Volume 31, Number 4 July- August 2010

Twenty-six-week efficacy and safety study of mometasone furoate/formoterol 200/10 g combination treatment in patients with persistent asthma previously receiving medium-dose inhaled corticosteroids
Robert A. Nathan, M.D., Hendrik Nolte, M.D., Ph.D., and David S. Pearlman, M.D., on Behalf of the P04334 Study Investigators

Twenty-six-week efficacy and safety study of mometasone furoate/formoterol 200/10 g combination treatment in patients with persistent asthma previously receiving medium-dose inhaled corticosteroids
Robert A. Nathan, M.D.,1 Hendrik Nolte, M.D., Ph.D.,2 and David S. Pearlman, M.D.,3 on Behalf of the P04334 Study Investigators
ABSTRACT Asthma is a heterogeneous condition characterized by reduced lung function, chronic inflammation, and periodic asthma deteriorations. This study was performed to evaluate the effect of mometasone furoate (MF)/formoterol (F) combination, 200/10 g, administered twice daily (b.i.d.) on asthma deteriorations and pulmonary function in patients with asthma uncontrolled on medium-dose inhaled corticosteroid (ICS). After 2- to 3-week open-label run-in with MF 200 g b.i.d., patients (12 years) were randomized to 26 weeks of treatment with MF/F 200/10 g, MF 200 g, F 10 g, or placebo b.i.d. Coprimary end points were time to first asthma deterioration (MF/F versus F) and bronchodilation, assessed by the area under the curve of the change in forced expiratory volume in 1 second 0 12 hours (FEV1 AUC0 12h; MF/F versus MF). A total of 781 patients were randomized. Treatment with MF/F 200/10 g reduced asthma deteriorations and clinically judged deteriorations (i.e., deterioration resulting in emergency treatment, hospitalization, or treatment with additional excluded asthma medication [i.e., systemic corticosteroids]). The proportion of patients experiencing asthma deteriorations was MF/F, 30.4%; MF, 33.9%; F, 54.0%; placebo, 55.6% (p 0.001, MF/F versus F and placebo). There was a sixfold reduction in clinically judged deteriorations with MF/F versus F and placebo (p 0.001). Lung function improved more rapidly with MF/F than MF and placebo. Mean change from baseline FEV1 AUC0 12h at week 12 was MF/F, 11.7% versus MF, 5.7%; F, 8.5%; and placebo, 3.9% (p 0.001). Treatment-related AEs were rare and similar across groups. Treatment with MF/F 200/10 g was effective in reducing the risk of asthma deteriorations. MF/F was safe and provided rapid and sustained bronchodilation in patients with asthma. (Allergy Asthma Proc 31:269 279, 2010; doi: 10.2500/aap.2010.31.3364) Key words: Asthma deteriorations, clinical trial, combination therapy, formoterol, lung function, medium dose, mometasone furoate, quality of life, symptoms, uncontrolled asthma sthma is a chronic and complex disease characterized by impaired respiratory function and airway inflammation.1,2 Patients with asthma often experience
From the 1Asthma and Allergy Associates and Research Center, Colorado Springs, Colorado, 2Merck Research Laboratories, Kenilworth, New Jersey, and 3Colorado Allergy and Asthma Centers, P.C., Denver, Colorado Portions of these data were presented at the meeting of the American College of Allergy, Asthma & Immunology, November 5, 2009, Miami, Florida; abstract published in Ann Allergy Asthma Immunol 2009; 103(5, Suppl 3):A58 This study was funded by Merck & Co; R. Nathan has received grant support from Abbott, Alcon, AstraZeneca, Ception, Dey, Dyax, Genentech, GSK, MAP, MedImmune, Novartis, sanofi-aventis, Schering-Plough, Sepracor, and TEVA, and he has served on speakers bureaus for AstraZeneca, Genentech, GSK, Novartis, sanofiaventis, Schering-Plough, and UCB and he has served as a consultant for Genentech, GSK, Merck, Novartis, Schering-Plough, and TEVA; H. Nolte is an employee of Schering-Plough Corporation, now a division of Merck & Co.; D. Pearlman has served on advisory boards or received honoraria for speaking from Abbott, AstraZeneca, Icagen, Merck, Novartis, sanofi-aventis, Schering-Plough, Sepracor, TEVA, and UCB Human Trial: This protocol was reviewed and approved by all internal Institutional Review Boards. Registry URC www.ClinicalTrials.gov, assigned database no. NCT00383240 Address correspondence and reprint requests to Robert A. Nathan, M.D., Asthma and Allergy Associates and Research Center, 2709 North Tejon Street, Colorado Springs, CO 80907 E-mail address: drrnathan@aol.com Copyright 2010, OceanSide Publications, Inc., U.S.A.

periodic worsening of symptoms, severe exacerbations (i.e., asthma deteriorations), and clinically judged deteriorations that may require emergency treatment and hospitalization.35 Preventing asthma deteriorations is clinically important because they may result in further asthma deteriorations,5 decline in lung function, increase in asthma mortality,4 and impaired patient quality of life (QoL). The goal of asthma treatment is to increase lung function, reduce the severity of asthma symptoms, and reduce the risk of asthma deteriorations to improve patient health and QoL.6 Clinical trials have generally focused on assessment of lung function (e.g., forced expiratory volume in 1 second [FEV1] or peak expiratory flow [PEF]) to measure treatment efficacy. However, without additional end points, such measurements can fail to address the underlying inflammatory aspects of asthma and may correlate poorly with asthma deteriorations, an important clinical outcome that contributes to risk and adversely impacts patient health. Clinical trials have shown that addition of a long-acting inhaled 2-agonist (LABA) to an inhaled corticosteroid (ICS) maintenance

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Patients Enrolled n=984

Discontinued n=203
Adverse event - 14 Lost to follow-up - 4 Did not continue for reasons related to study drug - 2 Did not meet protocol eligibility - 129 Treatment failure - 9 Did not continue for reasons unrelated to study drug - 24 Noncompliance with protocol - 20 Administrative - 1

n=781 Subjects randomized 1:1:1:1 to the double-blind treatment period

MF/F 200/10 g b.i.d n=191 (100%)

n=35 (18%) Discontinued due to:
Adverse event - 4 Treatment failure - 8 Lost to follow-up - 3 Did not continue for reasons unrelated to study drug - 6 Did not continue for reasons related to study drug - 0 Noncompliance with protocol - 4 Did not meet protocol eligibility - 9 Administrative - 1

MF 200 g b.i.d n=192 (100%)

n=33 (17%) Discontinued due to:
Adverse event - 6 Treatment failure - 13 Lost to follow-up - 0 Did not continue for reasons unrelated to study drug - 3 Did not continue for reasons related to study drug - 1 Noncompliance with protocol - 5 Did not meet protocol eligibility - 4 Administrative - 1

F 10 g b.i.d n=202 (100%)

n=85 (42%) Discontinued due to:
Adverse event - 9 Treatment failure - 47 Lost to follow-up - 0 Did not continue for reasons unrelated to study drug - 8 Did not continue for reasons related to study drug - 3 Noncompliance with protocol - 9 Did not meet protocol eligibility - 9 Administrative - 0

Placebo n=196 (100%)

n=77 (39%) Discontinued due to:
Adverse event - 7 Treatment failure - 46 Lost to follow-up - 2 Did not continue for reasons unrelated to study drug - 8 Did not continue for reasons related to study drug - 5 Noncompliance with protocol - 6 Did not meet protocol eligibility - 3 Administrative - 0

n=156 (82%) Completed Treatment Period

n=159 (83%) Completed Treatment Period

n=117 (58%) Completed Treatment Period

n=119 (61%) Completed Treatment Period

Figure 1. Patient disposition. b.i.d., twice daily; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol combination therapy.

therapy helps with disease control in patients with persistent asthma who remain uncontrolled on ICS treatment.6 8 At daily doses of 100 800 g, mometasone furoate (MF), a potent ICS with high affinity for glucocorticoid receptors and a history of clinical efficacy as an antiinflammatory agent, improves lung function and reduces symptoms and frequency and severity of asthma deteriorations.9 11 Formoterol fumarate (F), a LABA, induces rapid bronchodilation, an effect that is sustained for at least 12 hours.12 Thus, a combination of MF and F could provide physicians with a novel, safe, and effective therapy to treat and improve asthma control in patients with persistent asthma. In this prospective, 26-week study, the efficacy, safety, and prevention of asthma deteriorations in response to treatment with a fixed-dose MF/F combination, administered in a single metered-dose inhaler, were assessed in patients aged 12 years with persistent asthma uncontrolled on medium-dose ICS. Some of the results of this study have been previously reported in the form of an abstract.13 METHODS Study Design This 26-week, randomized, multicenter, double-blind, double-dummy, placebo-controlled, parallel-group study

was conducted in 152 sites across North America, Latin America, Europe, and Asia in accordance with Good Clinical Practice. Respective institutional internal review boards reviewed and approved the study protocol. All patients gave written informed consent before enrollment. Screening was followed by a 2- to 3-week, openlabel, run-in period with MF metered-dose inhaler, 200 g, twice daily (b.i.d.). Patients were randomized 1:1: 1:1 to receive two inhalations/dose of MF/F 200/10 g (100/5 g/inhalation), MF 200 g (100 g/inhalation), F 10 g (5 g/inhalation), or placebo (Fig. 1). All patients were (a) monitored for asthma deteriorations throughout the study; (b) provided with an asthma action plan, immediate access to rescue medication (oral steroids and short-acting 2-agonists [SABA]); and (c) had regular office visits and 24-hour access to physician contact. Patients aged 12 years with a documented history of asthma for 12 months on a stable asthma regimen (daily dose unchanged) for 2 weeks at screening and with a history of medium-dose ICS use (equipotent daily dose of 400 g of beclomethasone dipropionate) for 12 weeks, with or without additional LABA, were eligible. Adolescents (aged 1217 years) were not enrolled in countries that permitted only adult patients to participate in clinical studies. For inclusion, patients

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had to fulfill one of the following criteria: an increase in FEV1 of 12% or a volume increase of 200 mL after 1520 minutes of albuterol/salbutamol administration or of a nebulized SABA; PEF variability of 20%; or a diurnal variation PEF of 20%. At screening, patients FEV1 was required to be between 60 and 90% of predicted. At baseline, patients FEV1 was required to be 60 and 85% of predicted, when all restricted medications had been withheld for 4 hours. Key exclusion criteria were unstable asthma per protocol between screening and baseline and emergency room treatment for an asthma deterioration requiring systemic corticosteroid therapy or hospitalization for management of airway obstruction within the 3 months before baseline. Other exclusion criteria included patients requiring concomitant asthma medication, a history of current or past smoking (10 packyears), a clinically significant abnormal vital sign, or visible evidence of oropharyngeal candidiasis at baseline or earlier. Clinical visits occurred at screening; prebaseline; baseline (day 1); weeks 1, 4, 8, 12, 16, 20, and 26; and/or end of treatment (EOT; generally defined as the last week of treatment for each subject). Efficacy was evaluated by pulmonary function tests at all visits and serial spirometry was performed at baseline and weeks 1, 12, and 26 and/or EOT visits. Patients recorded SABA usage, oral prednisone/prednisolone use, number of nocturnal awakenings requiring SABA use, PEF measurements, and A.M. and P.M. asthma symptom scores (0 no symptoms and 3 severe) daily in e-diaries. The Asthma Quality of Life Questionnaire with standardized activities (AQLQ[S])14 and Asthma Control Questionnaire (ACQ)15 were completed at baseline; weeks 4, 12, and 26; and/or EOT. Study End Points Coprimary end points addressing both inflammatory and respiratory aspects of the disease were (1) the time to first asthma deterioration for MF/F versus F and (2) the bronchodilatory effect of MF/F versus MF. An asthma deterioration was defined as any one of the three following events: (1) an occurrence of any clinically judged deterioration that resulted in emergency treatment, hospitalization due to asthma, or treatment with additional excluded asthma medication (i.e., systemic corticosteroids); (2) a 20% decrease from the average of the two predose FEV1 measurements taken just before the first dose of randomized study medication; or (3) a 30% decrease from the respective average A.M. or P.M. PEF baseline measurements (obtained over the 7 days immediately before receiving the first dose of randomized study medication) for at least 2 consecutive days. The bronchodilatory effect was measured by the mean change in FEV1 area Allergy and Asthma Proceedings

under the curve (AUC) of serial spirometry measurements over the 12-hour period directly after the A.M. dose (FEV1 AUC0 12h) from baseline to week 12 using validated equipment per the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines (Appendix 1).2 Key secondary end points were the change from baseline to week 26 in (1) AQLQ(S) total score for MF/F versus placebo; (2) ACQ total score for MF/F versus placebo; and (3) proportion of nocturnal awakenings due to asthma requiring SABA rescue medication, where baseline was the proportion of nights with nocturnal awakenings (days 7 to 1) before the first treatment dose. Additional secondary end points included trough FEV1, to evaluate the end of the dosing interval; changes from baseline in A.M. PEF and symptom scores; total 24-hour SABA usage; and time to first moderate asthma exacerbation, defined as any one of the following criteria: two consecutive nights with one or more nocturnal awakenings due to asthma symptoms requiring SABA rescue medication; a decrease in A.M. or P.M. PEF of 25% on 2 consecutive days of treatment; or a clinically significant increase in shortacting bronchodilator, defined by 2 consecutive days of 8 U (i.e., 8 puffs) of any combination of SABA or nebulized treatments (one nebulizer treatment was equivalent to 6 puffs of SABA). Safety and Tolerability To evaluate the safety and tolerability of the study drugs, clinical assessment and review of laboratory data included monitoring adverse events (AEs) and serious AEs (SAEs), defined using Coding Symbols for a Thesaurus of Adverse Reaction Terms, physical examinations, clinical laboratory tests, vital signs, and electrocardiograms. Statistical Analysis A sample size of 169 patients/group (to ensure 135 patients/group at 26 weeks) was required to detect a difference between MF/F and MF treatments of 3.1 L hour change from baseline in FEV1 AUC0 12h with 96% power at a 5% significance level, assuming a pooled standard deviation of 6.7 L hour. The target sample size of 676 allowed for 20% dropout before EOT. For serial spirometry, FEV1 AUC0 12h measurement of 3.1 L hour is equivalent to an average difference of 0.26 L in FEV1 across the 12-hour period. Analysis of covariance (ANCOVA) determining effects due to treatment and study site with baseline as a continuous covariate was used to analyze the change from baseline to week 12 in mean FEV1 AUC0 12h. For time to first asthma deterioration, assuming a 5% event rate for MF/F 200/10 g and an 18% event rate for F 10 g, this sample size will provide 90% power to

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Table 1 Patient demographics and baseline characteristics overall and by treatment group Treatment Groups (MDI, b.i.d.) MF/F 200/10 g (n 191) General demographic characteristics Sex, female, n (%) Race, white, n (%) Age, yr, mean (SD) Asthma-related baseline characteristics Duration of asthma, yr, mean (SD) Prebronchodilator PEF, A.M., mean (SD) FEV1, mean L (SD) FEV1, mean % predicted (SD) FEV1/FVC, mean (SD) AQLQ(S) total score, mean (SD) ACQ total score, mean (SD) Prior ICS use without LABA, n (%)* Prior ICS use with LABA, n (%)* 97 (50.8) 136 (71.2) 42.9 (16.3) 15.8 (14.0) 381.7 (111.3) 2.4 (0.7) 72.4 (9.7) 0.7 (0.1) 5.3 (1.1) 1.5 (0.8) 121 (63.4) 75 (39.3) MF 200 g (n 192) 112 (58.3) 135 (70.3) 42.8 (14.9) F 10 g (n 202) 129 (63.9) 146 (72.3) 41.9 (15.3) Placebo (n 196) 122 (62.2) 143 (73.0) 41.9 (15.3) Total (n 781) 460 (58.9) 560 (71.7) 42.4 (15.4)

17.5 (14.6) 15.6 (12.6) 15.4 (13.8) 16.1 (13.8) 375.8 (120.0) 361.4 (119.4) 374.9 (118.9) 373.3 (117.5) 2.4 (0.7) 72.6 (7.9) 0.7 (0.1) 5.4 (1.1) 1.5 (0.8) 117 (60.9) 80 (41.7) 2.3 (0.6) 73.2 (8.8) 0.7 (0.1) 5.4 (1.1) 1.5 (0.8) 125 (61.9) 78 (38.6) 2.3 (0.6) 72.4 (8.4) 0.7 (0.1) 5.5 (1.0) 1.5 (0.8) 124 (63.3) 77 (39.3) 2.3 (0.7) 72.6 (8.7) 0.7 (0.1) 5.4 (1.0) 1.5 (0.8) 487 (62.4) 310 (39.7)

*Patients could have used more than one reporting ICS and/or ICS LABA medication during the 3 mo before screening date. ACQ Asthma Control Questionnaire; AQLQ(S) Asthma Quality of Life Questionnaire With Standardized Activities; b.i.d. twice-daily; F formoterol; FEV1 forced expiratory volume (L) in 1 s; FVC forced vital capacity; ICS inhaled corticosteroid; LABA long-acting 2-agonist; MDI metered-dose inhaler; MF mometasone furoate; MF/F mometasone furoate/formoterol combination therapy; PEF peak expiratory flow; SD standard deviation.

detect a treatment difference in survival curves. A log-rank test comparing the equality of survival curves was used to analyze time to first asthma deterioration. RESULTS Study Population Of 984 patients enrolled in the study and starting the open-label run-in, 203 discontinued before randomization (not meeting study eligibility criteria, n 129). The remaining 781 patients were randomized to receive MF/F 200/10 g (n 191), MF 200 g (n 192), F 10 g (n 202), or placebo (n 196); 551 (71%) completed treatment; and 230 discontinued early (Fig. 1). Placebo (n 77 [39%]) and F (n 85 [42%]) groups experienced much higher rates of discontinuation than did MF (n 33 [17%]) or MF/F (n 35 [18%]) groups. The primary reason for discontinuation was treatment failure in a total of 114 patients (15%) (MF/F, n 8; MF, n 13; F, n 47; placebo, n 46). Very few patients discontinued due to AEs (n 26), with no difference in rates across groups (MF/F, n 4; MF, n 6; F, n 9; placebo, n 7). Baseline demographic characteristics were comparable between all groups (Table 1). The mean age was 42.4 years, the mean body mass index was 27.9 kg/m2, and 63% of patients had a body mass index 25

kg/m2. For all randomized patients the mean duration of asthma at baseline was 16.1 years with mean FEV1 of 2.3 L. Lung function was impaired in all groups, with mean percent predicted FEV1 of 73%. Patients had impaired QoL (AQLQ[S] mean total score 5.38) and asthma was uncontrolled (ACQ mean total score 1.51) in all groups at baseline. Reduction in Asthma Deteriorations A total of 341 patients experienced asthma deterioration at some point during the study. The slopes of the KaplanMeier survival curves (Fig. 2 A) show the delay in time to first asthma deterioration by MF/F and MF compared with F and placebo (both p 0.001). The median times to first asthma deterioration were days 92 and 131 for those receiving F and placebo, respectively. Because 50% of the patients in the MF/F and MF groups experienced an asthma deterioration, median times to first asthma deterioration could not be determined. Significantly fewer patients receiving MF/F and MF compared with F and placebo experienced an asthma deterioration (all p 0.001; Fig. 2 B): MF/F 200/10 g, 30.4%; MF 200 g, 33.9%; F 10 g, 54.0%; and placebo, 55.6%. Thirty-one patients experienced a clinically judged deterioration (i.e., an event resulting in emergency treatment, hospitalization, or treatment with systemic

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Figure 2. Asthma deteriorations. (A) Time to first asthma deterioration by treatment group: Kaplan Meier survival plot. (B) Number of patients with one or more asthma deteriorations or one or more clinically judged deteriorations (*p 0.001 versus F and placebo [asthma deteriorations]; p 0.001 versus F and placebo [clinically judged deteriorations]). F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol combination therapy.

corticosteroids) as the criterion for their first asthma deterioration and were discontinued from the study. An additional 48 patients who experienced an asthma deterioration based on reductions in lung function (i.e., 20% decrease from baseline FEV1 or 30% decrease from baseline PEF for at least 2 consecutive days) later went on to experience a clinically judged deterioration, and were then discontinued. As such, a total of 79 patients experienced a clinically judged deterioration during the study (Fig 2 B). The percentages of patients who experienced a clinically judged deterioration per treatment group were MF/F, 2.6%; MF, 5.2%; F, 15.3%; and placebo, 16.8%. As was observed for the asthma deteriorations category mentioned previously, patients in the MF/F 200/10 g b.i.d. treatment group experienced statistically significantly fewer clinically judged deteriorations than patients in the F 10 g b.i.d. and placebo treatment groups (p 0.001 for both comparisons). Patients in the MF alone treatment group also had statistically significantly fewer clinically judged deteriorations than patients in the F 10 g b.i.d. and placebo groups (p 0.001 for both comparisons). Reductions were also seen in the proportion of patients

who experienced moderate asthma exacerbations: 46.1, 50.0, 67.3, and 70.9% in the MF/F, MF, F, and placebo groups, respectively (p 0.001 for both MF/F and MF versus F and placebo). Improvement in Lung Function Lung function improved rapidly with MF/F treatment. Baseline FEV1 AUC0 12h was assessed directly after MF run-in. Day 1 improvements in lung function were evident for both MF/F and F groups as early as 5 minutes, peaked at 23 hours, and were sustained above predose levels throughout the 12-hour assessment period (Fig. 3 A). At week 12, mean FEV1 AUC0 12h improvements from baseline were 3.1, 1.3, 1.9, and 0.6 L hours for the MF/F, MF, F, and placebo groups, respectively (Table 2), corresponding to increases of 0.26 L (11.7%), 0.11 L (5.7%), 0.16 L (8.5%), and 0.05 L (3.9%), when averaged across the 12-hour serial evaluation period (Fig. 3 B). FEV1 AUC0 12h improved more with MF/F than with MF (p 0.001) or placebo (p 0.001) at all time points throughout the study and with F at week 12 (p 0.017; Table 2). Additionally, F

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significant improvement with MF/F versus F and placebo. Mean trough FEV1 values were balanced across the groups at baseline (range, 2.29 2.36 L) and mean changes from baseline at week 12 were MF/F, 0.13 L; MF, 0.07 L; F, 0.00 L; and placebo, 0.05 L. Treatment with MF/F was significantly better than treatment with F after week 1 (p 0.001) and placebo at all time points (p 0.006). Treatment with MF/F was also statistically better than treatment with MF at several time points, including week 26 (p 0.023). At EOT, A.M. PEF improved by an average of 46.5 L/minute in the MF/F-treated patients versus those treated with placebo. Improvements in the weekly averages of PEF assessed immediately before inhaling A.M. doses of study medication were evident in the MF/F group by week 1 compared with placebo (p 0.001) and sustained throughout the study (Fig. 4). At EOT, the mean changes from baseline in A.M. PEF values were 7.0, 3.2, 2.9, and 6.0%, for MF/F, MF, F, and placebo, respectively. At EOT, the change from baseline in A.M. PEF was significantly greater for the MF/F group than for the other groups (p 0.008), and treatment with MF alone was statistically significant versus placebo (p 0.001).

Figure 3. (A) Change from baseline by treatment group (all randomized patients) in lung function after an open-label run-in period as assessed by serial evaluations (0 12 hours) of FEV1 at day 1 (*p 0.001 versus MF and placebo; p 0.001 versus MF and placebo). (B) Change from baseline by treatment group (all randomized patients) in lung function after an open-label run-in period as assessed by serial evaluations (0 12 hours) of FEV1 at week 12 (*p 0.001 versus MF and placebo; p 0.017 versus F; p 0.009 versus placebo). For day 1 and week 12 analyses, baseline represents the average value of FEV1 measurements obtained 30 minutes before and immediately before (0 h) the first treatment dose on day 1. F, formoterol; FEV1, forced expiratory volume in 1 second; MF, mometasone furoate; MF/F, mometasone furoate/formoterol combination therapy.

monotherapy was superior to placebo for bronchodilation (p 0.009), an effect that was maintained across the 12-hour evaluation period at day 1 and weeks 12 and 26. Trough FEV1 measured before inhalation of the A.M. dose (i.e., at least 12 hours after the P.M. dose) showed

Effect of MF/F on Asthma Control and QoL There was a statistically significant and clinically important improvement in asthma control (ACQ total scores) for patients treated with MF/F (Table 3): MF/F (0.52) versus F (0.20) or versus placebo (0.22; p 0.001 for both). The MF group showed numerical improvements in asthma control versus F and versus placebo at week 26. However, treatment with F monotherapy did not show significantly improved asthma control versus placebo at any time point. At EOT, the minimal important difference (MID) of 0.5 was achieved with MF/F versus placebo. The MF/F group showed improved asthma control, with ACQ scores approaching the well-controlled threshold (ACQ score, 1.0). Mean baseline AQLQ(S) scores indicated impaired QoL in the study population. There was statistically significantly greater mean improvement in AQLQ(S) score between baseline and week 26 for MF/F versus F (p 0.001) and placebo (p 0.004; Table 3). Mean improvement from baseline in AQLQ(S) score at week 26 was statistically significantly greater for MF versus F (p 0.039), but similar for MF and placebo (p 0.130); AQLQ(S) outcomes did not differ significantly for F versus placebo at any time point during treatment (Table 3). At EOT, there was a clinically important improvement (MID, 0.5) from baseline in AQLQ(S) score for MF/F (0.49) versus placebo (0.01), but not for MF (0.37) versus placebo.

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Table 2 Change from baseline in least squares mean FEV1 AUC0 12h (L hr) Treatment Groups (MDI, b.i.d.) MF/F MF F Placebo 200/10 g 200 g 10 g A B C D Day 1 n Mean FEV1 AUC012h Week 1 n Mean FEV1 AUC012h Week 12 n Mean FEV1 AUC012h Week 26 n Mean FEV1 AUC012h End of treatment* n Mean FEV1 AUC012h 188 3.2 179 2.8 166 3.1 152 3.3 190 3.2 189 1.3 184 1.4 169 1.3 153 1.5 190 1.3 198 2.7 189 2.2 135 1.9 118 2.6 202 1.6 192 1.4 177 0.4 128 0.6 114 0.6 193 0.5 AB Pairwise Comparison p Value AC AD BC BD CD

0.001 0.001 0.001 0.001

0.124 0.001 0.001 0.687 0.001 0.128 0.001 0.017 0.001 0.138 0.001 0.054 0.013 0.001

0.198 0.140

0.009

0.037 0.094 0.001

0.001 0.001 0.001

0.491 0.055

0.008

*Corresponds to postbaseline FEV1 AUC0 12h measurement for last visit with complete serial FEV1 data carried forward. AUC0 12h area under the curve from time 0 to 12 hr; b.i.d. twice-daily; F formoterol; FEV1 forced expiratory volume (L) in 1 s; MDI metered-dose inhaler; MF mometasone furoate; MF/F mometasone furoate/formoterol combination therapy. Effect of MF/F on Asthma Symptoms and SABA Use At EOT, 24-hour asthma symptom scores were significantly improved from baseline levels in the MF/F group compared with both the F and placebo groups (p 0.001); mean changes from baseline were 0.50, 0.41, 0.11, and 0.09, for the MF/F, MF, F, and placebo groups, respectively. Treatment with MF also showed significant improvements over both F and placebo (p 0.001). Both MF/F and MF groups exhibited superior changes from baseline for nocturnal awakenings due to asthma requiring the use of SABA versus F (MF/F, p 0.001; MF, p 0.001), and placebo (MF/F, p 0.001; MF, p 0.003; Table 3). There was, however, no significant difference between F and placebo. Additionally, at EOT, 24-hour SABA use was significantly reduced from baseline levels in both the MF/F (61.1%) and the MF (22.1%) groups versus either the F (184.1%) or the placebo (79.1%) groups (p 0.001).
Figure 4. Weekly change from baseline in A.M. peak expiratory flow (L/minute) over the 26-week treatment period (*p 0.001 versus F and placebo; p 0.008 versus MF; p 0.001 versus F and placebo). EOT, end of treatment; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol combination therapy; PEF, peak expiratory flow.

Safety and Tolerability The most common treatment-emergent AEs (Table 4) were nasopharyngitis (MF/F, 6.3%; MF, 7.8%; F, 6.4%; placebo, 3.6%), upper respiratory tract infection (MF/F,

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276 Treatment Group (MDI, b.i.d.) MF 200 g B D F 10 g C Placebo AB AC AD BC Pairwise Comparison, p Values BD CD 0.001 0.001 0.129 0.187 0.857 0.001 0.004 0.039 0.130 0.612 0.001 0.001 0.001 0.003 0.601

Table 3 Least squares mean Asthma Control Questionnaire and Asthma Quality of Life Questionnaire with Standardized Activities total scores, and proportion of nights with nocturnal awakening due to asthma requiring short-acting 2-agonist use

MF/F 200/10 g A

Asthma Control Questionnaire*# Baseline 1.47 1.46 1.43 1.41 n 179 186 184 187 Week 26 0.95 1.14 1.23 1.19 n 152 154 119 121 Change 0.52 0.32 0.20 0.22 0.005 Asthma Quality of Life Questionnaire with Standardized Activities* Baseline 5.38 5.40 5.51 5.56 n 183 189 187 189 Week 26 5.99 5.90 5.82 5.92 n 153 157 121 121 Change 0.61 0.50 0.31 0.36 0.152 Proportion of nights with nocturnal awakenings due to asthma requiring SABA use n 186 191 199 194 Baseline 0.18 0.16 0.16 0.15 End of treatment 0.10 0.11 0.17 0.15 Change (%) 0.08 (60) 0.05 (60) 0.01 (5) 0.00 (15) 0.063

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*Baseline includes patients with baseline and 1 postbaseline measurements; week 26 includes patients with baseline and week 26 measurements. #Response rated on a 7-point scale (0 best asthma control; 6 worst asthma control). Response rated on a 7-point scale (1 worst quality of life; 7 best quality of life). Up to end point (including data from the entire 26-wk treatment period). b.i.d. twice daily; F formoterol; MDI metered-dose inhaler; MF mometasone furoate; MF/F mometasone furoate formoterol combination therapy.

Table 4 Adverse event (AE) summary during the treatment period Treatment Group (MDI, b.i.d.) MF/F 200/10 g (n 191) General disorders and administration site conditions Chest pain 2 (1.0) Pyrexia 6 (3.1) Infections and infestations Bronchitis 5 (2.6) Gastroenteritis 1 (0.5) Influenza 5 (2.6) Nasopharyngitis 12 (6.3) Pharyngitis 8 (4.2) Rhinitis 5 (2.6) Sinusitis 5 (2.6) Upper respiratory tract infection 11 (5.8) Viral infection 6 (3.1) Nervous system disorders Headache 9 (4.7) Respiratory, thoracic, and mediastinal disorders Cough 3 (1.6) Pharyngolaryngeal pain 6 (3.1) AE Summary Any treatment-emergent AEs 97 (50.8) Treatment-related AEs 17 (8.9) Severe/life-threatening AEs 5 (2.6) Serious AEs 5 (2.6) MF 200 g (n 192) 2 (1.0) 5 (2.6) 3 (1.6) 4 (2.1) 7 (3.6) 15 (7.8) 6 (3.1) 3 (1.6) 6 (3.1) 16 (8.3) 0 10 (5.2) 4 (2.1) 4 (2.1) 88 (45.8) 11 (5.7) 8 (4.2) 3 (1.6) F 10 g (n 202) 1 (0.5) 2 (1.0) 5 (2.5) 2 (1.0) 5 (2.5) 13 (6.4) 3 (1.5) 1 (0.5) 7 (3.5) 12 (5.9) 1 (0.5) 6 (3.0) 2 (1.0) 3 (1.5) 90 (44.6) 11 (5.4) 9 (4.5) 3 (1.5) Placebo (n 196) 4 (2.0) 1 (0.5) 4 (2.0) 0 5 (2.6) 7 (3.6) 6 (3.1) 4 (2.0) 2 (1.0) 17 (8.7) 1 (0.5) 7 (3.6) 4 (2.0) 7 (3.6) 82 (41.8) 15 (7.7) 4 (2.0) 3 (1.5) Total (n 781) 9 (1.2) 14 (1.8) 17 (2.2) 7 (0.9) 22 (2.8) 47 (6.0) 23 (2.9) 13 (1.7) 20 (2.6) 56 (7.2) 8 (1.0) 32 (4.1) 13 (1.7) 20 (2.6) 357 (45.7) 54 (6.9) 26 (3.3) 14 (1.8)

Number (%) of treatment-emergent AEs occurring in 2% of patients in any treatment group and treatment-related AEs (includes all AEs considered possibly related to study medication), severe/life-threatening AEs, and serious AEs in all patients. b.i.d. twice daily; F formoterol; MDI metered dose inhaler; MF mometasone furoate; MF/F mometasone furoate/formoterol combination therapy. 5.8%; MF, 8.3%; F, 5.9%; placebo, 8.7%), and headache (MF/F, 4.7%; MF, 5.2%; F, 3.0%; placebo, 3.6%). The numbers of patients with treatment-related AEs (Table 4) were MF/F, n 17 (8.9%); MF, n 11 (5.7%); F, n 11 (5.4%); and placebo, n 15 (7.7%). The most commonly reported treatment-related AEs among all patients were oral candidiasis, n 6 (0.8%) and dysphonia, n 5 (0.6%). The number of discontinuations due to AEs (Fig. 1) was low in all groups: range, 2% (MF/F) to 4% (for placebo). During the study, SAEs were uncommon in all groups and only the severe asthma exacerbation (as defined by the Coding Symbols for Thesaurus of Adverse Reaction Terms) in the F group was considered possibly related to study medication. Severe AEs (i.e., incapacitating, significantly affected the patients clinical status, or warranted intervention) or life-threatening AEs (i.e., placed the patient at immediate risk of death) were observed in 2.6%, 4.2%, 4.5%, and 2.0% of patients in the MF/F, MF, F, and placebo groups, respectively (Table 4). More than one severe/life-threatening AE may have occurred in any given patient; these events included gastrointestinal disorders (MF, n 3; placebo, n 2), infections and infestations (MF/F, n 2; MF, n 4; F, n 3), muscle strain (MF/F, n 1), metabolism/ nutrition disorders (MF, n 1; F, n 1), musculoskeletal/connective tissue disorders (F, n 3), uterine leiomyosarcoma (MF/F, n 1), nervous system disorders (MF/F, n 1; MF, n 1; F, n 1), asthma (F, n 1; placebo, n 1), atopic dermatitis (placebo, n 1), and surgical/medical procedures (MF, n 1; placebo, n 1). There were no clinically meaningful changes in clinical laboratory test and electrocardiogram parameters, physical examination findings, or vital signs during MF/F treatment. DISCUSSION The effect of MF/F on asthma deteriorations was assessed prospectively in this trial using a comprehensive definition of asthma deteriorations, including multiple criteria such as diminished lung function (PEF for at least 2 days, FEV1) or clinically judged deteriorations 277

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(hospitalization, emergency department visit, or treatment with systemic steroids for asthma), which is similar to the 2009 ATS/ERS statement definition for severe asthma exacerbation (Appendix 1).2 Although prevention of asthma deteriorations is accepted as a key aspect of asthma control,6 8 the exact definition of an asthma deterioration has varied in clinical trials making comparisons difficult. Nevertheless, this 26week study indicated that treatment with MF/F compared with F monotherapy and placebo reduced asthma deteriorations. Additionally, because the trial design had an active run-in period on MF without any washout, improvements observed in lung function or reduction in asthma deteriorations were above those attributable to receiving at least 2 weeks of ICS monotherapy. However, this trial design and these data may represent more clinically relevant assessments of patients with asthma uncontrolled on ICS monotherapy than those from trials without an active ICS-containing run-in period. Furthermore, this trial was designed to prevent the earlier ethical and safety concerns regarding the inclusion of placebo and LABA monotherapy groups in trials involving patients with persistent asthma on ICS therapy by including constant monitoring of patient e-diary data, thereby ensuring that any deterioration was detected quickly. The use of e-diaries prevented retrospective data entry and are therefore more likely to be accurate reflections of significant lung function changes and SABA use.2 To adequately evaluate contributions from each component of this ICS/LABA combination, this 26-week study assessed both clinically judged deteriorations and lung function. The contribution of F was clearly shown by the superior effect of MF/F versus MF on lung function as shown by the mean improvements in FEV1 AUC0 12h from baseline to week 12. As early as day 1, improvements in lung function with MF/F compared with MF occurred within 5 minutes, and the duration of effects were sustained throughout the study as assessed by FEV1 AUC0 12h (change from baseline at week 12, 3.1 L hour for MF/F versus 1.3 L hour for MF; Table 2) and PEF (change from baseline at EOT, 18.1 L/minute for MF/F versus 1.7 L/minute for MF; Fig. 4) measurements, which indicates that patients did not experience tachyphylaxis. Mometasone also appeared to have an additive and stabilizing effect on FEV1 and daily PEF compared with F alone as noted by a significant drop in lung function in patients treated with F alone. Patients receiving MF/F reported clinically meaningful improvements in asthma control with ACQ scores at week 26 going below 1.00, the threshold for well-controlled asthma.16 None of the other treatment groups improved as much. Patients receiving MF/F also reported clinically meaningful improvements in day and

nighttime symptoms, QoL, and reduced requirement for rescue medication compared with other treatment groups. Overall, the additional end points supported the coprimary efficacy results and showed the complementary effect of the components in the combination. All study drugs were well tolerated with no new safety signals detected with the combination of MF/F or either of the individual components. The rates of treatment-related oral candidiasis and dysphonia observed in this study in the MF/F treatment group (1.0% for each) were comparable with those reported for other ICS/LABA combination products.17,18 CONCLUSIONS This study shows that MF/F 200/10 g b.i.d. was more effective than predefined monocomponent comparators in controlling asthma and reducing the risk of asthma deteriorations in patients with persistent asthma uncontrolled on medium-dose ICS. Furthermore, MF/F 200/10 g b.i.d. improved lung function more than treatment with either of the individual constituent compounds. This supports the use of MF/F in the management of asthma patients not well controlled by their ICS, further supporting the recommendations of national and international guidelines. The combination MF/F treatment was well tolerated and no new safety signals were detected. APPENDIX 1 ATS/ERS Definition of Severe Asthma Exacerbations in Clinical Trials
The recently published ATS/ERS guidelines2 provide the following definition for severe asthma exacerbations: Use of systemic corticosteroids or an increased dose from a stable maintenance level, for at least 3 days (courses of corticosteroid treatment separated by 1 week should be considered as separate incidences). Asthma-related hospitalization or emergency room visit, requiring use of systemic corticosteroids. In addition, the following criteria are being evaluated for further validation (the changes should persist for 2 days): Changes in PEF from baseline. Changes in asthma symptoms. Changes in 2-agonist use.

APPENDIX 2 Investigator List

Canada: Amarjit Cheema, Mississauga, ON; Jacques Hebert, Quebec, QC; Gordon Sussman, Toronto, ON; William Yang, Ottawa, ON. Colombia: Guido Cardona-Arango, Bogota; Horacio Giraldo-Estrada, Bogota; Carlos E. Matiz-Bueno, Bogota. Costa Rica: Wing C.C. Cheng, San Jose; Emilio Guevara Jimenez, San Jose; Ted A. Mitchell Brumley, San Jose. Croatia: Vladimir Ahel, Rijeka; Drago Caleta, Zagreb; Jasna Cepin-Bogovic, Zagreb; Fadila Pavicic, Zagreb; Asja StipicMarkovic, Zagreb; Neven Tudoric, Zagreb. Denmark: Vibeke Backer, Copenhagen; Martin Doessing, Frederikssund. Ecuador: Manuel I.

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Cherrez Ojeda, Guayaquil. Estonia: Rain Jogi, Tartu; Ave Nagelmann, Tallinn; Pritt Samaruutel, Tallinn. Guatemala: Victor H. Chur Gonzalez, Guatemala City; Macro V. Flores Belteton, Guatemala City; Jeremias S. Guerra Mejia, Guatemala City. Hungary: Beatrix Balint, Deszk; Laszlo Barkai, Miskolc; Lajos Kosa, Budapest; Zsuzsanna Mark, Torokbalint; Edit Mohacsi, Budapest; Kristof Nekam, Budapest; Gyula Panczel, Kecskemet; Judit Schlezak, Komarom; Zsuzsanna Szalai, Mosonmagyarovar; Ilona Vinkler, Nyiregyhaza. India: Ashok Bajpai, Indore; Salil Bhargava, Indore; Devasahayam Christopher, Vellore; George A. DSouza, Bangalore; Madhav Kale, Pune; Surya Kant, Lucknow; Ratnavelu V. Kumar, Hyderabad; Pramod Niphadkar, Mumbai; Sujit Rajan, Mumbai; Mohan Rao, Bangalore; Sandeep Saboo, Hyderabad; Tushar Sahasrabudhe, Pune; Ravindra M. Sarnaik, Nagpur; Deepak Talwar, Noida; Pradyut Waghray, Hyderabad. Mexico: Patricia E. Aguilar Dominguez, Huixquilucan; Dante D. Hernandez-Colin, Guadalajara; Luis A. Rendon-Perez, Monterrey; Francisco Sanchez Llamas, Guadalajara. Philippines: Tito Atienza, Quezon City; Abundio Balgos, Manila; Gary Carlos, Cavite; Teresita de Guia, Quezon City; Dina Diaz, Quezon City; Camilo Roa, Manila; Joel Santiaguel, Quezon City; Ma. Bella Siasoco, Quezon City. Poland: Monica Bobrowska-Korzeniowska, Lodz; Zenon Bukowczan, Bienkowka; Ryszarda Chazan, Warszawa; Marek Jutel, Wroclaw; Beata Kuklinska, Bialystok; Piotr Kuna, Lodz; Wladyslaw Pierzchala, Katowice; Grazyna Pulka, Krakow; Barbara Rogala, Zabrze; Ryszard Sciborski, Olawa; Ewa Springer, Pozan; Iwona Stelmach, Lodz; Hanna Szelerska-Twardosz, Poznan. Puerto Rico: Domingo Chardon-Feliciano, Ponce; Jose R. Rodriguez-Santana, San Juan. Russia: Natalia Astafyeva, Saratov; Alexander Emelyanov, Saint Petersburg; Alexander Gorelov, Saint Petersburg; Ludmilla Goryachkina, Moscow; Natalia IIjina, Moscow; Nikolay Klimko, Saint Petersburg; Oxana Korovina, Saint Petersburg; Vasiliy Trofimov, Saint Petersburg; Arkady Vertkin, Moscow; Alexander Vizel, Kazan. Thailand: Chalerat Direkwattanachai, Bangkok; Anon Jatakanon, Bangkok; Arth Nana, Bangkok; Vilaiwan Viriyachaiyo, Hat Yai, Songkhla. Ukraine: Volodymyr Biloglazov, Symferopol AR Crimea; Oleksandr Dziublyk, Kiev; Yuryi Feshchenko, Kiev; Volodymyr Gavrysyuk, Kiev; Natalia Gorovenko, Kiev; Iryna Lysenko, Zaporizhzhia; Nadiya Monogarova, Donetsk; Tetyana Pertseva, Dnipropetrovsk; Sergiy Soldatchenko, Yalta AR Crimea; Lyudmyla Yashyna, Kiev. United States: Niran Amar, Waco, TX; Garrison Ayars, Kirkland, WA; George Bensch, Stockton, CA; William Berger, Mission Viejo, CA; David Bernstein, Cincinnati, OH; Edward J. Campbell, Provo, UT; Paul Carter, Knoxville, TN; Jonathan Corren, Los Angeles, CA; Joseph Diaz, San Antonio, TX; Lawrence DuBuske, Gardner, MA; Linda Ford, Papillion, NE; Bruce Friedman, Fountain Valley, CA; Sandra M. Gawchick, Upland, PA; Khaled Girgis, Overland Park, KS; Gregory Gottschlich, Cincinnati, OH; Leon Greos, Aurora, CO; Gary Gross, Dallas, TX; Frank Hampel, Jr., New Braunfels, TX; Alan Heller, San Jose, CA; Harold Kaiser, Minneapolis, MN; Neil Kao, Greenville, SC; Edward Kerwin, Medford, OR; Craig F. LaForce, Raleigh, NC; Edward Lane, Bridgeport, CT; Donald Levy, Orange, CA; William Lumry, Dallas, TX; Lyndon E. Mansfield, El Paso, TX; Eli Meltzer, San Diego, CA; Steven M. Meltzer, Long Beach, CA; S. David Miller, North Dartmouth, MA; Kevin Murphy, Omaha, NE; Robert A. Nathan, Colorado Springs, CO; Anjuli Nayak, Normal, IL; Thomas Nilsson, Omaha, NE; Michael Noonan, Portland, OR; Grant Olson, Lakewood, CO; James Pearle, Fullerton, CA; Andrew Pedinoff, Skillman, NJ; David Pearlman, Denver, CO; Warren Pleskow, Encinitas, CA; Bruce Prenner, San Diego, CA; Gordon Raphael, Bethesda, MD; Paul Ratner, San Antonio, TX; Lawrence Sher, Rolling Hills Estates, CA; Weily Soong, Birmingham, AL; Martha Tarpay, Oklahoma City, OK; Suzanne Weakley, Houston, TX; Steven Weinstein, Huntington Beach, CA; Martha White, Wheaton, MD; James Wolfe, San Jose, CA; Robert Wolfe, Los Angeles, CA.

ACKNOWLEDGMENTS
This study was sponsored by Merck & Co. The authors acknowledge Davis Gates and Wen-Ling Kuo of Merck Research Laboratories for their assistance with statistical design and analyses. Original editorial support was provided by Ray Beck, Jr., Ph.D., Paul Lane, Ph.D., and Mukund Nori, Ph.D., M.B.A., C.M.P.P. of UBC Scientific Solutions; additional editorial support was provided by Brett D. Mahon, Ph.D. of Complete Publication Solutions, LLC. Editorial support was funded by Merck & Co.

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