Respiratory Medicine (2010) 104, 1629e1637

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24-h bronchodilator efficacy of single doses ofindacaterol in Japanese patients with asthma:A comparison with placebo and salmeterol

Naruhiko Sugihara a, Shigeto Kanada b, Michiko Haida c, Masakazu Ichinose d,Mitsuru Adachi e, Motoi Hosoe f,*, Charlotte Emery g, Mark Higgins g,Benjamin Kramer h

a Jinyu Clinic Hospital, Jinyukai Healthcare Corporation, 2-45-10 Honmachi, Nakano-ku, Tokyo 164-0012, JapanbOCROM Clinic, Henshinkai Healthcare Corporation, 4-12-11 Kasuga Suita-shi, Osaka 565-0853, JapancHanzomon Hospital, Mokeikai Healthcare Corporation, 1-10 Koujimachi, Chiyoda-ku, Tokyo 102-0083, JapandThird Department of Internal Medicine, Wakayama Medical University, School of Medicine, Wakayama 641-8509, Japane First Department of Internal Medicine, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo142-8666, JapanfNovartis Pharma KK, 4-17-30 Nishi-Azabu, Minato-ku, Tokyo 106-8618, JapangNovartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UKhNovartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936-1080, USA

Received 10 March 2010; accepted 14 June 2010Available online 8 July 2010

KEYWORDSAsthma;Bronchodilator;Corticosteroids;Indacaterol;Salmeterol

* Corresponding author. Tel.: þ81 3E-mail address: motoi.hosoe@nova

0954-6111/$ - see front matter ª 201doi:10.1016/j.rmed.2010.06.011

Summary

Background: Indacaterol is a novel, inhaled once-daily ultra-long-acting beta-2 agonist underdevelopment as a fixed-dose combination with an inhaled corticosteroid (ICS) for asthma treat-ment. This study evaluated the 24-h bronchodilator efficacy of indacaterol in Japanesepatients with asthma.Methods: Randomised, placebo-controlled, 5-period crossover study. Patients with persistentasthma (18e75 years, FEV1 50e85% predicted, �12% and 200 mL FEV1 reversibility) receivingICS were randomised to double-blind single dose indacaterol 150, 300, or 600 mg or placebo,with open-label salmeterol 50 mg twice-daily for one day in the 5th period. Primary endpointwas FEV1AUC22e24h.Results: Of 41 randomised patients (48.8% male; mean age: 47.8 years), 39 completed. All in-dacaterol doses showed significantly higher FEV1AUC22e24h than placebo (P< 0.001), withtreatmenteplacebo differences of 180, 220, and 260 mL for indacaterol 150, 300, and600 mg, respectively (salmeteroleplacebo difference 170 mL; P < 0.001). For individualtime-point FEV1, all indacaterol doses were superior to placebo from 5 min to 24 h post-dose

3797 5254; fax: þ81 3 3797 5426.rtis.com (M. Hosoe).

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1630 N. Sugihara et al.

(P < 0.001). Compared with salmeterol, all indacaterol doses were superior from 5 to 30 min(P < 0.05); in addition indacaterol 300 mg and 600 mg were superior at a number of subsequenttime points. Changes in safety parameters with indacaterol were similar to placebo. All inda-caterol doses were well tolerated.Conclusion: Single dose indacaterol provided sustained 24-h bronchodilation with a fasteronset of action than salmeterol and a good overall safety and tolerability profile in Japanesepatients with asthma. These results are consistent with data from Caucasian populations.ª 2010 Elsevier Ltd. All rights reserved.

Introduction

Worldwide, asthma affects people of all ages causingsubstantial debilitating symptoms and leading to a reducedquality of life.1,2 Evidence from most studies, includinglongitudinal surveys, suggests that the prevalence ofasthma has increased over the past decades in many partsof the world, including Japan.3e7 Persistent asthma is mosteffectively controlled with inhaled corticosteroids (ICSs)administered daily on a long-term basis.8 For patients withasthma not adequately controlled with a low-dose ICSalone, current treatment guidelines recommend the addi-tion of a long-acting beta-2 agonist (LABA) to the existingICS therapy.7e10

The goal of asthma management is to achieve and main-tain control of symptoms e a major obstacle to which hasbeen low patient adherence to medication plans.11 A keyfactor contributing to poor adherence is a complicated ormultiple treatment regimen, with simplified dosing regimensknown to improve compliance.11,12 Currently availableinhaled LABAs (e.g., salmeterol and formoterol) have anapproximately 12-h duration of action, necessitating twice-daily (bid) dosing to provide optimal clinical efficacy.13,14

Thus the availability of a once-daily beta-2 agonist witha24-hdurationof actioncombinedwitha once-daily ICS couldimprove clinical outcomes in asthma by providing increasedpatient convenience and sustained bronchodilation.

Indacaterol is a novel, once-daily, inhaled, ultra-LABAunder development as a fixed-dose combination with ICS forthe treatment of asthma. In preclinical studies, indacateroldemonstrated a sustained bronchodilator and bronchopro-tective effect, with a fast onset of action (comparable tosalbutamol and formoterol) and greater cardiovascularsafety margin than formoterol or salmeterol.15,16 Further-more, in earlier clinical studies involving mostly theCaucasian population, indacaterol showed effective 24-hbronchodilation, with a fast onset of action and a goodoverall safety and tolerability profile.17e21 The presentdose-ranging study was the first to investigate the 24-hbronchodilatory efficacy and safety of single doses ofindacaterol 150, 300, and 600 mg delivered via a single-dosedry-powder inhaler (SDDPI) in Japanese patients withasthma. Given its similarity to a study conducted ina Caucasian population it helps to evaluate the ethnicsensitivity of the efficacy and safety of indacaterol.21

Methods

This was a Phase II, multicentre, randomised, double-blind,placebo-controlled, crossover, dose-ranging study conducted

between November 2006 and November 2007 at 11 speci-alised allergy and respiratory care units in Japan(ClinicalTrials.gov registration no.: NCT00403754).22 Thestudy was performed in accordance with the Declaration ofHelsinki and the International Conference on HarmonisationGood Clinical Practice guidelines. The study was approved bythe institutional review board of each participating studycentre, and all patients provided written informed consentbefore participating in the study.

Study population

The study recruited Japanese patients (aged 18e75 years)with a clinical diagnosis of asthma according to the 2006Japanese asthma prevention and management guideline7

(FEV1 between 50% and 85% of the predicted normal valueat screening, with �12% and 200 mL reversibility in FEV1

within 30 min after inhalation of salbutamol 200 mg). Inaddition, patients must have received daily ICS treat-mentddefined as fluticasone propionate 200e800 mg (orequivalent)din a stable regimen for at least 4 weeks beforethe screening visit (Visit 1).

Patients were excluded if they underwent hospitaliza-tion or emergency room treatment for an acute exacerba-tion of asthma in the 6 months before Visit 1, hadrespiratory disease other than asthma, had respiratorytract infection within 4 weeks before Visit 1, used tobaccoproducts within 6 months before Visit 1, or had a smokinghistory of more than 10 pack-years. The other exclusioncriteria included seasonal allergies that might cause dete-rioration of asthma; allergy to beta-2 agonists, sympatho-mimetics, and inhaled medications; ischemic heart disease;arrhythmia; uncontrolled hypertension; type 1 diabetes;cancer; and a prolonged QT interval.

Study design and treatments

The study comprised a 14-day screening period, fourdouble-blind treatment periods (Visits 2e9), and an open-label treatment period (Visits 10 and 11) (Fig. 1). The visitson Day 1 and Day 2 of each treatment period were onconsecutive days. Following screening, all eligible patientswere randomised equally (at Visit 2), using a validatedautomated system, to one of four treatment sequences toreceive a single dose of indacaterol 150, 300, and 600 mg orplacebo via an SDDPI. Patients who completed the double-blind treatment period entered a single-day, open-labeltreatment period with salmeterol 50 mg bid delivered viathe manufacturer’s proprietary multidose dry-powderinhaler.

Figure 1 Study design. ( ) placebo, ( ) salmeterol 50 mg (bid), ( ) indacaterol 150 mg, ( ) indacaterol 300 mg and( ) indacaterol 600 mg.

Efficacy of indacaterol in asthma 1631

During the double-blind treatment periods, the studydrug was inhaled between 08:00 and 10:00 AM on Day 1(Visits 2, 4, 6, and 8). During the open-label period (Visit10), the first salmeterol dose was inhaled between 08:00and 10:00 AM, and the second dose was inhaled afterspirometry at 12 h post-dose. Each treatment period wasseparated by a 14e28 day washout period. Treatmentallocation was concealed from the patients, investigatingstaff, and the clinical trial team by using study drugs thatwere identical in packaging, labelling, appearance, andadministration schedule.

Concomitant medication

Other than ICS in a fixed-dose regimen that had been sta-bilised for at least 4 weeks prior to Visit 1 with the ICS doseremaining unchanged throughout the study, the followingasthma treatments were allowed between the treatmentperiods (following the same regimen as the one before Visit1): short-acting beta-2 agonists (6 h), LABAs (48 h),xanthine derivatives (7 days), leukotriene antagonists(72 h), and short-acting anticholinergics (8 h). Thesetreatments, however, had to be discontinued no later thanthe specified time (mentioned within the parenthesesabove) before Visits 1, 2, 4, 6, 8, and 10, and were not to berecommenced until the completion of the last spirometryevaluations at Visits 3, 5, 7, 9, and 11. Salbutamol was theonly rescue medication permitted throughout the study,although visits had to be rescheduled if it was taken within6 h prior to the first spirometry measurements during thatvisit.

Assessments

Efficacy and safety were assessed for 24 h post-dose in eachtreatment period. Efficacywas assessed by spirometry usingthe same model of spirometer at all sites (MICROSPIRO HI-201�, Nihon Kohden Corporation, Tokyo, Japan). FEV1, FVC,and FEF25e75% were determined pre-dose (15 min before

inhalation of the studymedication), and at 5, 15, and 30 minand 1, 2, 4, 8, 12, 22, 23, and 24 h post-dose. The primaryefficacy outcomewas the time-standardised area under thecurve (AUC) of FEV1 values measured between 22 and 24 hpost-dose (FEV1AUC22e24h). By using data from up to threetime points, this endpoint (which can be considered anaverage of data from the three evaluations) has theadvantage of a smaller standard deviation compared witha single time point, and provides more power for a givennumber of patients. Further, since data forming thisendpoint are from the end of the dosing interval, thisendpoint should capture the lowest measured treat-menteplacebo differences. Secondary efficacy outcomesincluded percent change in FEV1 from baseline at eachindividual time point post-dose; peak FEV1 (defined as themaximum FEV1 value recorded between 5 min and 4 h post-dose); standardised FEV1AUC0e24h; and individual timepoint FEV1, FVC, and FEF25e75%.

Safety assessments involved recording of all adverseevents (AEs) and serious adverse events (SAEs) in alltreatment periods. The occurrence of AEs was sought bynon-directive questioning of patients at each visit duringthe study, and may also have been detected when vol-unteered by patients during or between visits or throughphysical examination, laboratory test, or other assess-ments. In addition, during the double-blind treatmentperiods, safety was assessed by monitoringdat regulartime points in each treatment perioddof haematology andblood biochemistry (including serum potassium and bloodglucose); urinalysis; and regular assessments of vital signsand ECGs. During the open-label treatment period, with theexception of adverse events no other safety data wascollected.

Sample size calculation and statistical analyses

The three main treatment comparisons were indacaterol150 mg versus placebo, indacaterol 300 mg versus placebo,and indacaterol 600 mg versus placebo. The sample size

1632 N. Sugihara et al.

calculation was based on the post-dose primary efficacyvariable, standardised FEV1AUC22e24h. A standard deviation(SD) of 283 mL,23 reversibility threshold of 12%, two-sidedsignificance level of 10% (adjusted to 3.3% using a Bonfer-roni correction for the three main treatment comparisons),and power of 85% were chosen for the sample size calcu-lation. Assuming a drop out rate of 15% and to ensurebalance across the treatment sequences, 40 patients wereto be randomised in order to have at least 32 patientscompleting the study.

The primary efficacy analysis was performed on a modi-fied intention-to-treat (mITT) population, which includedall randomised patients who received at least one dose ofthe study drug. Patients receiving only one treatment didnot contribute to the analyses of treatment contrasts butremained in the population for the calculation of treatmentmeans. The safety population included all patients whoreceived at least one dose of the study drug and was used inthe analysis of all safety variables. For both populations,the patients were analysed according to the treatment theyreceived.

For the primary efficacy variable, standardised FEV1AUC22e24h, treatment differences between each indacateroldose and placebo were tested using analysis of covariance(ANCOVA), with patient, period, and treatment groupmodelled as fixed effects and period baseline FEV1 asa covariate. Adjustment for multiple comparisons was madeusing a stepwise Dunnett test. ANCOVA models were alsoused to analyse all the secondary efficacy variables. ANCOVAmodels were also used to provide between-indacaterol-dosecomparisons and comparisons with salmeterol; however,these analyses were regarded as exploratory, because thestudy was not powered for comparisons between the activetreatment groups. The corrected QT (QTc) interval was

Table 1 Patient demographics and baseline characteristics (saf

Parameters

Age, years

SexMaleFemale

Weight, kgBMI, kg/m2

Duration of asthma, years

ICS daily dose fluticasone propionate equivalent, mg

FEV1 (pre-bronchodilator) at screening, L% predicted FEV1 (pre-bronchodilator) at screening

FEV1 (post-bronchodilator) at screening, LFEV1 reversibility*Smoking historyNon-smokersEx-smokers

Smoking history, pack-years

ICS, inhaled corticosteroid; BMI, body mass index.*% increase in FEV1 within 30 min after inhalation of salbutamol from

calculated from the QT and RR intervals using Fridericia’sformula (QTcF).24 All tests of hypotheses used were two-tailed and interpreted at the 10% significance level (as thiswas a dose-finding study). The data were analysed using SASstatistical software version 8.1 (or higher) for Windows (SASInstitute Inc., Cary, NC, USA).

Results

Patient disposition, demographics, and baselinecharacteristics

Of 93 screened patients, 41 were randomised to treatment.Out of the 41 randomised patients, 39 (95.1%) completedthe study. Two patients (4.9%) discontinued, one due tounsatisfactory therapeutic effect after the second treat-ment period (having received indacaterol 300 mg andplacebo) and the other withdrew consent after the firsttreatment period (having received indacaterol 150 mg).Table 1 shows the demographics and baseline characteris-tics of the patients in the study, all of whom wereJapanese.

Efficacy

Indacaterol at all doses resulted in a statistically superior(P < 0.001) adjusted mean standardised FEV1AUC22e24h

compared to placebo (Fig. 2), with treatmenteplacebodifferences of 180 (90% CI: 120, 250), 220 (150, 280), and260 (190, 320) mL for the 150, 300, and 600 mg doses,respectively, compared with a salmeteroleplacebodifference of 170 (120, 220) mL. At all time points from5 min to 24 h post-dose, all indacaterol doses showed

ety population).

Statistic Total (N Z 41)

Mean (SD) 47.8 (14.90)Range 22e74

n (%) 20 (48.80)n (%) 21 (51.20)Mean (SD) 62.1 (11.50)Mean (SD) 23.3 (3.39)Mean (SD) 17.5 (14.60)Range 0.1e49Mean (SD) 351.2 (177.65)Range 200e800Mean (SD) 2.01 (0.66)Mean (SD) 67.3 (9.87)Range 50.5e84.2Mean (SD) 2.4 (0.79)Mean (SD) 20.1 (7.90)

n (%) 29 (70.7)n (%) 12 (29.3)Mean (SD) 4.3 (2.83)

FEV1 before inhalation of salbutamol.

Figure 2 Primary endpoint: standardised FEV1AUC22-24h LS mean (SE) (mITT population). AUC, area under curve; SE, standarderror; LS, least squares; mITT, modified intent-to-treat. *P < 0.001 vs placebo; yP < 0.05 vs indacaterol 150 mg; zP < 0.05 vssalmeterol 50 mg bid.

Figure 3 LS mean FEV1 (a) over 24 h and (b) 0e4 h post-dose(mITT population). LS, least squares; mITT, modified intent-to-treat. ( ) placebo, ( ) salmeterol 50 mg bid, ( )indacaterol 150 mg, ( ) indacaterol 300 mg and ( )indacaterol 600 mg. All indacaterol doses superior to placebo(p < 0.001) at all post-dose time points and superior tosalmeterol (p < 0.05) from 5 to 30 min post-dose.

Efficacy of indacaterol in asthma 1633

statistically significant differences (P < 0.001) in theadjusted mean FEV1 as compared with placebo (Fig. 3). Inaddition, all doses of indacaterol were statistically supe-rior (P < 0.05) to salmeterol from 5 min to 30 min post-dose.

Indacaterol resulted in a significantly greater peak FEV1

compared with placebo (P < 0.001) and numerically (150and 300 mg) or statistically (600 mg) higher peak FEV1

compared with salmeterol 50 mg bid. All indacaterol dosesresulted in significantly higher (P < 0.001) adjusted meanFEV1AUC0e24h than placebo with treatmenteplacebodifferences of 220 (90% CI: 170, 270) mL, 270 (220, 320) mL,and 310 (260, 360) mL for the 150, 300, and 600 mg doses,respectively, and a salmeteroleplacebo difference of 200(150, 240) mL. When compared with salmeterol, thestandardised FEV1AUC0e24h was significantly greater withindacaterol 600 mg (110 mL; P < 0.001) and 300 mg (80 mL;PZ 0.0096), and numerically higher with indacaterol150 mg (30 mL; PZ 0.34). All indacaterol doses showedsignificantly higher FVC, FEF25e75%, and percent changefrom period baseline in FEV1 than placebo at all post-dosetime points (P < 0.002), with profiles similar to thoseobserved for FEV1 (data not shown). Indacaterol alsoshowed higher FVC, FEF25e75%, and percent change fromperiod baseline in FEV1 than salmeterol at the majority ofthe post-dose time points.

Safety

Indacaterol doses were well tolerated, with no deaths orSAEs reported. The overall incidence of AEs during thedouble-blind treatment phase was 27.5% (11/40), 45.0%(18/40), 40.0% (16/40), and 56.4% (22/39) for placebo andindacaterol 150, 300, and 600 mg, respectively (Table 2).The most commonly reported AE with indacaterol treat-ment was cough, which was mostly mild in severity andtransient in nature, occurring just after inhalation of thestudy drug.

There were no minimum post-baseline potassium values(below 3.0 mmol/L) with any of the treatments, maximumpost-baseline glucose values (above 9.99 mmol/L) were

Table 2 Number of patients (%) with AEs and by primary SOC (safety population).

AEs Indacaterol Salmeterol Placebo

150 mgN Z 40

300 mgN Z 40

600 mgN Z 39

50 mg bidN Z 39

N Z 40

n (%)

Total number of patients with AEs 18 (45.0) 16 (40.0) 22 (56.4) 2 (5.1) 11 (27.5)Primary SOC affectedRespiratory, thoracic, and mediastinal disorders 14 (35.0) 13 (32.5) 15 (38.5) 0 5 (12.5)Nervous system disorders 2 (5.0) 3 (7.5) 1 (2.6) 1 (2.6) 3 (7.5)Gastrointestinal disorders 2 (5.0) 1 (2.5) 0 1 (2.6) 0Infections and infestations 2 (5.0) 0 2 (5.1) 0 1 (2.5)Investigations 2 (5.0) 0 1 (2.6) 0 1 (2.5)Musculoskeletal and connective tissue disorders 2 (5.0) 0 1 (2.6) 1 (2.6) 1 (2.5)Ear and labyrinth disorders 0 1 (2.5) 1 (2.6) 0 1 (2.5)Hepatobiliary disorders 1 (2.5) 0 0 0 0Immune system disorders 0 0 1 (2.6) 0 0Injury, poisoning, and procedural complications 0 0 1 (2.6) 0 0Psychiatric disorders 1 (2.5) 0 0 0 0Skin and subcutaneous tissue disorders 0 1 (2.5) 1 (2.6) 0 1 (2.5)

AEs, adverse events; SOC, system organ class.A patient with multiple AEs on one treatment and under one SOC is counted only once for that organ class and the treatment regardlessof the number of AEs.

Table 3 Overall incidence of hypokalaemia, hyperglycaemia, abnormal values of pulse rate and blood pressure, and changefrom baseline in QTc interval (Fridericia’s formula) (safety population).

Indacaterol Placebo

150 mgN Z 40

300 mgN Z 40

600 mgN Z 39

N Z 40

n (%)

Serum potassium: minimum post-baseline valuea

Below lower limit of normal range 1 (2.5) 4 (10.0) 3 (7.7) 2 (5.0)Below 3.0 mmol/L 0 0 0 0

Blood glucose: maximum post-baseline valuea

Above upper limit of normal range 22 (55.0) 21 (52.5) 26 (66.7) 20 (50.0)Above 9.99 mmol/L 0 3 (7.5) 1 (2.6) 0

Pulse rate e maximum post-baseline valueb

Above 90 bpm 0 2 (5.0) 0 1 (2.5)Systolic blood pressure e maximum post-baseline valuec

Above 140 mm Hg 7 (17.5) 6 (15.0) 5 (12.8) 5 (12.5)Diastolic blood pressure e minimum post-baseline valuec

Above 90 mm Hg 6 (15.0) 6 (15.0) 4 (10.3) 7 (17.5)QTc value e (Fridericia’s formula)d

Absolute values>450 ms (males) 0 0 0 0>470 ms (females) 0 0 0 0Change from baseline>60 ms 0 0 0 0

a The measurement of serum potassium and blood glucose levels were taken at pre-dose, and 15 min, 1 h, 4 h and 24 h post-dose foreach treatment.b The measurement of pulse rate was taken at pre-dose, and at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 22 h, 23 h, and 24 h post-dose for

each treatment.c The measurement of blood pressure was taken at pre-dose, and 15 min, 1 h, 4 h, 12 h and 24 h post-dose for each treatment.d ECG was taken at pre-dose, 1 h, 4 h, and 24 h post-dose for each treatment.

1634 N. Sugihara et al.

Efficacy of indacaterol in asthma 1635

reported with three patients following indacaterol 300 mgand one patient following 600 mg, none of which were,however, associated with AEs (Table 3).

As summarised in Table 3, the incidence of abnormalvalues for pulse rate (>90 bpm) and diastolic (>90 mm Hg)and systolic (>140 mm Hg) blood pressure was similarbetween placebo and the indacaterol treatments, indicatingno relationship with indacaterol dose. No clinically signifi-cant ECG abnormalities and no abnormal QTcF prolongation(male: QTcF >450 ms; female: >470 ms) or change in QTcFfrom baseline (>60 ms) were observed with any of thetreatments (Table 4).

Discussion

This was the first study to evaluate the 24-h bronchodilatorefficacy of single doses of indacaterol 150, 300, and 600 mgin Japanese patients with asthma. This crossover studyshowed that indacaterol provided sustained 24-h broncho-dilation, with a fast onset of action and a good overallsafety and tolerability profile. A crossover design waspreferred because variations in FEV1 within patients wereexpected to be less compared with variations in FEV1

between patients.In the present study, the primary efficacy analysis

showed that all indacaterol doses were associated withstatistically significantly greater (P < 0.001) standardisedFEV1AUC22e24h than placeboda finding consistent witha previous dose-ranging study.19 Furthermore, the corre-sponding 90% CIs of the differences between the indaca-terol doses and placebo were relatively narrow, indicatingthe precision of the estimated differences. In terms ofcomparisons between indacaterol doses, the 600 mg dosewas statistically superior to the 150 mg dose for thisendpoint, whereas there was no statistically significantdifference between indacaterol 150 and 300 mg. In previousstudies in patients with asthma in which indacaterol wasadministered at a dose of 50e600 mg, there were similarseparations in efficacy between the lowest and highestindacaterol dose.19e21,23,25 The current study wouldsuggest that, given the similar efficacy to salmeterol,150 mg could be the minimal effective dose of indacaterolin asthmae this would, however, need confirming in a morecomprehensive dose-finding study. The results of theprimary analysis of this study was supported by those of thesecondary efficacy analyses, demonstrating that all threeindacaterol doses had statistically significant higher peakFEV1 and standardised FEV1AUC0e24h compared withplacebo (P < 0.001). In addition, all indacaterol dosesshowed notable improvements in FEV1 at nearly all timepoints over 24 h compared with placeboda finding alsoconsistent with earlier studies conducted mostly on theCaucasian population.18e21,25 These results, together withthe 24-h profiles of FVC and FEF25e75%, indicate that inda-caterol provided effective and sustained 24-h bronchodi-lation, which further supports the potential fora once-daily dosing regimen. Given the similar efficacydemonstrated by indacaterol in Japanese and Caucasianpatients, this is an indication that indacaterol is likely to beeffective in the management of asthma regardless ofa patient’s ethnicity. This is an important consideration forany bronchodilator, given there is an evidence of

divergence in beta-2 adrenoceptor polymorphism haplo-type frequency in the ethnic groups26 In addition, severalstudies have investigated the polymorphisms of beta-2adrenoceptor with regard to the bronchodilator responseto inhaled beta-2 agonists.27,28 However, in clinical studiesinvestigating the use of LABAs in COPD patients, there areseveral reports that demonstrate similar response inJapanese and Caucasian populations.29,30

In previous studies in the Caucasian population, inda-caterol has shown a fast onset of action, similar to that ofsalbutamol (a short-acting beta-2 agonist) and faster thansalmeterol.18 The results of our study are also consistentwith these findings, as significant improvements in FEV1appeared as early as 5 min post-indacaterol dose (theearliest time point evaluated), with all indacaterol dosesshowing statistical superiority (P < 0.05) to salmeterol untilat least 30 min post-dose.

The convenience of once-daily dosing together withsustained bronchodilation and a fast onset of action couldpotentially enable enhanced patient compliance andasthma control compared with twice-daily therapies.20

Thus indacaterol, when combined with a once-daily ICS,could have an advantage in terms of patient acceptability,convenience, and adherence to therapy. These aspects ofindacaterol treatment could not be assessed in the currentstudy, given the single-day dosing study design. Further-more, salmeterol was administered on an open-label basisin the final treatment period for all patients. This was forpractical purposes, and made the study design less complex(with only one type of placebo inhaler required), and itshould be noted that the primary comparison was betweenindacaterol and placebo. However, the inclusion of a LABAactive comparator is helpful in the interpretation of thestudy results.

All indacaterol doses in the present study were welltolerated and showed a good overall safety profile. Nopatient treated with indacaterol discontinued the studydue to AEs. Most AEs reported in this study were expectedin this patient population and were similar to thoseobserved in previous studies conducted outsideJapan.17,18,20,31 The incidence of AEs reported in this studywas higher with indacaterol treatment than with open-label salmeterol (which was taken by all patients duringthe final treatment period). This difference in the rate ofAEs was due to the higher incidence of cough in patientstreated with indacaterol. The majority of cough AEs weremild in severity, occurred just after inhalation of studydrug and were transient in nature. Notably, recording ofAEs was the only safety assessment performed forsalmeterol.

No deaths or SAEs were reported in this study. Given theclass effects of beta-2 agonists on serum potassium andblood glucose, these parameters were analysed exten-sively, and there was no clear relationship between theincidence of hypokalaemia or hyperglycaemia and theindacaterol doses. Furthermore, no major effect on the QTinterval and pulse rate was observed with the indacateroldoses.

The overall safety and tolerability profile of indacaterolwas consistent with the previous studies that involvedrepeated indacaterol doses for up to 28 days.17,27 Furtherstudies investigating the long-term efficacy and safety of

1636 N. Sugihara et al.

indacaterol in a fixed-dose combination with an ICS areplanned.

In conclusion, single doses of indacaterol 150, 300, and600 mg in combination with an ICS provided superior bron-chodilation for 24-h with a faster onset of action comparedwith salmeterol 50 mg bid in combination with an ICS inJapanese patients with asthma. In addition, indacateroldemonstrated a good overall safety and tolerability profilein this patient population. Therefore, the development ofindacaterol in conjunction with an ICS could be a usefultreatment option for Japanese patients with asthma.

Acknowledgements

The authors thank the patients who took part and the staffat the participating clinical centres. Special thanks for theconduct of this study to Ken Ohta (Teikyo University),Yasujiro Matsunaga (Shuwa General Hospital), HisakuniSekino (Sekino Hospital), Tadashi Arai (SEMPOS Tokyo-Takanawa Hospital), Motokazu Kato (Kishiwada CityHospital), Hitomi Tatsuta (Wakayama Rosai Hospital),Hironori Sagara (Dokkyo Medical University Hospital), Hir-oshi Takahashi (Kanagawa Cardiovascular and RespiratoryCenter). This study was funded by Novartis Pharma AG,Basel, Switzerland.

The authors would like to thank Dr.Yogeeta Maju,professional medical writer (Novartis) and David Young(Novartis) for assistance in preparing the manuscript, andYuko Asahara (Novartis) for preparing the study report.

Conflict of interest statement

This study was funded by Novartis Pharma AG, Basel,Switzerland. Motoi Hosoe, Benjamin Kramer, Mark Higginsand Charlotte Emery are employees of Novartis. BenjaminKramer and Mark Higgins holds shares in Novartis. MitsuruAdachi has previously served on scientific advisory boardsof GlaxoSmithKline KK, Nippon Boehringer Ingelheim,Novartis Pharma KK, AstraZeneca KK, Shering-Plough KK,and KYORIN Pharmaceutical Co., Ltd. He has receivedlecture fees from GlaxoSmithKline KK, Nippon BoehringerIngelheim, Novartis Pharma KK, AstraZeneca KK, Shering-Plough KK, and KYORIN Pharmaceutical Co., Ltd. andunrestricted grants from GlaxoSmithKine KK, NipponBoehringer Ingelheim and Novartis Pharma KK. MasakazuIchinose has previously served on scientific advisoryboards of GlaxoSmithKline KK, Nippon Boehringer Ingel-heim, Novartis Pharma KK and AstraZeneca KK. He hasreceived lecture fees from GlaxoSmithKline KK, AstraZe-neca KK and Nippon Boehringer Ingelheim and unre-stricted grants from GlaxoSmithKine KK and NipponBoehringer Ingelheim. Naruhiko Sugihara, Shigeto Kanadaand Michiko Haida have no relevant conflicts of interestor financial disclosures. Naruhiko Sugihara, ShigetoKanada, Michiko Haida, Masakazu Ichinose and MitsuruAdachi contributed to the data collection. Motoi Hosoe,Benjamin Kramer and Charlotte Emery were involved inthe study design and in overseeing conduct, analysis andinterpretation of data. All authors contributed to thedevelopment of the manuscript, and approved the deci-sion to submit the manuscript.

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