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Volume 31, Number 4July- August2010

Twenty-six-week efficacy and safety study of mometasonefuroate/formoterol 200/10 g combination treatment inpatients with persistent asthma previously receivingmedium-dose inhaled corticosteroids

Robert A. Nathan, M.D., Hendrik Nolte, M.D., Ph.D., and David S. Pearlman, M.D., on Behalf ofthe P04334 Study Investigators

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Twenty-six-week efficacy and safety study of mometasonefuroate/formoterol 200/10 g combination treatment inpatients with persistent asthma previously receivingmedium-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 ofthe P04334 Study Investigators

ABSTRACT

Asthma is a heterogeneous condition characterized by reduced lung function, chronic inflammation, and periodic asthmadeteriorations. This study was performed to evaluate the effect of mometasone furoate (MF)/formoterol (F) combination, 200/10g, administered twice daily (b.i.d.) on asthma deteriorations and pulmonary function in patients with asthma uncontrolledon 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 endpoints were time to first asthma deterioration (MF/F versus F) and bronchodilation, assessed by the area under the curve ofthe change in forced expiratory volume in 1 second 012 hours (FEV1 AUC012h; 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 judgeddeteriorations with MF/F versus F and placebo (p 0.001). Lung function improved more rapidly with MF/F than MF andplacebo. Mean change from baseline FEV1 AUC012h 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 inreducing the risk of asthma deteriorations. MF/F was safe and provided rapid and sustained bronchodilation in patients with asthma.

(Allergy Asthma Proc 31:269279, 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

Asthma is a chronic and complex disease character-ized by impaired respiratory function and airwayinflammation.1,2 Patients with asthma often experience

periodic worsening of symptoms, severe exacerbations(i.e., asthma deteriorations), and clinically judged deteri-orations that may require emergency treatment and hos-pitalization.35 Preventing asthma deteriorations isclinically important because they may result in furtherasthma deteriorations,5 decline in lung function, in-crease in asthma mortality,4 and impaired patient qual-ity of life (QoL). The goal of asthma treatment is toincrease lung function, reduce the severity of asthmasymptoms, and reduce the risk of asthma deteriora-tions to improve patient health and QoL.6

Clinical trials have generally focused on assessmentof lung function (e.g., forced expiratory volume in 1second [FEV1] or peak expiratory flow [PEF]) to mea-sure treatment efficacy. However, without additionalend points, such measurements can fail to address theunderlying inflammatory aspects of asthma and maycorrelate poorly with asthma deteriorations, an impor-tant clinical outcome that contributes to risk and ad-versely impacts patient health. Clinical trials haveshown that addition of a long-acting inhaled 2-agonist(LABA) to an inhaled corticosteroid (ICS) maintenance

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 pub-

lished 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, Med-

Immune, Novartis, sanofi-aventis, Schering-Plough, Sepracor, and TEVA, and he has

served on speakers bureaus for AstraZeneca, Genentech, GSK, Novartis, sanofi-

aventis, 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 corre spondence and reprint reques ts to Robert A. Nathan, M.D., Asthma and

Allergy Ass ociates and Research Center, 2709 North Tejon St reet, Colorado Springs,

CO 80907

E-mail address: [email protected]

Copyright 2010, OceanSide Publications, Inc., U.S.A.

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had to fulfill one of the following criteria: an increase inFEV1 of12% or a volume increase of200 mL after1520 minutes of albuterol/salbutamol administra-tion or of a nebulized SABA; PEF variability of20%;or a diurnal variation PEF of 20%. At screening,patients FEV1 was required to be between 60 and90% of predicted. At baseline, patients FEV1 wasrequired to be 60 and 85% of predicted, when allrestricted medications had been withheld for4 hours.Key exclusion criteria were unstable asthma per pro-tocol between screening and baseline and emergencyroom treatment for an asthma deterioration requiringsystemic corticosteroid therapy or hospitalization formanagement of airway obstruction within the 3months before baseline. Other exclusion criteria in-cluded patients requiring concomitant asthma medica-tion, a history of current or past smoking (10 pack-years), a clinically significant abnormal vital sign, orvisible evidence of oropharyngeal candidiasis at base-line or earlier.

Clinical visits occurred at screening; prebaseline;baseline (day 1); weeks 1, 4, 8, 12, 16, 20, and 26; and/orend of treatment (EOT; generally defined as the lastweek of treatment for each subject). Efficacy was eval-uated by pulmonary function tests at all visits andserial spirometry was performed at baseline and weeks1, 12, and 26 and/or EOT visits. Patients recordedSABA usage, oral prednisone/prednisolone use, num-ber of nocturnal awakenings requiring SABA use, PEFmeasurements, and A.M. and P.M. asthma symptomscores (0 no symptoms and 3 severe) daily ine-diaries. The Asthma Quality of Life Questionnairewith standardized activities (AQLQ[S])14 and Asthma

Control Questionnaire (ACQ)15 were completed atbaseline; weeks 4, 12, and 26; and/or EOT.

Study End Points

Coprimary end points addressing both inflammatoryand respiratory aspects of the disease were (1) the timeto first asthma deterioration for MF/F versus F and (2)the bronchodilatory effect of MF/F versus MF. Anasthma deterioration was defined as any one of thethree following events: (1) an occurrence of any clini-cally judged deterioration that resulted in emergency

treatment, hospitalization due to asthma, or treatmentwith additional excluded asthma medication (i.e., sys-temic corticosteroids); (2) a 20% decrease from theaverage of the two predose FEV1 measurements takenjust before the first dose of randomized study medica-tion; or (3) a 30% decrease from the respective aver-age A.M. or P.M. PEF baseline measurements (ob-tained over the 7 days immediately before receivingthe first dose of randomized study medication) for atleast 2 consecutive days. The bronchodilatory effectwas measured by the mean change in FEV1 area

under the curve (AUC) of serial spirometry measure-ments over the 12-hour period directly after the A.M.dose (FEV1 AUC012h) from baseline to week 12 us-ing validated equipment per the American ThoracicSociety (ATS)/European Respiratory Society (ERS)guidelines (Appendix 1).2

Key secondary end points were the change frombaseline to week 26 in (1) AQLQ(S) total score forMF/F versus placebo; (2) ACQ total score for MF/Fversus placebo; and (3) proportion of nocturnal awak-enings due to asthma requiring SABA rescue medica-tion, where baseline was the proportion of nights withnocturnal awakenings (days 7 to 1) before the firsttreatment dose. Additional secondary end points in-cluded trough FEV1, to evaluate the end of the dosinginterval; changes from baseline in A.M. PEF and symp-tom scores; total 24-hour SABA usage; and time to firstmoderate asthma exacerbation, defined as any one ofthe following criteria: two consecutive nights with oneor more nocturnal awakenings due to asthma symp-

toms requiring SABA rescue medication; a decrease inA.M. or P.M. PEF of25% on 2 consecutive days oftreatment; or a clinically significant increase in short-acting bronchodilator, defined by 2 consecutive days of8 U (i.e., 8 puffs) of any combination of SABA ornebulized treatments (one nebulizer treatment wasequivalent to 6 puffs of SABA).

Safety and Tolerability

To evaluate the safety and tolerability of the studydrugs, clinical assessment and review of laboratorydata included monitoring adverse events (AEs) and

serious AEs (SAEs), defined using Coding Symbols fora Thesaurus of Adverse Reaction Terms, physical ex-aminations, clinical laboratory tests, vital signs, andelectrocardiograms.

Statistical Analysis

A sample size of 169 patients/group (to ensure 135patients/group at 26 weeks) was required to detect adifference between MF/F and MF treatments of 3.1 Lhour change from baseline in FEV1 AUC012h with 96%power at a 5% significance level, assuming a pooledstandard deviation of 6.7 L hour. The target sample

size of 676 allowed for 20% dropout before EOT. Forserial spirometry, FEV1 AUC012h measurement of 3.1L hour is equivalent to an average difference of 0.26L in FEV1 across the 12-hour period. Analysis ofcovariance (ANCOVA) determining effects due totreatment and study site with baseline as a continu-ous covariate was used to analyze the change frombaseline to week 12 in mean FEV1 AUC012h. For timeto first asthma deterioration, assuming a 5% eventrate for MF/F 200/10 g and an 18% event rate for F10 g, this sample size will provide 90% power to


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detect a treatment difference in survival curves. Alog-rank test comparing the equality of survivalcurves was used to analyze time to first asthmadeterioration.

RESULTS

Study Population

Of 984 patients enrolled in the study and starting theopen-label run-in, 203 discontinued before randomiza-tion (not meeting study eligibility criteria, n 129).The remaining 781 patients were randomized to re-ceive 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%]) groupsexperienced much higher rates of discontinuation than

did MF (n

33 [17%]) or MF/F (n

35 [18%]) groups.The primary reason for discontinuation was treatmentfailure in a total of 114 patients (15%) (MF/F, n 8;MF, n 13; F, n 47; placebo, n 46). Very fewpatients discontinued due to AEs (n 26), with nodifference in rates across groups (MF/F, n 4; MF, n6; F, n 9; placebo, n 7).

Baseline demographic characteristics were compara-ble between all groups (Table 1). The mean age was42.4 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 durationof asthma at baseline was 16.1 years with mean FEV1 of2.3 L. Lung function was impaired in all groups, withmean percent predicted FEV1 of73%. Patients had

impaired QoL (AQLQ[S] mean total score 5.38) andasthma was uncontrolled (ACQ mean total score 1.51)in all groups at baseline.

Reduction in Asthma Deteriorations

A total of 341 patients experienced asthma deterio-ration at some point during the study. The slopes of theKaplanMeier survival curves (Fig. 2 A) show the de-lay in time to first asthma deterioration by MF/F andMF compared with F and placebo (both p 0.001). Themedian times to first asthma deterioration were days92 and 131 for those receiving F and placebo, respec-

tively. Because

50% of the patients in the MF/F andMF groups experienced an asthma deterioration, me-dian times to first asthma deterioration could not bedetermined. Significantly fewer patients receivingMF/F and MF compared with F and placebo experi-enced 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 judgeddeterioration (i.e., an event resulting in emergencytreatment, hospitalization, or treatment with systemic

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)

MF 200 g(n 192)

F 10 g(n 202)

Placebo(n 196)

Total(n 781)

General demographic characteristicsSex, female, n (%) 97 (50.8) 112 (58.3) 129 (63.9) 122 (62.2) 460 (58.9)

Race, white, n (%) 136 (71.2) 135 (70.3) 146 (72.3) 143 (73.0) 560 (71.7)Age, yr, mean (SD) 42.9 (16.3) 42.8 (14.9) 41.9 (15.3) 41.9 (15.3) 42.4 (15.4)

Asthma-related baseline characteristicsDuration of asthma, yr, mean (SD) 15.8 (14.0) 17.5 (14.6) 15.6 (12.6) 15.4 (13.8) 16.1 (13.8)Prebronchodilator PEF, A.M.,

mean (SD)381.7 (111.3) 375.8 (120.0) 361.4 (119.4) 374.9 (118.9) 373.3 (117.5)

FEV1, mean L (SD) 2.4 (0.7) 2.4 (0.7) 2.3 (0.6) 2.3 (0.6) 2.3 (0.7)FEV1, mean % predicted (SD) 72.4 (9.7) 72.6 (7.9) 73.2 (8.8) 72.4 (8.4) 72.6 (8.7)FEV1/FVC, mean (SD) 0.7 (0.1) 0.7 (0.1) 0.7 (0.1) 0.7 (0.1) 0.7 (0.1)AQLQ(S) total score, mean (SD) 5.3 (1.1) 5.4 (1.1) 5.4 (1.1) 5.5 (1.0) 5.4 (1.0)ACQ total score, mean (SD) 1.5 (0.8) 1.5 (0.8) 1.5 (0.8) 1.5 (0.8) 1.5 (0.8)Prior ICS use without LABA, n (%)* 121 (63.4) 117 (60.9) 125 (61.9) 124 (63.3) 487 (62.4)

Prior ICS use with LABA, n (%)* 75 (39.3) 80 (41.7) 78 (38.6) 77 (39.3) 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 inhaledcorticosteroid; LABA long-acting 2-agonist; MDI metered-dose inhaler; MF mometasone furoate; MF/F mometa-sone furoate/formoterol combination therapy; PEF peak expiratory flow; SD standard deviation.

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corticosteroids) as the criterion for their first asthmadeterioration and were discontinued from the study.An additional 48 patients who experienced an asthmadeterioration based on reductions in lung function (i.e.,20% decrease from baseline FEV1 or 30% decreasefrom baseline PEF for at least 2 consecutive days) laterwent on to experience a clinically judged deterioration,and were then discontinued. As such, a total of 79patients experienced a clinically judged deteriorationduring the study (Fig 2 B). The percentages of patientswho experienced a clinically judged deterioration pertreatment group were MF/F, 2.6%; MF, 5.2%; F, 15.3%;

and placebo, 16.8%. As was observed for the asthmadeteriorations category mentioned previously, patientsin the MF/F 200/10 g b.i.d. treatment group experi-enced statistically significantly fewer clinically judgeddeteriorations than patients in the F 10 g b.i.d. andplacebo treatment groups (p 0.001 for both compar-isons). Patients in the MF alone treatment group alsohad statistically significantly fewer clinically judgeddeteriorations than patients in the F 10 g b.i.d. andplacebo groups (p 0.001 for both comparisons). Re-ductions 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 placebogroups, respectively (p 0.001 for both MF/F and MFversus F and placebo).

Improvement in Lung Function

Lung function improved rapidly with MF/F treat-ment. Baseline FEV1 AUC012h was assessed directlyafter MF run-in. Day 1 improvements in lung functionwere evident for both MF/F and F groups as early as 5minutes, peaked at 23 hours, and were sustained

above predose levels throughout the 12-hour assessmentperiod (Fig. 3 A). At week 12, mean FEV1 AUC012himprovements from baseline were 3.1, 1.3, 1.9, and 0.6L hours for the MF/F, MF, F, and placebo groups,respectively (Table 2), corresponding to increases of0.26 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 eval-uation period (Fig. 3 B). FEV1 AUC012h improvedmore with MF/F than with MF (p 0.001) or placebo(p 0.001) at all time points throughout the study andwith F at week 12 (p 0.017; Table 2). Additionally, F

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 pla-

cebo [asthma deteriorations]; p 0.001 versus F and

placebo [clinically judged deteriorations]). F, formo-

terol; MF, mometasone furoate; MF/F, mometasone

furoate/formoterol combination therapy.


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monotherapy was superior to placebo for bronchodi-lation (p 0.009), an effect that was maintained acrossthe 12-hour evaluation period at day 1 and weeks 12and 26.

Trough FEV1 measured before inhalation of the A.M.dose (i.e., at least 12 hours after the P.M. dose) showed

significant improvement with MF/F versus F and pla-cebo. Mean trough FEV1 values were balanced acrossthe groups at baseline (range, 2.292.36 L) and meanchanges from baseline at week 12 were MF/F, 0.13 L;MF, 0.07 L; F, 0.00 L; and placebo, 0.05 L. Treatmentwith MF/F was significantly better than treatmentwith F after week 1 (p 0.001) and placebo at all timepoints (p 0.006). Treatment with MF/F was alsostatistically better than treatment with MF at severaltime points, including week 26 (p 0.023).

At EOT, A.M. PEF improved by an average of 46.5L/minute in the MF/F-treated patients versus thosetreated with placebo. Improvements in the weekly av-erages of PEF assessed immediately before inhalingA.M. doses of study medication were evident in theMF/F group by week 1 compared with placebo (p 0.001) and sustained throughout the study (Fig. 4). AtEOT, the mean changes from baseline in A.M. PEFvalues were 7.0, 3.2,2.9, and6.0%, for MF/F, MF, F,and placebo, respectively. At EOT, the change from

baseline in A.M. PEF was significantly greater for theMF/F group than for the other groups (p 0.008), andtreatment with MF alone was statistically significantversus placebo (p 0.001).

Effect of MF/F on Asthma Control and QoL

There was a statistically significant and clinicallyimportant improvement in asthma control (ACQ totalscores) 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 im-

provements in asthma control versus F and versusplacebo at week 26. However, treatment with F mono-therapy did not show significantly improved asthmacontrol versus placebo at any time point. At EOT, theminimal important difference (MID) of 0.5 wasachieved with MF/F versus placebo. The MF/F groupshowed improved asthma control, with ACQ scoresapproaching the well-controlled threshold (ACQscore, 1.0).

Mean baseline AQLQ(S) scores indicated impairedQoL in the study population. There was statisticallysignificantly 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). Meanimprovement from baseline in AQLQ(S) score at week26 was statistically significantly greater for MF versusF (p 0.039), but similar for MF and placebo (p 0.130); AQLQ(S) outcomes did not differ significantlyfor F versus placebo at any time point during treatment(Table 3). At EOT, there was a clinically importantimprovement (MID, 0.5) from baseline in AQLQ(S)score for MF/F (0.49) versus placebo (0.01), but notfor MF (0.37) versus placebo.

Figure 3. (A) Change from baseline by treatment group (all ran-

domized 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 ob-

tained 30 minutes before and immediately before (0 h) the firsttreatment dose on day 1. F, formoterol; FEV1, forced expiratory

volume in 1 second; MF, mometasone furoate; MF/F, mometasone

furoate/formoterol combination therapy.


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Effect of MF/F on Asthma Symptoms and SABAUse

At EOT, 24-hour asthma symptom scores were sig-

nificantly improved from baseline levels in the MF/Fgroup 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 placebogroups, respectively. Treatment with MF also showedsignificant improvements over both F and placebo (p0.001).

Both MF/F and MF groups exhibited superior changesfrom baseline for nocturnal awakenings due to asthmarequiring 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, atEOT, 24-hour SABA use was significantly reducedfrom baseline levels in both the MF/F (61.1%) andthe MF (22.1%) groups versus either the F (184.1%)or the placebo (79.1%) groups (p 0.001).

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,

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, mometa-

sone furoate; MF/F, mometasone furoate/formoterol combination

therapy; PEF, peak expiratory flow.

Table 2 Change from baseline in least squares mean FEV1 AUC012h (L hr)

Treatment Groups(MDI, b.i.d.)

Pairwise Comparisonp Value

MF/F200/10 g

A

MF200 g

B

F10 g

C

Placebo

D

AB AC AD BC BD CD

Day 1n 188 189 198 192

0.001 0.124 0.001 0.001 0.687 0.001Mean FEV1 AUC012h 3.2 1.3 2.7 1.4Week 1

n 179 184 189 1770.001 0.128 0.001 0.054 0.013 0.001Mean FEV1 AUC012h 2.8 1.4 2.2 0.4

Week 12n 166 169 135 128

0.001 0.017 0.001 0.198 0.140 0.009Mean FEV1 AUC012h 3.1 1.3 1.9 0.6Week 26

n 152 153 118 1140.001 0.138 0.001 0.037 0.094 0.001Mean FEV1 AUC012h 3.3 1.5 2.6 0.6

End of treatment*n 190 190 202 1930.0010.001 0.001 0.491 0.055 0.008Mean FEV1 AUC012h 3.2 1.3 1.6 0.5

*Corresponds to postbaseline FEV1 AUC012h measurement for last visit with complete serial FEV1 data carried forward.AUC012h area under the curve from time 0 to 12 hr; b.i.d. twice-daily; Fformoterol; FEV1forced expiratory volume(L) in 1 s; MDI metered-dose inhaler; MF mometasone furoate; MF/F mometasone furoate/formoterol combinationtherapy.


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Table3

LeastsquaresmeanAsthmaControlQuestionnaireandAsthmaQualityofLifeQuestionnairewithStandardizedA

ctivitiestotal

scores,andproportionofn

ightswithnocturnalawakening

duetoasthmarequiringshort-a

cting

2-agonistuse

TreatmentGroup(MDI

,b.i.d.)

PairwiseComparison,pValues

MF/F

20

0/10g

A

MF

200g

B

F

10

g

C

Placebo

D

A

B

A

C

A

D

B

C

B

D

C

D

AsthmaControlQuestionnaire*#

Baseline

1.4

7

1.4

6

1

.43

1.41

n

179

186

1

84

187

Week26

0.9

5

1.1

4

1

.23

1.19

n

152

154

1

19

121

Change

0.52

0.3

2

0.2

0

0.2

2

0.005

0.0

01

0.001

0.1

29

0.187

0.857

AsthmaQualityofLifeQuestionnairewithStandardizedActivities*

Baseline

5.3

8

5.4

0

5

.51

5.56

n

183

189

1

87

189

Week26

5.9

9

5.9

0

5

.82

5.92

n

153

157

1

21

121

Change

0.6

1

0.5

0

0

.31

0.36

0.152

0.0

01

0.004

0.0

39

0.130

0.612

Proportionofnightswithn

octurnalawakeningsduetoasthmarequiringSABAuse

n

186

191

1

99

194

Baseline

0.1

8

0.1

6

0

.16

0.15

Endoftreatment

0.1

0

0.1

1

0

.17

0.15

Change(%)

0.0

8(60)

0.05(60)

0.01

(5)

0.0

0(15)

0.063

0.0

01

0.001

0.001

0.003

0.601

*Baselineincludespatientswithbaselineand1postbaselinemeasurements;week26includespatients

withbaselineandweek26measurements.

#Responseratedona7-pointscale(0

bestasthmacontrol;6

worstasthmacontrol).

Responseratedona7-pointscale(1

worstqualityoflife;7

bestqualityoflife).

Uptoendpoint(includingd

atafromtheentire26-wktreatment

period).

b.i.d.

twicedaily;F

form

oterol;MDI

metered-doseinhaler;MF

mometasonefuroate;MF/F

mometasonefuroateformoterolcom

binationtherapy.


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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 num-bers of patients with treatment-related AEs (Table 4) wereMF/F, n 17 (8.9%); MF, n 11 (5.7%); F, n 11 (5.4%);and placebo, n 15 (7.7%). The most commonly reportedtreatment-related AEs among all patients were oral can-didiasis, n 6 (0.8%) and dysphonia, n 5 (0.6%). Thenumber of discontinuations due to AEs (Fig. 1) was lowin 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 (asdefined by the Coding Symbols for Thesaurus of Ad-verse Reaction Terms) in the F group was consideredpossibly related to study medication. Severe AEs (i.e.,incapacitating, significantly affected the patients clinicalstatus, or warranted intervention) or life-threateningAEs (i.e., placed the patient at immediate risk of death)were observed in 2.6%, 4.2%, 4.5%, and 2.0% of patientsin the MF/F, MF, F, and placebo groups, respectively(Table 4). More than one severe/life-threatening AE mayhave 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), musculoskel-etal/connective tissue disorders (F, n 3), uterineleiomyosarcoma (MF/F, n 1), nervous system disor-ders (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 parame-ters, physical examination findings, or vital signs dur-ing MF/F treatment.

DISCUSSION

The effect of MF/F on asthma deteriorations wasassessed prospectively in this trial using a comprehen-sive definition of asthma deteriorations, including mul-tiple criteria such as diminished lung function (PEF forat least 2 days, FEV1) or clinically judged deteriorations

Table 4 Adverse event (AE) summary during the treatment period

Treatment Group (MDI, b.i.d.)

MF/F 200/10 g(n 191)

MF 200 g(n 192)

F 10 g(n 202)

Placebo(n 196)

Total(n 781)

General disorders and administration site conditionsChest pain 2 (1.0) 2 (1.0) 1 (0.5) 4 (2.0) 9 (1.2)

Pyrexia 6 (3.1) 5 (2.6) 2 (1.0) 1 (0.5) 14 (1.8)Infections and infestations

Bronchitis 5 (2.6) 3 (1.6) 5 (2.5) 4 (2.0) 17 (2.2)Gastroenteritis 1 (0.5) 4 (2.1) 2 (1.0) 0 7 (0.9)Influenza 5 (2.6) 7 (3.6) 5 (2.5) 5 (2.6) 22 (2.8)Nasopharyngitis 12 (6.3) 15 (7.8) 13 (6.4) 7 (3.6) 47 (6.0)Pharyngitis 8 (4.2) 6 (3.1) 3 (1.5) 6 (3.1) 23 (2.9)Rhinitis 5 (2.6) 3 (1.6) 1 (0.5) 4 (2.0) 13 (1.7)Sinusitis 5 (2.6) 6 (3.1) 7 (3.5) 2 (1.0) 20 (2.6)Upper respiratory tract infection 11 (5.8) 16 (8.3) 12 (5.9) 17 (8.7) 56 (7.2)Viral infection 6 (3.1) 0 1 (0.5) 1 (0.5) 8 (1.0)

Nervous system disorders

Headache 9 (4.7) 10 (5.2) 6 (3.0) 7 (3.6) 32 (4.1)Respiratory, thoracic, and mediastinal disordersCough 3 (1.6) 4 (2.1) 2 (1.0) 4 (2.0) 13 (1.7)Pharyngolaryngeal pain 6 (3.1) 4 (2.1) 3 (1.5) 7 (3.6) 20 (2.6)

AE SummaryAny treatment-emergent AEs 97 (50.8) 88 (45.8) 90 (44.6) 82 (41.8) 357 (45.7)Treatment-related AEs 17 (8.9) 11 (5.7) 11 (5.4) 15 (7.7) 54 (6.9)Severe/life-threatening AEs 5 (2.6) 8 (4.2) 9 (4.5) 4 (2.0) 26 (3.3)Serious AEs 5 (2.6) 3 (1.6) 3 (1.5) 3 (1.5) 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 mometasonefuroate/formoterol combination therapy.


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(hospitalization, emergency department visit, or treat-ment with systemic steroids for asthma), which is sim-ilar to the 2009 ATS/ERS statement definition for se-vere asthma exacerbation (Appendix 1).2 Althoughprevention of asthma deteriorations is accepted as akey aspect of asthma control,6 8 the exact definition ofan asthma deterioration has varied in clinical trialsmaking comparisons difficult. Nevertheless, this 26-week study indicated that treatment with MF/F com-pared with F monotherapy and placebo reducedasthma deteriorations. Additionally, because the trial de-sign had an active run-in period on MF without anywashout, improvements observed in lung function orreduction in asthma deteriorations were above those at-tributable to receiving at least 2 weeks of ICS mono-therapy. However, this trial design and these data mayrepresent more clinically relevant assessments of patientswith asthma uncontrolled on ICS monotherapy thanthose from trials without an active ICS-containing run-inperiod.

Furthermore, this trial was designed to prevent theearlier ethical and safety concerns regarding the inclu-sion of placebo and LABA monotherapy groups intrials involving patients with persistent asthma on ICStherapy by including constant monitoring of patiente-diary data, thereby ensuring that any deteriorationwas detected quickly. The use of e-diaries preventedretrospective data entry and are therefore more likelyto be accurate reflections of significant lung functionchanges and SABA use.2

To adequately evaluate contributions from each com-ponent of this ICS/LABA combination, this 26-weekstudy assessed both clinically judged deteriorations

and lung function. The contribution of F was clearlyshown by the superior effect of MF/F versus MF onlung function as shown by the mean improvements inFEV1 AUC012h from baseline to week 12. As early asday 1, improvements in lung function with MF/F com-pared with MF occurred within 5 minutes, and theduration of effects were sustained throughout thestudy as assessed by FEV1 AUC012h (change frombaseline at week 12, 3.1 L hour for MF/F versus 1.3L hour for MF; Table 2) and PEF (change frombaseline at EOT, 18.1 L/minute for MF/F versus 1.7L/minute for MF; Fig. 4) measurements, which indi-

cates that patients did not experience tachyphylaxis.Mometasone also appeared to have an additive andstabilizing effect on FEV1 and daily PEF comparedwith F alone as noted by a significant drop in lungfunction in patients treated with F alone.

Patients receiving MF/F reported clinically meaningfulimprovements in asthma control with ACQ scores atweek 26 going below 1.00, the threshold for well-con-trolled asthma.16 None of the other treatment groupsimproved as much. Patients receiving MF/F also re-ported clinically meaningful improvements in day and

nighttime symptoms, QoL, and reduced requirement forrescue medication compared with other treatmentgroups. Overall, the additional end points supported thecoprimary efficacy results and showed the complemen-tary effect of the components in the combination.

All study drugs were well tolerated with no newsafety signals detected with the combination of MF/For either of the individual components. The rates oftreatment-related oral candidiasis and dysphonia ob-served in this study in the MF/F treatment group (1.0%for each) were comparable with those reported forother ICS/LABA combination products.17,18

CONCLUSIONS

This study shows that MF/F 200/10 g b.i.d. wasmore effective than predefined monocomponent com-parators in controlling asthma and reducing the risk ofasthma deteriorations in patients with persistentasthma uncontrolled on medium-dose ICS. Further-more, MF/F 200/10 g b.i.d. improved lung function

more than treatment with either of the individual con-stituent compounds. This supports the use of MF/F inthe management of asthma patients not well controlledby their ICS, further supporting the recommendationsof national and international guidelines. The combina-tion MF/F treatment was well tolerated and no newsafety signals were detected.

APPENDIX 1

ATS/ERS Definition of Severe AsthmaExacerbations in Clinical Trials

The recently published ATS/ERS guidelines2 provide the follow-

ing definition for severe asthma exacerbations:

Use of systemic corticosteroids or an increased dose from a stablemaintenance level, for at least 3 days (courses of corticosteroidtreatment separated by 1 week should be considered as separateincidences).

Asthma-related hospitalization or emergency room visit, requir-ing use of systemic corticosteroids.

In addition, the following criteria are being evaluated for furthervalidation (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, Que-bec, 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 Brum-ley, San Jose. Croatia: Vladimir Ahel, Rijeka; Drago Caleta, Zagreb;Jasna Cepin-Bogovic, Zagreb; Fadila Pavicic, Zagreb; Asja Stipic-Markovic, 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 Gonza-lez, Guatemala City; Macro V. Flores Belteton, Guatemala City; Jer-

emias S. Guerra Mejia, Guatemala City. Hungary: Beatrix Balint,Deszk; Laszlo Barkai, Miskolc; Lajos Kosa, Budapest; Zsuzsanna

Mark, Torokbalint; Edit Mohacsi, Budapest; Kristof Nekam, Buda-pest; Gyula Panczel, Kecskemet; Judit Schlezak, Komarom; Zsu-zsanna Szalai, Mosonmagyarovar; Ilona Vinkler, Nyiregyhaza. India:

Ashok Bajpai, Indore; Salil Bhargava, Indore; Devasahayam Chris-

topher, Vellore; George A. DSouza, Bangalore; Madhav Kale, Pune;Surya Kant, Lucknow; Ratnavelu V. Kumar, Hyderabad; PramodNiphadkar, Mumbai; Sujit Rajan, Mumbai; Mohan Rao, Bangalore;

Sandeep Saboo, Hyderabad; Tushar Sahasrabudhe, Pune; RavindraM. Sarnaik, Nagpur; Deepak Talwar, Noida; Pradyut Waghray, Hy-

derabad. Mexico: Patricia E. Aguilar Dominguez, Huixquilucan;Dante D. Hernandez-Colin, Guadalajara; Luis A. Rendon-Perez,

Monterrey; Francisco Sanchez Llamas, Guadalajara. Philippines: TitoAtienza, Quezon City; Abundio Balgos, Manila; Gary Carlos, Cavite;

Teresita de Guia, Quezon City; Dina Diaz, Quezon City; CamiloRoa, Manila; Joel Santiaguel, Quezon City; Ma. Bella Siasoco, Quezon

City. Poland: Monica Bobrowska-Korzeniowska, Lodz; ZenonBukowczan, Bienkowka; Ryszarda Chazan, Warszawa; Marek Jutel,

Wroclaw; Beata Kuklinska, Bialystok; Piotr Kuna, Lodz; WladyslawPierzchala, Katowice; Grazyna Pulka, Krakow; Barbara Rogala,

Zabrze; Ryszard Sciborski, Olawa; Ewa Springer, Pozan; Iwona Stel-mach, Lodz; Hanna Szelerska-Twardosz, Poznan. Puerto Rico: Do-

mingo Chardon-Feliciano, Ponce; Jose R. Rodriguez-Santana, SanJuan. Russia: Natalia Astafyeva, Saratov; Alexander Emelyanov,

Saint Petersburg; Alexander Gorelov, Saint Petersburg; LudmillaGoryachkina, Moscow; Natalia IIjina, Moscow; Nikolay Klimko,

Saint Petersburg; Oxana Korovina, Saint Petersburg; Vasiliy Trofi-mov, Saint Petersburg; Arkady Vertkin, Moscow; Alexander Vizel,

Kazan. Thailand: Chalerat Direkwattanachai, Bangkok; Anon Jata-kanon, Bangkok; Arth Nana, Bangkok; Vilaiwan Viriyachaiyo, Hat

Yai, Songkhla. Ukraine: Volodymyr Biloglazov, Symferopol ARCrimea; Oleksandr Dziublyk, Kiev; Yuryi Feshchenko, Kiev; Volody-

myr Gavrysyuk, Kiev; Natalia Gorovenko, Kiev; Iryna Lysenko,Zaporizhzhia; Nadiya Monogarova, Donetsk; Tetyana Pertseva, Dni-

propetrovsk; Sergiy Soldatchenko, Yalta AR Crimea; LyudmylaYashyna, Kiev. United States: Niran Amar, Waco, TX; Garrison Ayars,

Kirkland, WA; George Bensch, Stockton, CA; William Berger, Mis-sion Viejo, CA; David Bernstein, Cincinnati, OH; Edward J. Camp-

bell, Provo, UT; Paul Carter, Knoxville, TN; Jonathan Corren, LosAngeles, CA; Joseph Diaz, San Antonio, TX; Lawrence DuBuske,

Gardner, MA; Linda Ford, Papillion, NE; Bruce Friedman, FountainValley, CA; Sandra M. Gawchick, Upland, PA; Khaled Girgis, Over-

land Park, KS; Gregory Gottschlich, Cincinnati, OH; Leon Greos,Aurora, CO; Gary Gross, Dallas, TX; Frank Hampel, Jr., New Braun-

fels, 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, Nor-

mal, IL; Thomas Nilsson, Omaha, NE; Michael Noonan, Portland,OR; Grant Olson, Lakewood, CO; James Pearle, Fullerton, CA; An-

drew Pedinoff, Skillman, NJ; David Pearlman, Denver, CO; WarrenPleskow, Encinitas, CA; Bruce Prenner, San Diego, CA; GordonRaphael, 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 acknowledgeDavis Gates and Wen-Ling Kuo of Merck Research Laboratories fortheir assistance with statistical design and analyses. Original editorialsupport was provided by Ray Beck, Jr., Ph.D., Paul Lane, Ph.D., andMukund 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 supportwas funded by Merck & Co.

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