoate, np

; 20-mg laninamivir octanoate, ; and oseltamivir, ). The median time to illness alleviation in

334 np 326 np 336

the 40-mg laninamivir octanoate, 20-mg laninamivir octanoate, and oseltamivir groups was 73.0, 85.8, and 73.6

h, respectively. The difference between laninamivir octanoate and oseltamivir was⫺0.6 h (95% conﬁdence interval,

⫺9.9 to 6.9 h) for the 40-mg group and 12.2 h (95% confidence interval, ⫺1.5 to 17.2 h) for the 20-mg group. The upper limits of the 95% confidence intervals were less than the prespecified noninferiority margin (18 h). The proportion of patients shedding virus at day 3 was significantly lower in the 40-mg laninamivir octanoate

group than in the oseltamivir group (Pp .006).

Conclusions. A single inhalation of laninamivir octanoate is effective for the treatment of seasonal inﬂuenza, including that caused by oseltamivir-resistant virus, in adults.

Clinical trials registration. NCT00803595. Inﬂuenza epidemics have raised medical and social con-cerns because they are associated with considerable morbidity and mortality [1]. Neuraminidase inhibitors have been preferred for the treatment of inﬂuenza

in-Received 6 May 2010; accepted 16 August 2010; electronically published 11 October 2010.

a

Members of the study group are listed at the end of the text.

Reprints or correspondence: Dr Akira Watanabe, Research Div for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku Univer-sity, Seiryomachi 4–1, Aoba-ku, Sendai, Miyagi 980–8575, Japan (akiwa@idac.tohoku .ac.jp).

Clinical Infectious Diseases 2010; 51(10):1167–1175

DOI: 10.1086/656802

fections [2]. However, the isolation of inﬂuenza virus strains that are resistant to neuraminidase inhibitors has been reported, and the spread of drug-resistance has become a major concern [3–8]. In addition, the World Health Organization declared that infections caused by the novel swine-origin H1N1 inﬂuenza vi-ruses had reached the pandemic phase in June 2009 [9], and oseltamivir-resistant 2009 pandemic H1N1 vi-ruses have been detected in several countries [10].

Laninamivir octanoate (CS-8958; Daiichi Sankyo) is an octanoyl ester prodrug of laninamivir that exhibits neuraminidase inhibitory activity against inﬂuenza A and B viruses, including oseltamivir-resistant viruses [11] and 2009 pandemic H1N1 viruses [12]. Moreover,

at Taipei Medical University Library on October 11, 2011

cid.oxfordjournals.org

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administration of laninamivir octanoate was similar to that of multiple administrations of zanamivir or oseltamivir [13] and that laninamivir was retained in the respiratory tract for a long time [14]. Laninamivir was slowly eliminated from healthy vol-unteers, lasting for up to 6 days after a single inhalation [15]. Considering these potential advantages, laninamivir octan-oate promises to be a convenient anti-influenza agent if it is indeed efficacious as a standard anti-influenza treatment. We conducted a randomized controlled trial to determine whether the efficacy of a single inhalation of laninamivir octanoate was noninferior to that of oseltamivir administered with multiple oral doses in treating adults with seasonal influenza.

METHODS

Study design and patients. This multicenter, double-blind, randomized controlled trial was conducted from November 2008 through March 2009 at 117 institutions in Japan, Taiwan, Korea, and Hong Kong. The study was undertaken in accor-dance with the Declaration of Helsinki and Good Clinical Prac-tice guidelines. The study protocol was approved by the insti-tutional review board of each institution. Written informed consent was obtained from each patient.

Eligible patients were aged⭓20 years who presented within

36 h after the onset of inﬂuenza symptoms and who had an

axillary temperature of⭓37.5C and a positive test result with

use of a rapid influenza diagnostic kit. The exclusion criteria were as follows: suspicion of infection with a bacterial species or noninfluenza virus within 1 week before enrollment; reported occurrence of any influenza-like symptom within 1 week before the onset of influenza; chronic respiratory disease; renal dys-function; history of alcohol or drug abuse; or treatment with amantadine, zanamivir, or oseltamivir within 4 weeks. Pregnant women, breast-feeding women, and women who wished to be-come pregnant during the period of the trial were also excluded.

Randomization and masking. Patients were randomly as-signed (1:1:1) to a 40-mg laninamivir octanoate, a 20-mg lan-inamivir octanoate, or an oseltamivir treatment group. Lani-namivir octanoate was delivered by oral inhalation with use of the dry powder inhaler. Laninamivir octanoate was adminis-tered as a single inhalation on day 1. Oseltamivir (75 mg) was administered orally twice daily for 5 days (days 1–5). The com-puter-generated block random allocation sequence was pro-vided by Acronet Corporation and was stratified according to the institution and type of influenza virus on the basis of the results of a rapid diagnostic kit capable of separately detecting influenza A and B. The patients, investigators, and trial per-sonnel were blinded to the allocation sequence throughout the trial with use of a double-dummy method. The administration of laninamivir octanoate and the first dose of oseltamivir were

use was recorded. The concomitant use of other drugs was prohibited for 15 days.

Procedures. Medical histories, vital signs, physical exami-nations, and baseline virological samples were obtained before treatment. Hematology, blood chemistry, and urinalysis were performed on days 1 (baseline) and 15 for safety assessment. Patients recorded their axillary temperature and severity of in-ﬂuenza symptoms (headache, myalgia/arthralgia, fatigue, chills/ sweats, nasal symptom, sore throat, and cough) 4 times daily for 15 days. The severity of each inﬂuenza symptom was graded into 4 categories (0, absent; 1, mild; 2, moderate; 3, severe) and was measured as the symptom score.

Influenza was screened using a rapid diagnostic kit (mainly Capilia FluA+B [Tauns] and QuickVue Rapid-SP influ [Qui-del]) [16, 17], and results were confirmed using laboratory virological tests. Anterior nose and/or posterior pharyngeal throat swabs were taken on days 1 (baseline), 3, and 6 (1 day for days 3 and 6) and were placed in viral transport

me-dium. The swab samples were eluted and frozen at⫺80C

10C until use. For the baseline assessment, the subtype of

influenza was determined based on an amplified DNA size by a reverse transcription polymerase chain reaction (RT-PCR) with subtype-specific primers designed from the hemagglutinin sequences of the seasonal H1N1, H3N2, and B viruses. Sus-ceptibilities to laninamivir and oseltamivir carboxylate were determined by a fluorescence-based neuraminidase inhibition assay [12] with use of culture supernatants propagated once from the thawed swab samples in Madin-Darby canine kidney cells. The detection of the oseltamivir-resistant H274Y mutation (N2 numbering) was performed using an RT-PCR–restriction fragment length polymorphism assay according to the reported procedure [18]. Virus titers were determined using the swab samples obtained at 3 time points. The thawed swab samples were serially diluted and cultured for 7 days in Madin-Darby canine kidney cells. Based on the dilution factor showing no

cytopathic effect, the virus titers were calculated as the log10

50% tissue culture infective dose per mL of the viral transport medium, according to the Behrens-Ka¨rber equation [19]. Se-rum samples were obtained on days 1 and 22 and were used to perform a hemagglutination-inhibition assay. The serological response was defined as a 4-fold or greater increase in subtype-specific antibody on day 22, compared with that on day 1. When the subtype of influenza could not be determined using RT-PCR, it was determined using the hemagglutination-inhi-bition assay. If the sample results were negative by both RT-PCR and hemagglutination-inhibition assay, the patient was regarded as not having a laboratory-confirmed influenza virus infection. All the virological tests were performed at Mitsubishi Chemical Medience.

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Figure 1. Patient ﬂow chart. *One patient who was allocated to the oseltamivir group received 40 mg of laninamivir octanoate. This patient was included in the originally allocated group in the full analysis set (FAS) but was analyzed according to the actually administered treatment in the per protocol set (PPS) and safety analysis set.

Study outcomes. The primary end point was the time to illness alleviation, defined as the time from the initiation of trial treatment to the beginning of the first 21.5-h period in which all influenza symptoms were “absent” or “mild.” The time to illness alleviation was defined as reported in a trial for oseltamivir [20–23]. Patients whose influenza symptoms had not been alleviated at the time of their withdrawal from the study or at the end of the observation period were censored. The time to the return of a normal body temperature was defined as the time until the beginning of the first 21.5-h period

in which the axillary temperature returned to⭐36.9C. The

proportion of patients shedding viruses at each time point was calculated for each group.

Statistical analysis. This trial was designed to conﬁrm the efﬁcacy of laninamivir octanoate by showing that the median time to illness alleviation in patients treated with laninamivir

octanoate was not118 h longer than that in patients treated

with oseltamivir. A noninferiority margin of 18 h was set to assure the superiority of laninamivir octanoate over a putative placebo. A meta-analysis using 3 placebo-controlled trials

re-ported that the difference between the median time to illness alleviation in the placebo and oseltamivir groups was 33.1 h and the 95% conﬁdence interval (CI) ranged from 19.1 to 47.1 h [20]. From this, a margin that was less than the lower limit of this 95% CI was selected. Based on the results of a phase II trial of laninamivir octanoate conducted in Japan (A.W. and Y.O., unpublished data), a sample size of 300 patients in each group was determined to achieve a power of at least 80% to show noninferiority at both dose levels of laninamivir octanoate with use of a Monte Carlo simulation.

To test the trial hypothesis, we calculated the differences in the median time to illness alleviation between each dose level of laninamivir octanoate and the oseltamivir group and the 2-sided nonparametric 95% CIs on the basis of the generalized Wilcoxon test. We then determined whether the upper limit of

each 95% CI was!18 h in the 40-mg group and the 20-mg

group, sequentially. As ancillary analyses, generalized Wilcoxon tests were performed between each comparison of the treatment groups. These analyses were also performed in subgroups strat-iﬁed according to the type of inﬂuenza virus. All analyses were

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Characteristic (np 334) (np 326) (np 336) Age

Mean years SD 34.9 11.5 35.6 11.7 34.7 11.3

Range, years 20–73 20–73 20–77

Male sex 179 (53.6) 162 (49.7) 178 (53.0)

Received vaccination against influenza 50 (15.0) 67 (20.6) 64 (19.0) Laboratory-confirmed influenza infectiona

A/H1N1 218 (65.3) 215 (66.0) 212 (63.1)

A/H3N2 108 (32.3) 102 (31.3) 112 (33.3)

B 0 (0.0) 2 (0.6) 1 (0.3)

Negative 8 (2.4) 7 (2.1) 11 (3.3)

Axillary temperature at enrollment, meanC SD 38.54 0.72 38.56 0.72 38.47 0.78 Symptom score at enrollment,bmean score SD 11.4 3.2 11.3 3.1 11.4 3.7 Duration of illness before treatment, mean h SD 23.52 8.27 24.01 7.89 24.25 8.28

Outpatient 334 (100) 325 (99.7) 332 (98.8)

Concomitant disease 125 (37.4) 117 (35.9) 120 (35.7)

NOTE. Data are no. (%) of patients, unless otherwise indicated. SD, standard deviation.

a_{All patients included in the full analysis set had a positive result of the rapid diagnostic test.}

b_{Symptom scores are described in the Methods section.}

performed using SAS System, version 8.2 (SAS Institute). All reported P values were 2-sided without adjustments for mul-tiple testing.

In the efﬁcacy analysis, the full analysis set [24] based on the intention-to-treat principle was deﬁned as the primary anal-ysis set, and the per protocol set [24] was used in the sensitivity analysis. These analysis sets were used because the full analysis set and per protocol set are equally important in a noninfer-iority trial [25]. The safety analysis included all the patients who had received at least 1 dose of trial treatment and had at least 1 safety assessment.

RESULTS

A total of 1003 patients were enrolled (Figure 1). Of these, 4 patients were excluded from all the analyses; 1 patient discon-tinued the trial before receiving any treatment, and the in-formed consent of 3 patients was inappropriate (the partners of 2 patients signed the informed consent document, and 1 patient signed another person’s name). Three other patients did not record their inﬂuenza symptoms and were excluded from the full analysis set. A total of 996 patients were included

in the full analysis set (40-mg laninamivir octanoate, np

; 20-mg laninamivir octanoate, ; and oseltamivir,

334 np 326

). Of these, 1 patient did not receive the treatment as

np 336

allocated; this patient was included in the originally allocated treatment group in the full analysis set but was analyzed ac-cording to the actually administered treatment in the per pro-tocol set and safety analysis set.

The baseline characteristics were well balanced among the 3 groups in the full analysis set (Table 1) and in the per protocol

set (data not shown). All the patients in the full analysis set had positive results with the rapid diagnostic kits. Laboratory virological tests were negative for influenza infection in 26 pa-tients, and these patients were excluded from the per protocol set. Most patients were infected with influenza A (645 patients with H1N1 and 322 patients with H3N2), and only 3 patients were infected with influenza B. All the H1N1 strains carried the H274Y mutation except for viruses from 2 patients. The median

50% inhibitory concentration (IC50) of oseltamivir carboxylate

against the neuraminidase activity of the H1N1 strain was 690 nmol/L (range, 89–1500 nmol/L), whereas that of laninamivir

was 1.70 nmol/L (range, 0.45–4.40 nmol/L). The median IC50

values of oseltamivir carboxylate and laninamivir against the H3N2 strain were 0.68 nmol/L (range, 0.27–1.40 nmol/L) and 2.30 nmol/L (range, 0.78–4.40 nmol/L), respectively.

The time courses for illness alleviation were similar among the 3 groups (Figure 2). In the full analysis set, the median time to illness alleviation was 73.0, 85.8, and 73.6 h in the 40-mg laninamivir octanoate, 20-40-mg laninamivir octanoate, and oseltamivir groups, respectively (Table 2). The differences be-tween the respective dose levels for the laninamivir octanoate

and oseltamivir groups were⫺0.6 h (95% CI, ⫺9.9 to 6.9 h;

) and 12.2 h (95% CI,⫺1.5 to 17.2 h; ) for

Pp .748 Pp .104

the 40-mg and 20-mg laninamivir octanoate groups, respec-tively. The upper limits of both 95% CIs were less than the prespeciﬁed noninferiority margin (18 h). However, the time to illness alleviation was signiﬁcantly shorter in the 40-mg group than in the 20-mg laninamivir octanoate group (95%

CI,⫺18.2 to ⫺0.4 h; Pp .038). The treatment effect in the

40-mg group was consistent in subgroup analyses according to

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Figure 2. Time to illness alleviation in patients included in the full analysis set. The open circles indicate the patients whose inﬂuenza symptoms had not yet been alleviated by the time of their withdrawal from the study or the end of the observation period.

the virus subtype (H1N1 and H3N2). The median time for the return to a normal axillary temperature was 55.3, 58.0, and 54.7 h in the 40-mg laninamivir octanoate, 20-mg laninamivir octanoate, and oseltamivir groups, respectively. Similar results were also obtained from the per protocol set (Table 2).

The median virus titers and the proportions of patients shed-ding virus at baseline were similar among the 3 groups (Table 3). However, the proportion of patients shedding virus on day 3 was signiﬁcantly lower in the 40-mg laninamivir octanoate group (27.6%) than in the oseltamivir group (37.7%), with an

absolute difference of⫺10.1% (95% CI, ⫺17.2% to ⫺3.1%;

). In the H1N1-infected subpopulation, the

propor-Pp .006

tion of patients shedding virus on day 3 also differed signiﬁ-cantly between these 2 groups, with an absolute difference of

⫺14.7% (95% CI, ⫺23.7% to ⫺5.7%;Pp .001).

Both drugs were well tolerated. The most common adverse events were gastrointestinal events such as diarrhea, nausea, and vomiting. The event rates for diarrhea were 7.7% (26 of 337 patients), 5.5% (18 of 326 patients), and 7.7% (26 of 336 patients) in the 40-mg laninamivir octanoate, 20-mg lanina-mivir octanoate, and oseltalanina-mivir groups, respectively. For nau-sea, the rates were 1.2% (4 of 337 patients), 2.1% (7 of 326 patients), and 1.8% (6 of 336 patients), respectively. For vom-iting, the rates were 0.3% (1 of 337 patients), 0.3% (1 of 326 patients), and 2.4% (8 of 336 patients), respectively. These events were mild to moderate and resolved within several days. Mild to moderate dizziness was observed only in patients re-ceiving laninamivir octanoate (3 [0.9%] of 337 patients in the

40-mg laninamivir octanoate group and 6 [1.8%] of 326 pa-tients in the 20-mg laninamivir octanoate group), but none of the patients discontinued the trial because of dizziness.

DISCUSSION

The efﬁcacy of a single inhaled dose of laninamivir octanoate was not inferior to that of 10 doses of oseltamivir administered orally over 5 days. A laninamivir octanoate dose of 40 mg was optimal, and the time to illness alleviation was shorter than that for a 20-mg dose.

During the 2008–2009 inﬂuenza season, oseltamivir-resistant H1N1 virus carrying the H274Y mutation spread worldwide

[8]. Unexpectedly, ∼65% of the patients in this study were

infected with the oseltamivir-resistant H1N1 virus carrying the H274Y mutation. However, the median time to illness allevi-ation in the oseltamivir group (73.6 h) was similar to the times reported in other trials (70.0 to 87.4 h for oseltamivir groups vs 93.3–116.5 h for placebo groups) [20–23]. The important design features and the performance of the oseltamivir group in our trial were similar to those of other reports. Therefore, we concluded that our trial had a sufficient assay sensitivity [26] and was capable of confirming the efficacy of laninami-vir octanoate.

Among the patients infected with H3N2 virus, the 40-mg laninamivir octanoate group showed similar efﬁcacy to the os-eltamivir group in both the duration of illness and virus shedding.

These results were consistent with the IC50values of oseltamivir

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Table 2. Effe cts of Laninami vi r O c tanoate and Os e ltami vi r o n Clinic al Ou tcome s V ari abl e Ful l ana ly sis set Per pro to c o l set Laninamivir 40 mg Laninamivir 20 mg Oseltamivir Laninamivir 40 mg Laninamivir 20 mg Oseltamivir T im e to a lle v ia ti o n o f in fluenza ill ness No. of pa tien ts 334 326 336 299 294 301 Med ia n h (95 % C I) a 7 3 .0 (6 8.4– 8 0.8 ) 8 5 .8 (7 6.5– 9 2.8 ) 7 3 .6 (6 8.5– 8 3.3 ) 7 4 .0 (6 9.3– 8 1.9 ) 8 2 .5 (7 4.4– 9 1.8 ) 7 1 .3 (6 7.2– Dif fer en c e , bm edia n h (95 % C I) ⫺ 0. 6 (⫺ 9 .9t o6 .9 ) 1 2 .2( ⫺ 1.5 to 1 7.2) … 2 .7 (⫺ 7.3 to 1 0.3) 1 1 .2 (⫺ 1.2 to 1 7.8) … P c .74 8 .10 4 … .73 9 .08 9 … Dif fer en c e , d m edia n h (95 % C I) ⫺ 1 2.8 (⫺ 18 .2 to -0. 4 ) … … ⫺ 8. 5 (⫺ 15 .9 to 2. 3) … … P c .03 8 … … .14 6 … … T im e to a lle v ia ti o n o f in fluenza ill ness (A /H 1N1 ) No. of pa tien ts 218 215 212 NA NA NA Med ia n h (95 % C I) a 7 4 .0 (6 9.3– 8 2.0 ) 8 2 .9 (7 3.0– 9 1.8 ) 7 7 .5 (7 0.2– 9 3.8 ) N A N A N Dif fer en c e , b m edia n h (95 % C I) ⫺ 3. 5 (⫺ 15 .2 to 6. 8) 5.4 (⫺ 10.7 to 1 1.6) … N A N A … P c .46 1 .91 4 … NA NA … T im e to a lle v ia ti o n o f in fluenza ill ness (A /H 3N2 ) No. of pa tien ts 108 102 112 NA NA NA Med ia n h (95 % C I) a 7 2 .5 (5 7.8– 8 8.6 ) 9 1 .2 (7 1.6– 1 16.8 ) 6 7 .5 (5 3.5– 7 6.3 ) N A N A N Dif fer en c e , b m edia n h (95 % C I) 5 .0 (⫺ 7.3 to 1 9.8) 2 3 .7 (3 .4– 3 8.7 ) … N A N A -P c .36 6 .01 4 … NA NA -Tim e for ret ur n to n o rmal axill ar y te m p e ratur e No. of pa tien ts 334 326 336 299 294 301 Med ia n h (95 % C I) a 5 5 .3 (4 6.6– 6 4.0 ) 5 8 .0 (5 2.3– 6 6.9 ) 5 4 .7 (4 8.2– 6 2.2 ) 5 5 .3 (4 6.5– 6 4.1 ) 5 7 .2 (5 1.9– 6 4.2 ) 5 2 .3 (4 7.4– Dif fer en c e , bm edia n h (95 % C I) 0 .6 (⫺ 5.8 to 5 .7) 3 .3 (⫺ 2.8 to 9 .1) … 3 .0 (⫺ 4.7 to 7 .2) 4 .9 (⫺ 2.1 to 1 0.2) … P c .98 1 .31 8 … .69 9 .20 4 … N O TE. CI, confidence inter val; NA, not a nalyzed. a Esti mate d b y th e Kapl an-M e ie r m e th o d . b Com pa re d w it h osel ta mivir gr o u p . c Analyzed using the generalized W ilcoxon test. d Compared with laninamivir 20-mg group.

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Table 3. Effe cts of Laninami vi r O c tanoate and Os e ltami vi r o n V iru s Titers V ari abl e Ful l ana lysis set , vir us ty pe All ty pe s A/H 1N 1 A/H 3N 2 Lani na mi vir 40 mg Lani na mi vir 20 mg Osel ta miv ir Lani na mi vir 40 mg Lani na mi vir 20 mg Osel ta miv ir Lani na mi vir 40 mg Lani na mi vir 20 mg Osel ta miv ir Day 1 (b a sel ine ) No. of pa tien ts 334 325 336 218 214 212 108 102 112 V ir u s tite r, me d ia n log TC ID 50 /mL (r a n ge) 2 .5 0 (1.5 – 7 .5) 2 .7 0 (1.5 – 7 .5) 2 .7 0 (1.5 – 7 .5) 2 .5 0 (1.5 – 7 .5) 2 .7 0 (1.5 – 7 .5) 2 .7 0 (1.5 – 7 .5) 2 .7 0 (1.5 – 5 .5) 2 .7 0 (1.5 – 6 .0) 2 .7 0 (1.5 – 5 .7) She d d ing vir u s No. (% ) o f pati en ts a 2 9 4 (88.0) 2 9 0 (89.2) 3 0 6 (9 1.1) 1 9 9 (91.3) 1 9 4 (90.7) 1 9 7 (92.9) 9 4 (8 7.0) 9 2 (90.2) 1 0 4 (92.9) D if fere nce , b % (95% C I) ⫺ 3. 0 (⫺ 7 .7 to 1 .6) ⫺ 1. 8 (⫺ 6 .4 to 2 .7) … ⫺ 1. 6 (⫺ 6 .7 to 3 .5) ⫺ 2. 3 (⫺ 7 .5 to 2 .9) … ⫺ 5. 8 (⫺ 1 3.7 to 2 .1) ⫺ 2. 7 (⫺ 1 0.1 to 4 .8) … P c .20 8 .43 6 … .59 3 .48 1 … .18 0 .62 3 … Day 3 (d a y 2– 4) No. of pa tien ts 330 323 334 216 213 212 107 101 110 V ir u s tite r, me d ia n log TC ID 50 /mL (r a n ge) 1 .5 0 (1.5 – 5 .0) 1 .5 0 (1.5 – 6 .0) 1 .5 0 (1.5 – 7 .5) 1 .5 0 (1.5 – 5 .0) 1 .5 0 (1.5 – 4 .5) 1 .5 0 (1.5 – 4 .7) 1 .5 0 (1.5 – 3 .7) 1 .5 0 (1.5 – 3 .5) 1 .5 0 (1.5 – 4 .3) She d d ing vir u s No. (% ) o f pati en ts a 91 (27.6) 110 (34.1) 126 (37.7) 61(28.2) 68 (31.9) 91(42.9) 30 (28.0) 39 (38.6) 31 (28.2) D if fere nce , b % (95% C I) ⫺ 1 0.1 (⫺ 17.2 to -3.1) ⫺ 3. 7 (⫺ 1 1.0 to 3 .7) … ⫺ 1 4.7 (⫺ 23.7 to -5.7) ⫺ 1 1.0 (⫺ 20.1 to -1.9) … ⫺ 0. 1 (⫺ 1 2.1 to 1 1.8) 1 0 .4 (⫺ 2. 3 to 23. 1 ) … P c .00 6 .33 0 … .00 1 .02 1 … 1 .9 9 .14 3 … Day 6 (d a y 5– 7) No. of pa tien ts 325 323 328 212 214 206 106 100 110 V ir u s tite r, me d ia n log TC ID 50 /mL (r a n ge) 1 .5 0 (1.5 – 2 .0) 1 .5 0 (1.5 – 1 .7) 1 .5 0 (1.5 – 2 .2) 1 .5 0 (1.5 – 2 .0) 1 .5 0 (1.5 – 1 .7) 1 .5 0 (1.5 – 2 .2) 1 .5 0 (1.5 – 1 .5) 1 .5 0 (1.5 – 1 .5) 1 .5 0 (1.5 – 1 .5) She d d ing vir u s No. (% ) o f pati en ts a 7 (2.2) 2 (0.6) 5 (1.5) 6 (2.8) 1 (0.5) 4 (1.9) 1 (0.9) 1 (1.0) 1 (0.9) D if fere nce , b % (9 5 % CI ) 0.6 (⫺ 1. 4 to 2 .7 ) ⫺ 0. 9 (⫺ 2. 5 to 0 .7 ) … 0.9 (⫺ 2. 0 to 3 .8 ) ⫺ 1. 5 (⫺ 3. 6 to 0 .6 ) … 0.0 (⫺ 2. 5 to 2 .6 ) 0 .1 (⫺ 2. 5 to 2 .7 ) … P c .57 6 .45 0 … .75 1 .20 7 … 1 .9 9 1 .9 9 … N O TE. CI, conﬁdence inter val; TCID 50 , log 10 50 % tis sue cul tu re inf e cti ve do s e . a No. of pa tien ts with de te c ta ble vir u s (a t lea st 1. 5 log TC ID 50 /m L). b Com pa re d w it h osel ta mivir gr o u p . c Com pa re d w it h o s e lt a mivir gr o u p , by Fi she r’s ex act te s t.

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the duration of illness had no signiﬁcant difference between the 40-mg laninamivir octanoate group and the oseltamivir group. However, the durations of virus shedding in the 40-mg and 20-mg laninamivir octanoate groups were signiﬁcantly shorter than

in the oseltamivir group, in keeping with the IC50values.

There-fore, laninamivir might effectively inhibit the replication of os-eltamivir-resistant H1N1 viruses.

In the parallel trial of pediatric patients, laninamivir octano-ate reduced the duration of influenza illness significantly, com-pared with oseltamivir, against H1N1 virus with the H274Y mutation [27]. In addition, recent studies have found that the clinical efficacy of oseltamivir against H1N1 virus with the H274Y mutation was reduced, especially among children [28, 29]. Given these findings, the clinical efficacy of oseltamivir could be different in adults and in children against oseltamivir-resistant H1N1 virus. Considering that the course of influenza among children was more protracted with longer periods of virus shedding than in adults [3], it is possible that the differ-ence between adult and children is related to the patients’ im-mune status. In our study, most of the patients were aged 20– 39 years and did not have any underlying diseases. In this population, it could be difficult to evaluate the difference of the clinical efficacy between laninamivir octanoate and osel-tamivir against H1N1 virus with H274Y mutation. Further study will need to prove whether laninamivir octanoate has a positive impact on the clinical course of patients with oselta-mivir-resistant virus infections.

Laninamivir octanoate was well tolerated. The most common adverse events were gastrointestinal events, but their rates were similar to those in the oseltamivir group. Although dizziness was observed only in the laninamivir octanoate groups, this symptom has been reported in 2% of patients treated with other neuraminidase inhibitors [30, 31].

Our trial excluded high-risk populations, such as patients with chronic respiratory disease. In addition, we did not have the chance to enroll patients infected with the 2009 pandemic H1N1 virus, which became widespread after the completion of our trial. The efﬁcacy and safety of laninamivir octanoate in these populations should be evaluated in future trials. Non-clinical study results have shown that laninamivir octanoate is effective against the 2009 pandemic H1N1 virus [12]; thus, an assessment of its clinical efﬁcacy is warranted.

In conclusion, a single inhalation of laninamivir octanoate was sufﬁcient to treat adults with seasonal inﬂuenza including that caused by oseltamivir-resistant viruses. Furthermore, this treatment was well tolerated.

ON LONG-ACTING NEURAMIDASE INHIBITOR (MARVEL) STUDY GROUP

Project steering committee. Akira Watanabe (Research Di-vision for Development of Anti-Infective Agents, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan), Norio Sugaya (Keiyu Hospital, Kanagawa, Japan), Dai-suke Hiro, Katsuyasu Ishida, Akiko Nakahira, Eiji Kawakatsu, Emiko Murayama, Makoto Yamashita, Mitsutoshi Uemori (Daiichi Sankyo).

Investigators who enrolled at least 1 patient (number of patients enrolled in each region). Japan (787): Tadahiko

Oga-sawara, Yasuo Sato, Yuriko Tarukawa, Norio Yamaguchi, Hisaho Takahashi, Keisuke Egashira, Yasuhiko Hirata, Kunio Kondo, Kiyotaka Nakajima, Hitoshi Fujiwara, Shunya Sato, Makoto Koizumi, Jun Ogawa, Munenori Okamoto, Tatsuyuki Sato, Isao Sato, Hideki Nakazawa, Tadayuki Igarashi, Akira Hirosaka, Na-oto Fueki, Izuru Kobayashi, Masaaki Yoshihara, Masahiko To-kushima, Hiromu Tei, Tetsuo Takeda, Nobuyuki Kaji, Shinichi Hino, Ryohei Hisaki, Harumichi Nakamura, Haruhiko Oku-mura, Fumio Sakaguchi, Nobuhide Hanada, Hisakuni Sekino, Shiro Ozawa, Kazuhiko Oki, Jun Yamagami, Norihiko Saito, Akio Kubo, Shinichi Tamura, Yutaka Wakasa, Toshiko Otsuka, Ichiro Otani, Michio Hayashi, Hiroshi Hirata, Osamu Moriya, Shin Kawahara, Keiichi Iguchi, Yuji Tsuji, Hiroaki Tanaka; Ko-ichi Mochizuki, Shigeto Araki, Yoshinobu Matsumura, Toshi-hiko Sunami, Yuko Morita, Yasuo Tanno, Jun Hashida, Kotaro Fujimoto, Kazuhiro Ashino, Norio Iwaki, Eiji Oyake, Tetsuhiko Nakamura, Takafumi Tsuya, Kuninori Soejima, Toshiro Ni-nomiya, Takehiro Miyagishi, Masao Yamauchi, Atsushi Shi-basaki, Hiroshi Kazuma, Haruyoshi Uematsu, Masanobu Fun-amoto, Hirohide Yoneyama, Shingo Harita, Wataru Kajiyama, Koichi Taya, Kenji Otsuka, Hirofumi Miwa, Yasuhiko Kawade, Masahiko Kondo, Kyonyobi Min, Shinichi Kataoka, Susumu Sakayori, Akiko Kurokawa, Kuniyuki Takai, Naoki Kawai, Ma-sakazu Menju, Tomofumi Yano, Hideyuki Ikematsu, Hidehisa Nakazato, Masayoshi Sone, Yoshinori Keira, Shuji Kurane, Hi-roshi Tani, Kiyoshi Yasui, Masato Baden, Wataru Ikematsu, Kiyoyasu Fukushima, Tsukasa Itabashi, Tetsuhiko Nagao, Ma-saaki Nakayama, Taiwan (188): Shan-Chwen Chang, Liang-Wen Hang, Yao-Shen Chen, Shin-Ming Tsao, Wann-Cherng Perng, Hua-Kung Wang, Wen-Sen Lee, Yu-Jiun Chan, Chang-Hua Chen, Gwan-Han Shen, Cheng-Chang-Hua Chang-Huang, Lih-Shinn Wang, Tu-Chen Liu; Korea (21): Min Ja Kim, Dae Won Park, Woo-Joo Kim; Hong Kong (7): Daniel Wai-sing Chu, Jun Liang.

Acknowledgments

Financial support. Daiichi Sankyo.

Potential conﬂicts of interest. A.W. has received consultaning fees from

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Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Toyama Chem-ical, and Otsuka Pharmaceutical. S.-C.C., M.J.K., and D.W.C. have received research grants from Daiichi Sankyo. Y.O. has received consultaning fees from Daiichi Sankyo and Chugai Pharmaceutical.

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