- Email: [email protected]
Bronchodilator efficacy of indacaterol, a novel once-daily β2-agonist, in patients with persistent asthma
Bronchodilator efficacy of indacaterol, a novel once-daily 2-agonist, in patients with persistent asthma David S. Pearlman, MD*; Leon Greos, MD†; Craig LaForce, MD‡; Chadwick J. Orevillo, MPH§; Roger Owen, PhD¶; and Mark Higgins, MD¶ Background: Indacaterol is a novel once-daily inhaled 2-agonist in development for the treatment of patients with asthma or chronic obstructive pulmonary disease. Objective: To investigate the bronchodilator efficacy of indacaterol in patients with persistent asthma. Methods: Patients received a randomized sequence of single doses of indacaterol, 400 g, via single-dose dry powder inhaler (SDDPI); indacaterol, 200 g, via multidose dry powder inhaler (MDDPI); and placebo. At each visit, the forced expiratory volume in 1 second (FEV1) was recorded at a series of time points during a 24-hour period. Results: Of 33 patients screened, 25 were randomized to treatment. Adjusted mean FEV1 was significantly higher (P ⱕ .005) for both indacaterol doses vs placebo at most time points. The first time points at which statistically significant treatment differences were observed for indacaterol and placebo in FEV1 were 0.17 L at 5 minutes after dosing for 400 g of indacaterol (SDDPI) and 0.21 L at 10 minutes for 200 g of indacaterol (MDDPI) (both P ⬍ .001 vs placebo). Differences relative to placebo at the final time point, 24 hours after dosing, were 0.29 L and 0.15 L for indacaterol, 400 g and 200 g, respectively (both P ⱕ .003 vs placebo). Overall, FEV1 was significantly higher for the 400-g dose compared with the 200-g dose from 15 minutes to 2 hours after dosing (P ⱕ .013) and from 5 hours onward (P ⱕ .022). Indacaterol was associated with good tolerability and safety. Conclusions: Indacaterol demonstrates sustained bronchodilator efficacy throughout the full 24-hour period, with a rapid onset of action and a good overall safety profile. Ann Allergy Asthma Immunol. 2008;101:90–95.
INTRODUCTION Guidelines such as those produced by the National Asthma Education and Prevention Program and the Global Initiative for Asthma1,2 recommend short-acting 2-agonists for prevention of exercise-induced bronchospasm and relief of symptoms. These guidelines also recommend the addition of currently available long-acting 2-agonists to standard initial doses of inhaled corticosteroids (ICS) for regular twice-daily dosing to enhance long-term control of symptoms, including nocturnal symptoms, in patients who are not adequately controlled with ICS alone. Indacaterol is a novel once-daily 2-agonist in development for the treatment of patients with asthma or chronic obstructive pulmonary disease. Clinical studies have shown
Affiliations: * Colorado Allergy and Asthma Centers, PC, Denver, Colorado; † Colorado Allergy and Asthma Centers, PC, Englewood, Colorado; ‡ North Carolina Clinical Research, Raleigh, North Carolina; § Novartis Pharmaceuticals Corp, East Hanover, New Jersey; ¶ Novartis Horsham Research Centre, Horsham, England. Disclosures: Authors have nothing to disclose. Funding Sources: This study was sponsored by Novartis Pharma AG. This study has been registered on the Novartis clinical trials Web site under study number CQAB149A2218 (accessible via http://www.novartis clinicaltrials.com/webapp/clinicaltrialrepository/public/login.jsp). Received for publication June 11, 2007; Received in revised form November 13, 2007; Accepted for publication January 10, 2007.
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that single doses of indacaterol given via hydrofluoroalkane (HFA) metered-dose inhaler (MDI) provide effective 24-hour bronchodilation with a fast onset of action and are well tolerated.3 A good safety profile was demonstrated with oncedaily dosing for 28 days.4 The aim of the present study was to investigate the 24-hour profile of bronchodilator efficacy of single doses of indacaterol, 400 g, via single-dose dry powder inhaler (SDDPI) and indacaterol, 200 g, via multidose dry powder inhaler (MDDPI; Certihaler and SkyeHaler, Novartis Pharma AG, Basel, and Skye Pharma AG, Muttenz, Switzerland) in patients with persistent asthma. Comparison of the 2 modes of drug delivery was of interest as part of the clinical development program for indacaterol. The study was also designed to evaluate the safety and tolerability of indacaterol at these doses via the 2 devices. METHODS Study Design This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter, single-dose, crossover study with a 5- to 7-day washout between treatment periods. The research protocol was approved by the relevant institutional review boards or ethics committees, and all patients gave written informed consent.
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Inclusion and Exclusion Criteria Male and female patients aged 12 to 75 years with persistent asthma5 were enrolled if they were receiving daily treatment with ICS (up to 1,600 g of beclomethasone dipropionate or equivalent) in a stable regimen for 1 month before screening. Patients had a forced expiratory volume in 1 second (FEV1) at screening of 50% to 80% predicted.6 This was demonstrated after a washout period of at least 6 hours, during which no short-acting 2-agonists were inhaled, and at least 24 hours after use of a long-acting 2-agonist. Patients also demonstrated an increase of at least 15% in FEV1 over baseline within 30 minutes of inhaling albuterol, 180 g. Patients were excluded if they had been hospitalized or had received emergency department treatment for an acute asthma attack in the 6 months before study. Patients with seasonal allergies or who had a respiratory tract infection within 1 month before screening were excluded. Other exclusions included a prolonged QTc interval and any clinically significant condition that might compromise safety or compliance. Use of the following medications within a specified washout period excluded patients: fixed combinations of ICS and 2-agonists (48 hours), parenteral and oral corticosteroids (3 months), theophylline and other xanthines (1 month), leukotriene antagonists (48 hours), vaccinations with live attenuated viruses (1 month), long-acting 2-agonists not in fixed combination with ICS (24 hours), and anticholinergics (short-acting, 8 hours; long-acting, 7 days). During the screening period, patients receiving fixed-dose combinations of ICS and long-acting 2-agonists were switched to the component monotherapies; the ICS dose and regimen were to remain unchanged during the study, and the 24-hour washout before study drug administration applied to the long-acting 2-agonist. Patients were excluded if allergen immunotherapy was initiated during this period. Study Treatment Each patient received each of 3 treatments in a prescribed randomized sequence: a single dose of 200 g of indacaterol administered via MDDPI plus placebo via SDDPI, 400 g of indacaterol via SDDPI plus placebo via MDDPI, and placebo via MDDPI and SDDPI. Rescue medication (inhaled albuterol) was used as required but not within 6 hours before each study visit, unless necessary. Patients continued to receive their maintenance ICS as per the inclusion criterion. Adherence to the ICS maintenance regimen was left to the responsibility of the investigator. A change in ICS dose or dosing regimen during study required patient discontinuation from the study. Study Assessments FEV1 and forced vital capacity (FVC) were measured before dosing; at 5, 10, 15, and 30 minutes and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 23, and 24 hours after dosing. Safety assessments included adverse events, hematologic testing, blood chemical analysis, urinalysis, measurement of vital signs and electrocardiograms, and physical examina-
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tions. Blood samples for hematologic and chemical testing were taken before dosing, at 15 minutes, and at 1, 4, 6, 12, 16, and 24 hours after dosing. Study End Points The primary efficacy variable was the 24-hour bronchodilator profile, defined by FEV1, of single doses of indacaterol (400 g via SDDPI and 200 g via MDDPI). Secondary efficacy end points included standardized area under the curve (AUC) of FEV1, peak FEV1, and FVC at individual time points. The safety and tolerability of indacaterol were evaluated by recording adverse events and monitoring blood glucose levels, serum potassium levels, and QTc intervals. Statistical Analyses Eighteen patients were required to receive each of the 3 treatments to attain 80% power to detect a treatment difference in FEV1 of 0.30 L, at a significance level of P ⫽ .05. Efficacy analyses were performed on the modified intent-totreat population (all randomized patients analyzed according to treatment received). Safety analyses were performed on the safety population (all patients who received at least 1 dose of trial medication analyzed according to treatment received). An analysis of covariance (ANCOVA) model was applied to the results of all efficacy variables to compare treatments, adjusting for patient, period, and baseline period FEV1. Spirometric data collected within 6 hours of the use of rescue medication were excluded from the primary analysis, and missing data were not imputed for individual time point analyses. Adverse events were included in the summaries of adverse events. Laboratory data were summarized at baseline and at all postbaseline time points (for serum potassium, 15 minutes and 1, 4, and 24 hours after dosing; for blood glucose, 15 minutes and 1, 4, 6, 12, 16, and 24 hours after dosing). Blood glucose and serum potassium values were analyzed using ANCOVA with patient, period, and treatment as fixed effects and baseline value as covariate. Postbaseline QTc, pulse rate, and blood pressure (systolic and diastolic) were analyzed using ANCOVA. QTc was calculated using the Fridericia formula (QTc ⫽ QT/3公RR) as a preferred approach when evaluating interventions that may affect heart rate.7,8 Notable QTc values were defined as more than 450 milliseconds in males and more than 470 milliseconds in females and a change from baseline as more than 60 milliseconds. RESULTS Patients Of 33 patients screened, 25 were randomized to treatment; all completed the 3 study treatment periods. One patient received placebo twice in error instead of 200 g of indacaterol via MDDPI. The efficacy analysis was repeated (and is reported herein) according to treatment received (with both placebo treatment days for this patient contributing to the analysis). Therefore, overall exposure was 400 g via SDDPI, 25
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patients; 200 g via MDDPI, 24 patients; and placebo, 25 patients. Patient characteristics are presented in Table 1. Efficacy Mean (SD) values of FEV1 at the separate baselines for each of the 3 treatments were 2.84 (0.624) L for indacaterol, 400 g; 2.89 (0.621) L for indacaterol, 200 g; and 2.85 (0.667) L for placebo. The adjusted mean FEV1 for both the 400-g via SDDPI and 200-g via MDDPI doses of indacaterol remained well above baseline for the full 24-hour period (Fig 1). Mean FEV1 increased 12% above treatment baseline at 15 minutes and onward with the 400-g via SDDPI dose and from 1 to 4 hours and at 18 hours with the 200-g via MDDPI dose. A more stringent 15% increase from baseline was met only with the higher SDDPI dose, which exceeded this threshold from 1 to 8 hours inclusive, and at 12, 18, 22, and 23 hours (increases of 14.9% occurred at 30 minutes and 24 hours). Adjusted mean FEV1 was significantly higher for the 2 indacaterol doses compared with placebo as early as 5 minutes after dosing for the 400-g via SDDPI dose (0.17 L; 95% confidence interval [CI], 0.07– 0.27 L; P ⬍ .001) and 10 minutes after dosing for the 200-g via MDDPI dose (0.21 L; 95% CI, 0.13– 0.29 L; P ⬍ .001). At 24 hours after dosing, the adjusted mean FEV1 remained significantly higher than placebo for both the 400-g dose (0.29 L; 95% CI, 0.20 – 0.38 L; P ⬍ .001) and the 200-g dose (0.15 L; 95% CI, 0.05– 0.24 L; P ⫽ .003). The adjusted mean FEV1 was significantly higher for the 400-g via SDDPI indacaterol dose compared with the 200-g via MDDPI dose apart from at 5 and 10 minutes and 3 and 4 hours after dosing. The FEV1 AUC and peak FEV1 showed the same trend as FEV1 for the 400-g via SDDPI and 200-g via MDDPI indacaterol doses. Compared with placebo, adjusted mean
Figure 1. Twenty-four-hour profile of adjusted mean forced expiratory volume in 1 second (FEV1). SDDPI indicates single-dose dry powder inhaler; MDDPI, multidose dry powder inhaler.
AUC0 to 24h was 0.34 L higher for the 400-g via SDDPI dose (95% CI, 0.26 – 0.42 L) and 0.22 L higher for the 200-g via MDDPI dose (95% CI, 0.13– 0.30 L; P ⬍ .001; for both indacaterol doses). The peak adjusted mean FEV1 value recorded between 5 minutes and 24 hours after dosing was also significantly higher (P ⬍ .001) for both the 400-g via SDDPI (3.50 L) and 200-g via MDDPI (3.35 L) indacaterol doses compared with placebo (3.16 L). The time of maximum effect in terms of indacaterol-placebo differences in FEV1 was 3 to 4 hours after dosing for both doses. Both the adjusted mean AUC0 to 24h and peak FEV1 were significantly
Table 1. Baseline Demographics of All Randomized Patients Demographic Age, mean (SD) 关range兴, y Sex, No. (%) Male Female Race, No. (%) White Black Height, mean (SD) [range], cm Weight, mean (SD) [range], kg Duration of asthma, mean (SD) [range], y FEV1 before inhalation of albuterol at screening, mean (SD) [range], L FEV1 before inhalation of albuterol at screening, mean (SD) [range], % predicted FEV1 after inhalation of albuterol at screening, mean (SD) [range], L FEV1 reversibility, mean (SD) [range], % increase of FEV1 FVC at screening, mean (SD) [range], L Smoking history, No. (%) Never smoked Ex-smoker Current smoker
Total (N ⴝ 25) 31.0 (14.03) [15–56] 16 (64) 9 (36) 22 (88) 3 (12) 173.5 (10.15) [155–193] 77.81 (15.667) [52.7–117.3] 20.9 (10.17) [4–42] 2.71 (0.535) [1.65–3.86] 70.3 (8.13) [52.05–80.08] 3.31 (0.644) [2.16–4.72] 22.6 (5.58) [15.22–38.75] 4.07 (0.903) [2.32–6.07] 23 (92) 2 (8) 0 (0)
Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.
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higher for the 400-g via SDDPI indacaterol dose compared with the 200-g via MDDPI dose with differences of 0.12 L (95% CI, 0.04 – 0.20 L; P ⫽ .003) and 0.15 L (95% CI, 0.05– 0.26 L; P ⫽ .006), respectively. Adjusted mean FVC was significantly increased relative to placebo with the 400-g indacaterol dose for most time points during the 24 hours after dosing, whereas the 200-g dose increased the FVC relative to placebo during the first hour only. Albuterol rescue medication was taken by 5 patients during placebo treatment visits and by 1 patient during the 200 g via MDDPI treatment visit. Safety All reported adverse events were mild or moderate in severity. The most frequent adverse event was cough (Table 2), which was reported by 3 patients receiving indacaterol, 400 g via SDDPI, and by 4 patients receiving indacaterol, 200 g via MDDPI; 1 of these patients reported a mild cough after both doses. All episodes of cough were suspected to be related to study drug administration. Overall, reported coughing events were of mild or moderate severity and resolved after 2 minutes without treatment. One patient reported feeling jittery and dizzy approximately 3 hours after taking placebo and reported another episode of feeling jittery 1.75 hours after taking indacaterol, 200 g via MDDPI. Both episodes were suspected to be study drug related but resolved without necessary action, and the patient continued in the study. No serious or other significant adverse events occurred, and no adverse events led to discontinuation of treatment. No exacerbations of asthma occurred during the study. In general, no differences were found among the groups in laboratory variables. No statistically significant differences
were found in mean serum potassium levels among treatments at any time point. Minimum adjusted mean (SE) values after baseline were 3.86 (0.035), 3.85 (0.036), and 3.88 (0.035) mmol/L for the 400-g, 200-g, and placebo treatments, respectively. Few patients experienced a decrease in serum potassium level from normal at baseline to below normal range (lower limit of normal, 3.50 mmol/L) after baseline (Table 2). Among those receiving indacaterol, below-normal serum potassium values were recorded for 1 patient taking 400 g of indacaterol at 24 hours and for 2 patients taking 200 g of indacaterol, 1 at 1 hour and 1 at 1 and 4 hours. One of these patients had below-normal values recorded after both indacaterol doses (predose values for this patient were borderline low at 3.50 and 3.60 mmol/L). Likewise, there were few cases of increases in blood glucose level from normal at baseline to above normal range (upper limit of normal, 7.77 mmol/L) after baseline (Table 2). Above-normal blood glucose values were recorded for 1 patient receiving 400 g of indacaterol at 12, 16, and 24 hours after dosing and for the same patient receiving 200 g at 15 minutes and 6 and 12 hours after dosing. Adjusted mean blood glucose values were generally similar at each time point, with the only statistically significant difference being a small elevation with 400 g via SDDPI of indacaterol (mean, 5.16 mmol/L) compared with placebo (mean, 4.74 mmol/L) at 1 hour after dosing (P ⫽ .038). Maximum mean (SE) values after baseline were 6.39 (0.138), 6.32 (0.142), and 5.94 (0.138) mmol/L for the 400-g, 200-g, and placebo treatments, respectively. Hematology variables showed only small changes in mean values that were not considered to be
Table 2. Patients Stratified by Adverse Events (System Organ Class Affected and Preferred Term) and Incidence of Notable Values for Serum Potassium and Blood Glucose Levels (Safety Population)
Patients with adverse events System organ class affected and preferred term Respiratory, thoracic, and mediastinal disordersa Cough General disorders and administration site disorders Feeling jittery Influenza-like illness Cardiac disorders Ventricular extrasystoles Nervous system disorders Dizziness Headache Syncope Incidence of abnormal serum potassium and glucose levels Decreased serum potassium level Increased blood glucose level
Indacaterol, 400 g via SDDPI, No. (%) (n ⴝ 25)
Indacaterol, 200 g via MDDPI, No. (%) (n ⴝ 24)
Placebo, No. (%) (n ⴝ 25)
5 (20)
6 (25)
4 (16)
3 (12) 3 (12) 0 0 0 0 0 1 (4) 1 (4) 0 0
4 (16) 4 (16) 2 (8) 1 (4) 0 1 (4) 1 (4) 0 0 0 0
0 0 1 (4) 1 (4) 1 0 0 3 (12) 1 (4) 1 (4) 1 (4)
1 (4) 1 (4)
2 (8) 1 (4)
1 (4) 0
Abbreviations: MDDPI, multidose dry powder inhaler; SDDPI, single-dose dry powder inhaler. Term that describes the primary system organ class affected, including typically disease-related adverse events such as asthma exacerbated, cough, dry throat, dyspnea, epistaxis, increased upper airway secretion, and wheezing. a
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clinically meaningful, with a similar proportion of patients reporting changes across all treatment groups. No statistically significant differences were found among treatments and no general trends in mean pulse rate during the 24 hours after dosing, although a small decrease of 7 to 8 beats/min across the groups occurred at 3 to 4 hours after dosing. No patient had a decrease in pulse rate to below 40 beats/min. Maximum adjusted mean (SE) values after baseline were 86.4 (1.66), 88.5 (1.72), and 87.2 (1.68) beats/min for the 400-g, 200-g, and placebo treatments, respectively. Mean blood pressure readings were similar for each treatment with no clinically significant changes after dosing. For the 400-g, 200-g, and placebo treatments, respective maximum adjusted mean (SE) values after baseline were 128.2 (1.15), 126.9 (1.19), and 125.1 (1.17) mm Hg for systolic pressure, and minimum adjusted mean (SE) values were 66.9 (1.09), 64.7 (1.15), and 66.4 (1.13) mm Hg for diastolic pressure. Summary statistics for the QTc interval did not show consistent, statistically significant, or clinically meaningful changes during the 24-hour postdose period, except for the 1-hour time point when the adjusted mean QTc interval was significantly higher for the 400-g via SDDPI indacaterol dose than placebo (394.0 vs 387.2 milliseconds; P ⫽ .045). No patient had notable (as previously defined) QTc interval values or changes. The maximum adjusted mean (SE) values after baseline were 400.4 (1.65), 402.2 (1.69), and 404.0 (1.63) milliseconds for the 400-g, 200-g, and placebo treatments, respectively. Other electrocardiogram variables did not show clinically meaningful changes. DISCUSSION This study demonstrates that indacaterol, at doses of 200 g and 400 g administered via MDDPI and SDDPI, respectively, provided 24-hour bronchodilator efficacy with a rapid onset of action, consistent with previous studies that have demonstrated a 24-hour duration of action with a fast onset (⬍5 minutes) at doses of 200 g and 400 g given via HFA pressurized MDI3 and 200 to 600 g given via SDDPI.9 Indacaterol given via either mode produced a substantial increase in FEV1 at nearly all time points of the 24-hour evaluation period, the only exceptions being the nonstatistically significant differences relative to placebo for the lower dose at the first and last time points (5 minutes and 24 hours). As observed previously,3,4,9 indacaterol treatment was well tolerated and not associated with typical 2-agonist mediated adverse effects. The only adverse event that showed a significant difference between treatment groups was postinhalation cough, which was of mild or moderate severity and resolved quickly without need for treatment. Such events have been observed in other clinical studies with indacaterol at similar frequency, for example, in 17% of patients receiving indacaterol, 400 g via SDDPI, or an HFA pressurized MDI.10,4 In two 7-day studies that compared the frequency of cough on the first and last days of dosing,9,11 cough was mainly associated with the first dose of indacaterol only.
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The doses chosen for the present study were based on previous clinical data showing bronchodilator efficacy and good tolerability of indacaterol, 400 g via SDDPI,9 along with technical data suggesting that the metered dose given via the MDDPI could be halved to provide a similar delivered dose to that used in the SDDPI. The 2:1 dose ratio was based on unpublished in vitro findings that showed that the MDDPI delivered approximately twice the fine particle fraction delivered via the SDDPI. This had been previously demonstrated in similar studies with formoterol delivered from these devices12,13 in which the MDDPI and SDDPI delivered fine particle fractions of 37% and 21%, respectively, at a flow rate of 60 L/min, with the assumption that a higher respirable fraction would equate to improved in vivo lung delivery. In fact, this study showed a greater bronchodilator effect for indacaterol, 400 g via SDDPI, compared with indacaterol, 200 g via MDDPI. Given that we were comparing different doses given via different devices, it is impossible to ascribe the difference in results to a single factor. Other clinical studies have confirmed that the same dose of indacaterol provides similar efficacy when administered via either of the 2 devices.11,14 Furthermore, a study that compared a range of doses via the same MDDPI used in the present study showed a significant increase in FEV1 with doses of 50 to 200 g at all time points relative to placebo, including 5 minutes and 24 hours (evaluated as a predose measurement in a multiple-dose study),11 suggesting that in the present study 200 g via MDDPI of indacaterol underperformed in its bronchodilator effect, for unknown reasons. Indacaterol is currently undergoing further evaluation in phase 3 of clinical development with administration via the SDDPI delivery device. A recent study that evaluated the 400-g dose via SDDPI in patients with asthma, although primarily aimed at evaluating safety, demonstrated a significant increase in FEV1 when measured before dosing (ie, the trough effect, 24 hours after the previous dose) at 14 and 28 days of treatment. Although the increases of 0.15 to 0.21 L relative to placebo were smaller than the increases measured in the present study, baseline FEV1 was somewhat lower at 2.77 L.10 The comparison of different single doses via different devices does not allow any conclusions regarding dose response, since it is impossible to determine the relative position on the dose-response curve. Ideally, such a comparison would involve at least 2 doses via each device testing against an end point that may be more discriminatory than bronchodilation per se, such as protection against exercise or chemically induced bronchospasm.15 In view of the difficulty in establishing the dose-response relationship for inhaled 2agonists and the pitfalls inherent in comparing different inhaler devices with different drug delivery characteristics requiring different techniques for optimal drug delivery, the present study is unhelpful in determining the clinical importance of the difference in efficacy between the 2 study treatments. However, the current findings are useful in helping to establish that the 400-g dose via SDDPI, which is the device
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undergoing further intensive evaluation in phase 3 studies, provides effective 24-hour bronchodilation with a rapid onset of action and a good overall safety profile. ACKNOWLEDGMENTS We thank patients and staff involved with the study and Sarah Filcek and Kathryn Palin for their help in preparing the manuscript (this support was funded by Novartis). REFERENCES 1. National Heart, Lung, and Blood Institute National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 07– 4051. Originally printed July 1997. Revised June 2002, August 2007. http:// www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed February 1, 2007. 2. National Institutes of Health (NIH), National Heart, Lung, and Blood Institute. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Bethesda, MD: NIH; 2006. NIH publication 02–3659. 3. Beeh KM, Derom E, Kanniess F, Cameron R, Higgins M, van As A. Indacaterol, a novel inhaled 2-agonist, provides sustained 24-hour bronchodilation in asthma. Eur Respir J. 2007;29:871– 878. 4. Chuchalin AG, Tsoi AN, Richter K, et al. Safety and tolerability of indacaterol in asthma: a randomized, placebo-controlled 28-day study. Respir Med. 2007;101:2065–2075. 5. National Institutes of Health (NIH), National Heart, Lung, and Blood Institute. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Bethesda, MD: NIH; 2003. NIH publication 02–3659. 6. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet the ATS recommendation. Am Rev Respir Dis. 1981;123:659 – 664. 7. Morganroth J. Cardiac repolarization and the safety of new drugs defined by electrocardiography. Clin Pharmacol Ther. 2007;81:108 –113.
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8. US Department of Health and Human Services, Food and Drug Administration. Guidance for Industry. E14 Clinical evaluation of QT/QTc interval prolongation and proarhythmic potential for non-antiarrhythmic drugs. October 2005. http://www.fda.gov/cder/guidance/index.htm. Accessed February 1, 2007. 9. Kanniess F, Cameron R, Owen R, Higgins M. Indacaterol, a novel 24-hour 2-agonist, demonstrates 24-hour efficacy and is well tolerated in patients with asthma: a multiple-dose, dose-ranging study. Eur Respir J 2005;26(suppl 49):253s, P1729. 10. Yang W, Martinot JB, Pohunek P, et al. Indacaterol, a novel once-daily 2-agonist, is well tolerated in patients with asthma: a randomized, placebo-controlled 28-day safety study. Ann Allergy Asthma Immunol. 2007;99:555–561. 11. LaForce C, Alexander M, Deckelmann R, et al. Indacaterol provides sustained 24 h bronchodilation on once-daily dosing in asthma: a 7-day, dose-ranging study. Allergy. 2008;63:103–111. 12. Krummen M, Kahli D, Hoerbing S, et al. Flow-rate dependency of the fine particle fraction and the uniformity of the delivered dose of several commercial formoterol dry powder inhalers [abstract]. J Aerosol Med 2006;19:221–241. 13. Krummen M, Singh D, Fiebich K, Haeberlin B. Flow-dependent performance of several formoterol dry powder inhalers (DPIs) [abstract]. Eur Respir J. 2006(suppl):435s. 14. Rennard S, Bantje T, Centanni S, et al. A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison. Respir Med. 2007; In press. 15. Ahrens RC. On comparing inhaled beta adrenergic agonists. Ann Allergy. 1991;67:296 –298. Requests for reprints should be addressed to: David S. Pearlman Rampart Campus 125 Rampart Way Suite 150 Denver, CO 80230 E-mail: [email protected]
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INTRODUCTION Guidelines such as those produced by the National Asthma Education and Prevention Program and the Global Initiative for Asthma1,2 recommend short-acting 2-agonists for prevention of exercise-induced bronchospasm and relief of symptoms. These guidelines also recommend the addition of currently available long-acting 2-agonists to standard initial doses of inhaled corticosteroids (ICS) for regular twice-daily dosing to enhance long-term control of symptoms, including nocturnal symptoms, in patients who are not adequately controlled with ICS alone. Indacaterol is a novel once-daily 2-agonist in development for the treatment of patients with asthma or chronic obstructive pulmonary disease. Clinical studies have shown
Affiliations: * Colorado Allergy and Asthma Centers, PC, Denver, Colorado; † Colorado Allergy and Asthma Centers, PC, Englewood, Colorado; ‡ North Carolina Clinical Research, Raleigh, North Carolina; § Novartis Pharmaceuticals Corp, East Hanover, New Jersey; ¶ Novartis Horsham Research Centre, Horsham, England. Disclosures: Authors have nothing to disclose. Funding Sources: This study was sponsored by Novartis Pharma AG. This study has been registered on the Novartis clinical trials Web site under study number CQAB149A2218 (accessible via http://www.novartis clinicaltrials.com/webapp/clinicaltrialrepository/public/login.jsp). Received for publication June 11, 2007; Received in revised form November 13, 2007; Accepted for publication January 10, 2007.
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that single doses of indacaterol given via hydrofluoroalkane (HFA) metered-dose inhaler (MDI) provide effective 24-hour bronchodilation with a fast onset of action and are well tolerated.3 A good safety profile was demonstrated with oncedaily dosing for 28 days.4 The aim of the present study was to investigate the 24-hour profile of bronchodilator efficacy of single doses of indacaterol, 400 g, via single-dose dry powder inhaler (SDDPI) and indacaterol, 200 g, via multidose dry powder inhaler (MDDPI; Certihaler and SkyeHaler, Novartis Pharma AG, Basel, and Skye Pharma AG, Muttenz, Switzerland) in patients with persistent asthma. Comparison of the 2 modes of drug delivery was of interest as part of the clinical development program for indacaterol. The study was also designed to evaluate the safety and tolerability of indacaterol at these doses via the 2 devices. METHODS Study Design This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter, single-dose, crossover study with a 5- to 7-day washout between treatment periods. The research protocol was approved by the relevant institutional review boards or ethics committees, and all patients gave written informed consent.
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Inclusion and Exclusion Criteria Male and female patients aged 12 to 75 years with persistent asthma5 were enrolled if they were receiving daily treatment with ICS (up to 1,600 g of beclomethasone dipropionate or equivalent) in a stable regimen for 1 month before screening. Patients had a forced expiratory volume in 1 second (FEV1) at screening of 50% to 80% predicted.6 This was demonstrated after a washout period of at least 6 hours, during which no short-acting 2-agonists were inhaled, and at least 24 hours after use of a long-acting 2-agonist. Patients also demonstrated an increase of at least 15% in FEV1 over baseline within 30 minutes of inhaling albuterol, 180 g. Patients were excluded if they had been hospitalized or had received emergency department treatment for an acute asthma attack in the 6 months before study. Patients with seasonal allergies or who had a respiratory tract infection within 1 month before screening were excluded. Other exclusions included a prolonged QTc interval and any clinically significant condition that might compromise safety or compliance. Use of the following medications within a specified washout period excluded patients: fixed combinations of ICS and 2-agonists (48 hours), parenteral and oral corticosteroids (3 months), theophylline and other xanthines (1 month), leukotriene antagonists (48 hours), vaccinations with live attenuated viruses (1 month), long-acting 2-agonists not in fixed combination with ICS (24 hours), and anticholinergics (short-acting, 8 hours; long-acting, 7 days). During the screening period, patients receiving fixed-dose combinations of ICS and long-acting 2-agonists were switched to the component monotherapies; the ICS dose and regimen were to remain unchanged during the study, and the 24-hour washout before study drug administration applied to the long-acting 2-agonist. Patients were excluded if allergen immunotherapy was initiated during this period. Study Treatment Each patient received each of 3 treatments in a prescribed randomized sequence: a single dose of 200 g of indacaterol administered via MDDPI plus placebo via SDDPI, 400 g of indacaterol via SDDPI plus placebo via MDDPI, and placebo via MDDPI and SDDPI. Rescue medication (inhaled albuterol) was used as required but not within 6 hours before each study visit, unless necessary. Patients continued to receive their maintenance ICS as per the inclusion criterion. Adherence to the ICS maintenance regimen was left to the responsibility of the investigator. A change in ICS dose or dosing regimen during study required patient discontinuation from the study. Study Assessments FEV1 and forced vital capacity (FVC) were measured before dosing; at 5, 10, 15, and 30 minutes and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 23, and 24 hours after dosing. Safety assessments included adverse events, hematologic testing, blood chemical analysis, urinalysis, measurement of vital signs and electrocardiograms, and physical examina-
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tions. Blood samples for hematologic and chemical testing were taken before dosing, at 15 minutes, and at 1, 4, 6, 12, 16, and 24 hours after dosing. Study End Points The primary efficacy variable was the 24-hour bronchodilator profile, defined by FEV1, of single doses of indacaterol (400 g via SDDPI and 200 g via MDDPI). Secondary efficacy end points included standardized area under the curve (AUC) of FEV1, peak FEV1, and FVC at individual time points. The safety and tolerability of indacaterol were evaluated by recording adverse events and monitoring blood glucose levels, serum potassium levels, and QTc intervals. Statistical Analyses Eighteen patients were required to receive each of the 3 treatments to attain 80% power to detect a treatment difference in FEV1 of 0.30 L, at a significance level of P ⫽ .05. Efficacy analyses were performed on the modified intent-totreat population (all randomized patients analyzed according to treatment received). Safety analyses were performed on the safety population (all patients who received at least 1 dose of trial medication analyzed according to treatment received). An analysis of covariance (ANCOVA) model was applied to the results of all efficacy variables to compare treatments, adjusting for patient, period, and baseline period FEV1. Spirometric data collected within 6 hours of the use of rescue medication were excluded from the primary analysis, and missing data were not imputed for individual time point analyses. Adverse events were included in the summaries of adverse events. Laboratory data were summarized at baseline and at all postbaseline time points (for serum potassium, 15 minutes and 1, 4, and 24 hours after dosing; for blood glucose, 15 minutes and 1, 4, 6, 12, 16, and 24 hours after dosing). Blood glucose and serum potassium values were analyzed using ANCOVA with patient, period, and treatment as fixed effects and baseline value as covariate. Postbaseline QTc, pulse rate, and blood pressure (systolic and diastolic) were analyzed using ANCOVA. QTc was calculated using the Fridericia formula (QTc ⫽ QT/3公RR) as a preferred approach when evaluating interventions that may affect heart rate.7,8 Notable QTc values were defined as more than 450 milliseconds in males and more than 470 milliseconds in females and a change from baseline as more than 60 milliseconds. RESULTS Patients Of 33 patients screened, 25 were randomized to treatment; all completed the 3 study treatment periods. One patient received placebo twice in error instead of 200 g of indacaterol via MDDPI. The efficacy analysis was repeated (and is reported herein) according to treatment received (with both placebo treatment days for this patient contributing to the analysis). Therefore, overall exposure was 400 g via SDDPI, 25
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patients; 200 g via MDDPI, 24 patients; and placebo, 25 patients. Patient characteristics are presented in Table 1. Efficacy Mean (SD) values of FEV1 at the separate baselines for each of the 3 treatments were 2.84 (0.624) L for indacaterol, 400 g; 2.89 (0.621) L for indacaterol, 200 g; and 2.85 (0.667) L for placebo. The adjusted mean FEV1 for both the 400-g via SDDPI and 200-g via MDDPI doses of indacaterol remained well above baseline for the full 24-hour period (Fig 1). Mean FEV1 increased 12% above treatment baseline at 15 minutes and onward with the 400-g via SDDPI dose and from 1 to 4 hours and at 18 hours with the 200-g via MDDPI dose. A more stringent 15% increase from baseline was met only with the higher SDDPI dose, which exceeded this threshold from 1 to 8 hours inclusive, and at 12, 18, 22, and 23 hours (increases of 14.9% occurred at 30 minutes and 24 hours). Adjusted mean FEV1 was significantly higher for the 2 indacaterol doses compared with placebo as early as 5 minutes after dosing for the 400-g via SDDPI dose (0.17 L; 95% confidence interval [CI], 0.07– 0.27 L; P ⬍ .001) and 10 minutes after dosing for the 200-g via MDDPI dose (0.21 L; 95% CI, 0.13– 0.29 L; P ⬍ .001). At 24 hours after dosing, the adjusted mean FEV1 remained significantly higher than placebo for both the 400-g dose (0.29 L; 95% CI, 0.20 – 0.38 L; P ⬍ .001) and the 200-g dose (0.15 L; 95% CI, 0.05– 0.24 L; P ⫽ .003). The adjusted mean FEV1 was significantly higher for the 400-g via SDDPI indacaterol dose compared with the 200-g via MDDPI dose apart from at 5 and 10 minutes and 3 and 4 hours after dosing. The FEV1 AUC and peak FEV1 showed the same trend as FEV1 for the 400-g via SDDPI and 200-g via MDDPI indacaterol doses. Compared with placebo, adjusted mean
Figure 1. Twenty-four-hour profile of adjusted mean forced expiratory volume in 1 second (FEV1). SDDPI indicates single-dose dry powder inhaler; MDDPI, multidose dry powder inhaler.
AUC0 to 24h was 0.34 L higher for the 400-g via SDDPI dose (95% CI, 0.26 – 0.42 L) and 0.22 L higher for the 200-g via MDDPI dose (95% CI, 0.13– 0.30 L; P ⬍ .001; for both indacaterol doses). The peak adjusted mean FEV1 value recorded between 5 minutes and 24 hours after dosing was also significantly higher (P ⬍ .001) for both the 400-g via SDDPI (3.50 L) and 200-g via MDDPI (3.35 L) indacaterol doses compared with placebo (3.16 L). The time of maximum effect in terms of indacaterol-placebo differences in FEV1 was 3 to 4 hours after dosing for both doses. Both the adjusted mean AUC0 to 24h and peak FEV1 were significantly
Table 1. Baseline Demographics of All Randomized Patients Demographic Age, mean (SD) 关range兴, y Sex, No. (%) Male Female Race, No. (%) White Black Height, mean (SD) [range], cm Weight, mean (SD) [range], kg Duration of asthma, mean (SD) [range], y FEV1 before inhalation of albuterol at screening, mean (SD) [range], L FEV1 before inhalation of albuterol at screening, mean (SD) [range], % predicted FEV1 after inhalation of albuterol at screening, mean (SD) [range], L FEV1 reversibility, mean (SD) [range], % increase of FEV1 FVC at screening, mean (SD) [range], L Smoking history, No. (%) Never smoked Ex-smoker Current smoker
Total (N ⴝ 25) 31.0 (14.03) [15–56] 16 (64) 9 (36) 22 (88) 3 (12) 173.5 (10.15) [155–193] 77.81 (15.667) [52.7–117.3] 20.9 (10.17) [4–42] 2.71 (0.535) [1.65–3.86] 70.3 (8.13) [52.05–80.08] 3.31 (0.644) [2.16–4.72] 22.6 (5.58) [15.22–38.75] 4.07 (0.903) [2.32–6.07] 23 (92) 2 (8) 0 (0)
Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.
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higher for the 400-g via SDDPI indacaterol dose compared with the 200-g via MDDPI dose with differences of 0.12 L (95% CI, 0.04 – 0.20 L; P ⫽ .003) and 0.15 L (95% CI, 0.05– 0.26 L; P ⫽ .006), respectively. Adjusted mean FVC was significantly increased relative to placebo with the 400-g indacaterol dose for most time points during the 24 hours after dosing, whereas the 200-g dose increased the FVC relative to placebo during the first hour only. Albuterol rescue medication was taken by 5 patients during placebo treatment visits and by 1 patient during the 200 g via MDDPI treatment visit. Safety All reported adverse events were mild or moderate in severity. The most frequent adverse event was cough (Table 2), which was reported by 3 patients receiving indacaterol, 400 g via SDDPI, and by 4 patients receiving indacaterol, 200 g via MDDPI; 1 of these patients reported a mild cough after both doses. All episodes of cough were suspected to be related to study drug administration. Overall, reported coughing events were of mild or moderate severity and resolved after 2 minutes without treatment. One patient reported feeling jittery and dizzy approximately 3 hours after taking placebo and reported another episode of feeling jittery 1.75 hours after taking indacaterol, 200 g via MDDPI. Both episodes were suspected to be study drug related but resolved without necessary action, and the patient continued in the study. No serious or other significant adverse events occurred, and no adverse events led to discontinuation of treatment. No exacerbations of asthma occurred during the study. In general, no differences were found among the groups in laboratory variables. No statistically significant differences
were found in mean serum potassium levels among treatments at any time point. Minimum adjusted mean (SE) values after baseline were 3.86 (0.035), 3.85 (0.036), and 3.88 (0.035) mmol/L for the 400-g, 200-g, and placebo treatments, respectively. Few patients experienced a decrease in serum potassium level from normal at baseline to below normal range (lower limit of normal, 3.50 mmol/L) after baseline (Table 2). Among those receiving indacaterol, below-normal serum potassium values were recorded for 1 patient taking 400 g of indacaterol at 24 hours and for 2 patients taking 200 g of indacaterol, 1 at 1 hour and 1 at 1 and 4 hours. One of these patients had below-normal values recorded after both indacaterol doses (predose values for this patient were borderline low at 3.50 and 3.60 mmol/L). Likewise, there were few cases of increases in blood glucose level from normal at baseline to above normal range (upper limit of normal, 7.77 mmol/L) after baseline (Table 2). Above-normal blood glucose values were recorded for 1 patient receiving 400 g of indacaterol at 12, 16, and 24 hours after dosing and for the same patient receiving 200 g at 15 minutes and 6 and 12 hours after dosing. Adjusted mean blood glucose values were generally similar at each time point, with the only statistically significant difference being a small elevation with 400 g via SDDPI of indacaterol (mean, 5.16 mmol/L) compared with placebo (mean, 4.74 mmol/L) at 1 hour after dosing (P ⫽ .038). Maximum mean (SE) values after baseline were 6.39 (0.138), 6.32 (0.142), and 5.94 (0.138) mmol/L for the 400-g, 200-g, and placebo treatments, respectively. Hematology variables showed only small changes in mean values that were not considered to be
Table 2. Patients Stratified by Adverse Events (System Organ Class Affected and Preferred Term) and Incidence of Notable Values for Serum Potassium and Blood Glucose Levels (Safety Population)
Patients with adverse events System organ class affected and preferred term Respiratory, thoracic, and mediastinal disordersa Cough General disorders and administration site disorders Feeling jittery Influenza-like illness Cardiac disorders Ventricular extrasystoles Nervous system disorders Dizziness Headache Syncope Incidence of abnormal serum potassium and glucose levels Decreased serum potassium level Increased blood glucose level
Indacaterol, 400 g via SDDPI, No. (%) (n ⴝ 25)
Indacaterol, 200 g via MDDPI, No. (%) (n ⴝ 24)
Placebo, No. (%) (n ⴝ 25)
5 (20)
6 (25)
4 (16)
3 (12) 3 (12) 0 0 0 0 0 1 (4) 1 (4) 0 0
4 (16) 4 (16) 2 (8) 1 (4) 0 1 (4) 1 (4) 0 0 0 0
0 0 1 (4) 1 (4) 1 0 0 3 (12) 1 (4) 1 (4) 1 (4)
1 (4) 1 (4)
2 (8) 1 (4)
1 (4) 0
Abbreviations: MDDPI, multidose dry powder inhaler; SDDPI, single-dose dry powder inhaler. Term that describes the primary system organ class affected, including typically disease-related adverse events such as asthma exacerbated, cough, dry throat, dyspnea, epistaxis, increased upper airway secretion, and wheezing. a
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clinically meaningful, with a similar proportion of patients reporting changes across all treatment groups. No statistically significant differences were found among treatments and no general trends in mean pulse rate during the 24 hours after dosing, although a small decrease of 7 to 8 beats/min across the groups occurred at 3 to 4 hours after dosing. No patient had a decrease in pulse rate to below 40 beats/min. Maximum adjusted mean (SE) values after baseline were 86.4 (1.66), 88.5 (1.72), and 87.2 (1.68) beats/min for the 400-g, 200-g, and placebo treatments, respectively. Mean blood pressure readings were similar for each treatment with no clinically significant changes after dosing. For the 400-g, 200-g, and placebo treatments, respective maximum adjusted mean (SE) values after baseline were 128.2 (1.15), 126.9 (1.19), and 125.1 (1.17) mm Hg for systolic pressure, and minimum adjusted mean (SE) values were 66.9 (1.09), 64.7 (1.15), and 66.4 (1.13) mm Hg for diastolic pressure. Summary statistics for the QTc interval did not show consistent, statistically significant, or clinically meaningful changes during the 24-hour postdose period, except for the 1-hour time point when the adjusted mean QTc interval was significantly higher for the 400-g via SDDPI indacaterol dose than placebo (394.0 vs 387.2 milliseconds; P ⫽ .045). No patient had notable (as previously defined) QTc interval values or changes. The maximum adjusted mean (SE) values after baseline were 400.4 (1.65), 402.2 (1.69), and 404.0 (1.63) milliseconds for the 400-g, 200-g, and placebo treatments, respectively. Other electrocardiogram variables did not show clinically meaningful changes. DISCUSSION This study demonstrates that indacaterol, at doses of 200 g and 400 g administered via MDDPI and SDDPI, respectively, provided 24-hour bronchodilator efficacy with a rapid onset of action, consistent with previous studies that have demonstrated a 24-hour duration of action with a fast onset (⬍5 minutes) at doses of 200 g and 400 g given via HFA pressurized MDI3 and 200 to 600 g given via SDDPI.9 Indacaterol given via either mode produced a substantial increase in FEV1 at nearly all time points of the 24-hour evaluation period, the only exceptions being the nonstatistically significant differences relative to placebo for the lower dose at the first and last time points (5 minutes and 24 hours). As observed previously,3,4,9 indacaterol treatment was well tolerated and not associated with typical 2-agonist mediated adverse effects. The only adverse event that showed a significant difference between treatment groups was postinhalation cough, which was of mild or moderate severity and resolved quickly without need for treatment. Such events have been observed in other clinical studies with indacaterol at similar frequency, for example, in 17% of patients receiving indacaterol, 400 g via SDDPI, or an HFA pressurized MDI.10,4 In two 7-day studies that compared the frequency of cough on the first and last days of dosing,9,11 cough was mainly associated with the first dose of indacaterol only.
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The doses chosen for the present study were based on previous clinical data showing bronchodilator efficacy and good tolerability of indacaterol, 400 g via SDDPI,9 along with technical data suggesting that the metered dose given via the MDDPI could be halved to provide a similar delivered dose to that used in the SDDPI. The 2:1 dose ratio was based on unpublished in vitro findings that showed that the MDDPI delivered approximately twice the fine particle fraction delivered via the SDDPI. This had been previously demonstrated in similar studies with formoterol delivered from these devices12,13 in which the MDDPI and SDDPI delivered fine particle fractions of 37% and 21%, respectively, at a flow rate of 60 L/min, with the assumption that a higher respirable fraction would equate to improved in vivo lung delivery. In fact, this study showed a greater bronchodilator effect for indacaterol, 400 g via SDDPI, compared with indacaterol, 200 g via MDDPI. Given that we were comparing different doses given via different devices, it is impossible to ascribe the difference in results to a single factor. Other clinical studies have confirmed that the same dose of indacaterol provides similar efficacy when administered via either of the 2 devices.11,14 Furthermore, a study that compared a range of doses via the same MDDPI used in the present study showed a significant increase in FEV1 with doses of 50 to 200 g at all time points relative to placebo, including 5 minutes and 24 hours (evaluated as a predose measurement in a multiple-dose study),11 suggesting that in the present study 200 g via MDDPI of indacaterol underperformed in its bronchodilator effect, for unknown reasons. Indacaterol is currently undergoing further evaluation in phase 3 of clinical development with administration via the SDDPI delivery device. A recent study that evaluated the 400-g dose via SDDPI in patients with asthma, although primarily aimed at evaluating safety, demonstrated a significant increase in FEV1 when measured before dosing (ie, the trough effect, 24 hours after the previous dose) at 14 and 28 days of treatment. Although the increases of 0.15 to 0.21 L relative to placebo were smaller than the increases measured in the present study, baseline FEV1 was somewhat lower at 2.77 L.10 The comparison of different single doses via different devices does not allow any conclusions regarding dose response, since it is impossible to determine the relative position on the dose-response curve. Ideally, such a comparison would involve at least 2 doses via each device testing against an end point that may be more discriminatory than bronchodilation per se, such as protection against exercise or chemically induced bronchospasm.15 In view of the difficulty in establishing the dose-response relationship for inhaled 2agonists and the pitfalls inherent in comparing different inhaler devices with different drug delivery characteristics requiring different techniques for optimal drug delivery, the present study is unhelpful in determining the clinical importance of the difference in efficacy between the 2 study treatments. However, the current findings are useful in helping to establish that the 400-g dose via SDDPI, which is the device
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undergoing further intensive evaluation in phase 3 studies, provides effective 24-hour bronchodilation with a rapid onset of action and a good overall safety profile. ACKNOWLEDGMENTS We thank patients and staff involved with the study and Sarah Filcek and Kathryn Palin for their help in preparing the manuscript (this support was funded by Novartis). REFERENCES 1. National Heart, Lung, and Blood Institute National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 07– 4051. Originally printed July 1997. Revised June 2002, August 2007. http:// www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed February 1, 2007. 2. National Institutes of Health (NIH), National Heart, Lung, and Blood Institute. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Bethesda, MD: NIH; 2006. NIH publication 02–3659. 3. Beeh KM, Derom E, Kanniess F, Cameron R, Higgins M, van As A. Indacaterol, a novel inhaled 2-agonist, provides sustained 24-hour bronchodilation in asthma. Eur Respir J. 2007;29:871– 878. 4. Chuchalin AG, Tsoi AN, Richter K, et al. Safety and tolerability of indacaterol in asthma: a randomized, placebo-controlled 28-day study. Respir Med. 2007;101:2065–2075. 5. National Institutes of Health (NIH), National Heart, Lung, and Blood Institute. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Bethesda, MD: NIH; 2003. NIH publication 02–3659. 6. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet the ATS recommendation. Am Rev Respir Dis. 1981;123:659 – 664. 7. Morganroth J. Cardiac repolarization and the safety of new drugs defined by electrocardiography. Clin Pharmacol Ther. 2007;81:108 –113.
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8. US Department of Health and Human Services, Food and Drug Administration. Guidance for Industry. E14 Clinical evaluation of QT/QTc interval prolongation and proarhythmic potential for non-antiarrhythmic drugs. October 2005. http://www.fda.gov/cder/guidance/index.htm. Accessed February 1, 2007. 9. Kanniess F, Cameron R, Owen R, Higgins M. Indacaterol, a novel 24-hour 2-agonist, demonstrates 24-hour efficacy and is well tolerated in patients with asthma: a multiple-dose, dose-ranging study. Eur Respir J 2005;26(suppl 49):253s, P1729. 10. Yang W, Martinot JB, Pohunek P, et al. Indacaterol, a novel once-daily 2-agonist, is well tolerated in patients with asthma: a randomized, placebo-controlled 28-day safety study. Ann Allergy Asthma Immunol. 2007;99:555–561. 11. LaForce C, Alexander M, Deckelmann R, et al. Indacaterol provides sustained 24 h bronchodilation on once-daily dosing in asthma: a 7-day, dose-ranging study. Allergy. 2008;63:103–111. 12. Krummen M, Kahli D, Hoerbing S, et al. Flow-rate dependency of the fine particle fraction and the uniformity of the delivered dose of several commercial formoterol dry powder inhalers [abstract]. J Aerosol Med 2006;19:221–241. 13. Krummen M, Singh D, Fiebich K, Haeberlin B. Flow-dependent performance of several formoterol dry powder inhalers (DPIs) [abstract]. Eur Respir J. 2006(suppl):435s. 14. Rennard S, Bantje T, Centanni S, et al. A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison. Respir Med. 2007; In press. 15. Ahrens RC. On comparing inhaled beta adrenergic agonists. Ann Allergy. 1991;67:296 –298. Requests for reprints should be addressed to: David S. Pearlman Rampart Campus 125 Rampart Way Suite 150 Denver, CO 80230 E-mail: [email protected]
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