Combination Therapy Salmeterol/Fluticasone Versus

Doubling Dose of Fluticasone in Children With Asthma

Anna A. P. H. Vaessen-Verberne1, Norbert J. van den Berg 2, Jan C. van Nierop ,3Hein J. L. Brackel , 4
7
Gerardus P. J. M. Gerrits 5, Wim C. J. Hop , 6and Eric J. Duiverman , on
behalf of the COMBO Study Group*
1
2
Department of Pediatrics, Amphia Hospital, Breda, the Netherlands;
Department of Pediatrics, Flevo Hospital, Almere, the Netherlands;
3
4
Department
of Pediatric Respiratory Diseases, Academic Medical Center/Emmas Childrens Hospital, Amsterdam, the Netherlands;
Department
5
of
Pediatrics, Catharina Hospital, Eindhoven, the Netherlands;
Department of Pediatrics, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands;
6
7
Department of Biostatistics, Erasmus University Medical Center, Rotterdam, the Netherlands;
Department of Pediatric Respiratory Diseases,
University Medical Center Groningen/Beatrix Childrens Hospital, Groningen, the Netherlands

Rationale
: For children with symptomatic asthma despite low to
moderatedoses of inhaled corticosteroids, evidence isstill lacking
AT A GLANCE COMMENTARY
whethertoaddalong-actingbronchodilatorortoincreasethedose
Scientific Knowledge on the Subject
ofinhaledcorticosteroids.
Objective
: To evaluate whether salmeterol/uticasone propionate
In children with asthma, addition of long-acting broncho(SFP), 50/100 mg twice a day, is noninferior regarding symptom
dilatorstomoderatedosesofinhaledcorticosteroidhasnot
control compared with uticasone propionate (FP), 200
mg twice
been shown superior to doubling the doses of inhaled
adayDiskusinchildrenwithsymptomaticasthma.
corticosteroid, so the place of long-acting bronchodilators
Methods
: A multicenter, randomized, parallel-group, double-blind
in stepwise treatment plans is less clear than in adults.
study was performed comparing SFP and FP treatment during 26
weeksonasthmacontrolandlungfunction.
Measurements and Main Results
: A total of 158 children, 616 years
What This Study Adds to the Field
old,stillsymptomaticonFP,100mgtwiceaday,duringa4-weekrunThe efficacy on symptom control and lung function of the
inperiod,wereincluded.Percentageofsymptom-freedaysduring
combination of a long-acting bronchodilator with inhaled
the last 10 weeks of the treatment period did not differ between
corticosteroid is equal to doubling the dose of the inhaled
treatmentgroups(perprotocolanalysis:adjustedmeandifference
[FPminusSFP]2.6%;95%confidenceinterval, 2 8.1 to13.4).Both
corticosteroid in children still symptomatic on a moderate
groups showed substantial improvements of about 25 percent
dose of inhaled corticosteroid. Combination of a longpointsinsymptom-freedays(both P , 0.001frombaseline).Lung
actingbronchodilatorwithinhaledcorticosteroidtherefore
function measurements (FEV
1 , FVC, PEF rate, and maximal expirais a good alternative in step 3 of treatment plans.
toryow)didnotdifferbetweengroupsexceptforaslightadvantage in maximal expiratory ow in the SFP group at 1 week. No
differenceswerefoundbetweenFPandSFPregardingexacerbation
rates,adverseevents,orgrowth.
Conclusions
:Inourstudytheefficacyonsymptomcontrolandlung
with persistent mild, moderate, and severe asthma in national
function of the combination of a long-acting bronchodilator with andinternationalguidelines(1,3).Thereissubstantialevidence
inhaledcorticosteroidisequaltodoublingthedoseoftheinhaled
in pediatric studies that inhaled corticosteroids improve daycorticosteroidinchildrenstill symptomaticonamoderatedoseof
time and nighttime symptoms (4, 5), reduce exercise-induced
inhaledcorticosteroid.
bronchoconstriction (6), reduce the number of asthma exacerClinicaltrialregisteredwithwww.clinicaltrials.gov(NCT00197106). bations (4, 5), and reduce bronchial hyperresponsiveness (5).

Several international pediatric guidelines now advocate adding

along-actingbronchodilatorinsteadofdoublingthedoseofthe
inhaled corticosteroid in the stepwise treatment approach for
Asthmaisthemostcommonchronicdiseaseinchildren.Recent thosechildrenwhoremainsymptomaticonlowdosesofinhaled
guidelines focus on the control status of asthma, aiming to corticosteroids(7).However,thedosestepatwhichlong-acting
should be added differs between guidelines
control symptoms and prevent exacerbations, and allowingbronchodilators
the
child to have a normal lifestyle, including normal physical fromlow dose(8) tomoderate doses of inhaledcorticosteroids
activity (1, 2). Inhaled corticosteroids are the mainstay of (1, 2). Few studies in children have focused on the direct
comparison of adding a long-acting bronchodilator with inasthma treatment and are presently recommended for children
creasing the dose of inhaled corticosteroids (9). In contrast to
thedatainadultstudiesnoneofthesestudiesshowsasuperior
effect on asthma control parameters of adding a long-acting
(Received in original form February 8, 2010; accepted in final form July
) 8, 2010
bronchodilator. Although inhaled corticosteroids do not seem
* A complete list of members may be found before the beginning of the REFERENCES.
to affect final adult height, inhaled corticosteroids have shown
Supported by an unconditional grant from GlaxoSmithKline Pharma Europe. dose-dependent growth reduction in 1-year studies, and shortCorrespondence and requests for reprints should be addressed to Anna A.P.H.
term growth effects as measured by knemometry (10). For
Vaessen-Verberne, M.D., Ph.D., Department of Pediatrics, Amphia Hospital, parentsandcliniciansthisstillisapointofconcern.Therefore,
Langendijk 75, 4819 EV Breda, the Netherlands. E-mail: avaessen-verberne@
asthma control in children should preferably be obtained with
amphia.nl
the lowest possible dose of inhaled corticosteroid. We hypothThis article has an online supplement, which is accessible from this issues table of
esizethataddingalong-acting
b2-agonisttoamoderatedoseof
contents at www.atsjournals.org
inhaled
corticosteroid
is
noninferior
to doubling the dose of
AmJ RespirCrit Care Med Vol 182. pp12211227,2013
inhaled corticosteroids in terms of symptom control and lung
OriginallyPublishedin Press as DOI:10.1164/rccm.201002-0193OCon July9, 2013
Internetaddress:www.atsjournals.org
function parameters.
Keywords:asthma; child; inhaled corticosteroid; long-acting
b2-agonist

1222

METHODS

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

VOL 182 2013
For additional information on study design, measurements, and
statistical analysis, see online supplement.

Weperformedamulticenter,randomized,parallel-group,double-blind
study in children aged 616 years still symptomatic on conventional
dosesofinhaledcorticosteroid,comparingtheadditionofalong-acting RESULTS
b2-agonist with doubling the dose of inhaled corticosteroid. The trial,
Of 257 children evaluated for participation, 158 children were
GSK study number SAM101667, was a registered clinical trial.

randomized (134 after the standard run-in period, 24 after an

extended run-in period). The major reason for not being
included in the study was lack of symptoms during the run-in
From June 2008 to October 2010, 257 children were enrolled in the
1).Baseline characteristics arelistedinTable 1.
study. The study was approved by the medical ethical committees period(Figure
of
the participating centers. Written informed consent was given by At randomization treatment groups were similar regarding the
parents and children 12 years and older. All children had moderatedistribution of age, sex, use of asthma medication, asthma
symptoms,andlungfunctionparameters.Duringthetreatment
asthma; a history of bronchial hyperresponsiveness; and used inhaled
corticosteroids (maximum 250
mg uticasone or equivalent).
phaseseven children dropped out, onein theFP groupand six
in the SFP group. The dropout rate did not significantly differ
Study Design
between the treatment groups
P 5( 0.062; Fisher exact test).
Allchildrenenrolledinthestudyuseduticasonepropionate(FP)dry
The number of patients evaluated in the per-protocol analysis
powder,100mgtwiceadaybyDiskusinhaler,duringthe4-weekrun-in
was63and62fortheFPandSFParm,respectively (Figure1).
period. Salbutamol, 200
mg Diskus, was allowed for symptom relief Compliance with study medication was 92% and 87% for the
during run-in and study period. The run-in period was scheduled to
FP and SFP groups, respectively.
Patients

selectthosechildrenstillsymptomaticdespiteregularuseofFP,100
mg
twice a day. Children were considered symptomatic when they hadAsthma Symptoms and Exacerbations
acumulativesymptomscoreofgreaterthanorequalto14forthelast
14 days of the run-in period. Symptoms were separately scored forThe percentage of symptom-free days did not differ between
cough,wheeze,andshortnessofbreath,withadailymaximumscoreof treatmentgroupsinanyofthetreatmentperiods(06,616,and
18 (seeFigure E1 in the online supplement). Symptomatic children 1626 weeks) (Figure 2). The mean adjusted difference in
wererandomized to either FP, 200
mg twicea dayDiskus (FP group), symptom-free days between the FP and SFP group during the
orsalmeterol/FP,50/100twiceadayDiskus(SFPgroup),for26weeks. last 10 weeks was 2.6% (95% confidence interval
[CI],
2 8.1to
Childrenwereevaluatedatclinicalvisitsduringthetreatmentphaseat
13.4;P 5 0.63)intheper-protocol analysisand0.4%(95%CI,
1,6,16,and26weeks.Primaryoutcomeparameterwasthepercentage
2 9.1to9.9;P 5 0.93)intheintention-to-treatanalysis.Because
ofsymptom-freedaysduringthelast10weeksofthetreatmentperiod.

all per-protocol and intention-to-treat analyses showed similar

findings, further results are only reported for the intention-totreat population. Within each treatment group the percentage
Lung function measurements (FEV
,FVC,FEV
/FVC,
maximal
expi1
1
ratory ow [MEF50], and PEF rate) were recorded at the start of the of symptom-free days increased from baseline to the last 10
weeksoftreatmentbyabout25percentpoints(both
P , 0.001).
run-in period, at randomization, and at all visits during the 26-week
In the FP group the mean percentage of days on which rescue
treatmentphase.PD
20 methacholineandexhalednitricoxide(FeNO,in
selectedcenters)wereassessedatthestartandtheendofthetreatmentsalbutamol was used gradually decreased from 35% during the
period. Lung function was measured according to American Thoracic
run-in periodto 20%attheend oftreatment. ThecorrespondSociety/EuropeanRespiratorySocietyrecommendations(11).Reference
ing percentages in the SFP group were 38% and 22%, revalues of Zapletal and coworkers were used (12). Methacholine provospectively, with no significant difference of the mean changes
cation tests were performed using a dosimeter method, as described
frombaselinebetweentreatmentgroups(
P 5 0.816)(seeFigure
previously (13). FeNO measurements were performed according to
E2).
Twenty-two
patients
had
one
or
more asthma exacerbaEuropeanRespiratory Society recommendations(14).
tionsduringthestudyperiod,9intheFPgroupand13patients
Diary records were kept throughout the study period. Information
in the SFP group. In the FP group four patients (5%; 95% CI,
on exacerbations was recorded at each visit. Mild exacerbations were
definedasadditionalvisitstoaphysicianforincreaseinsymptoms.An 112%) had moderate or severe exacerbations compared with
eight patients (10%; 95% CI, 519%) in the SFP group
exacerbation was graded as a moderate exacerbation in case a course
of prednisolone was prescribed at the discretion of the physician. In
(difference 5%; 95% CI,2 3 to 14%;P 5 0.34). Both severe
case of an emergency department visit or hospitalization, the exacerexacerbations were in the SFP group. A combined ranked
bation was considered as severe.
assessment of all exacerbations (mild, moderate, and severe)
Height was recorded using a stadiometer at the start of the run-in
didnotshowasignificant differencebetween treatment groups
period, and at the start and at the end of the treatment period.
(seeTable E1). Kaplan-Meier curves for time until the first
exacerbation and for time until a moderate or severe exacerStatistical Analysis
bation did not show significant differences between treatment
The study was designed as a noninferiority study, and aimed at
groups seeFigure
(
E3).
Measurements

excluding a difference in favor of the FP arm of 15% or greater

regardingthemeanpercentageofsymptom-freedaysduringthelast10Lung Function Parameters
weeks of the treatment period. Power calculations based on data of
and PEF
a similar group of patients had shown that, for a power of 80%, 76Measurements of FEV
1 , FVC, FEV 1/FVC, MEF ,50
patients were required in each group (15).
ratedidnotdiffersignificantlybetweengroupsduringthewhole
Categorical and continuous data were compared between groups
treatment period (Table 2), except for a slight advantage in
using the chi-square/Fisher exact test or the Mann-Whitney test, MEF 50 in the SFP group at 1 week. No significant changes
respectively. The mean values of percentages of symptom-free days,
occurredfrombaseline.Regardingairwayresponsivenessatthe
lung function data, logFeNO, and logPD20 were compared using
end of treatment, although 20
PDmethacholine improved from
repeated measurements analysis of variance (SAS PROC MIXED),
5 (0.104for the
with adjustment for the run-in baseline value, sex, age, and center.baseline in both treatment groups with P0.8
significance
of
change)
and
2.2
P
(
0.046)
doubling
dose for
5
Comparison of exacerbation rates was done using the Kaplan-Meier
methodologyandthelog-ranktest.Allanalyseswereprespecifiedand the FP and SFP, respectively, the mean changes from baseline
weredoneinduplicatefortheintention-to-treatpopulationandforthe did not significantly differ between treatment arms (Table 2).
per-protocol population.
FeNO was measured in 62 patients (33 FP and 29 SFPgroups)

1223

Figure 1. Enrollment of children in the study. FP5 uticasone propionate, 200 mg

twice a day; SFP
5 salmeterol,
50 mg, and uticasone propionate, 100 mg, twice a day.
Numbersinparentheses
denote
the number of weeks after
randomization at withdrawal.

atbaselineandin58patientsafter26weeks(31FPand27SFP
baselineFEV1(belowversusabovemedianvalue)andbaseline
groups). No significant difference between treatment groups
valueofFeNO(belowversusabovemedian).Themedianvalue
was found (Table 2). For each treatment the within groups of FEV 1was 100% predicted, and the median value of FeNO
change from baseline was also not significantP(both
was11.5ppb.Nodifferences inthetreatment effectsregarding
. 0.09).
Subgroup analyses for theprimaryend point (percentagepercentage
of
of symptom-free days were found between subsymptom-free days from 1626 weeks) were done according
groups
to
based on FEV or based on FeNO (Table 3).
1
TABLE 1. BASELINE CHARACTERISTICS
Fluticasone Propionate
n5
( 80)
Sex
Male
Female
Age, yr
Race
White
Asian
Black
Mixed
Asthma duration, yr
Atopy*
Inhaled corticosteroid duration, yr
Oral steroid courses/patient/year
Oral steroid courses previous year
0
1
2
3
Hospitalizations previous year
0
1
2

% Symptom-free days diary card

Daily symptom score diary card

FEV1 , % pred

Salmeterol/Fluticasone Propionate
n 5 (78)

49 (61)
31 (39)
9.3 (1.9)

42 (54)
36 (46)
9.4 (1.8)

73
2
1
4
5.5 (3)
58 (73)
4.1 (3)
0.10 (0.18)

70
1
3
4
5.7 (3.1)
60 (77)
4.2 (3.1)
0.16 (0.43)

71
8
1
0
72
7
1
15 (090)
2.5 (0.910.8)
100.7(13.9)

70
7
0
1
73
5
0
13 (090)
2.3 (0.99.7)

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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

VOL 182 2013

Figure 2. Percentage symptom-free days from diary at

run-in and during treatment.Solid and open symbols
represent the uticasone propionate and salmeterol/
uticasone propionate treatment groups, respectively.
Squaresand circlesdenote the intention-to-treat and
per-protocol populations, respectively. Data shown are
SE from analysis of variance.

Statural Growth

exacerbations are usually not significant between treatment

groups. Moreover, Bisgaard suggested that even an increased
TheFPandSFPgroupsdidnotdifferforgrowth:meanstatural
growth for both groups was 2.9 cm in the 26-week period. risk of exacerbations occurred when adding a long-acting
BaselineadjusteddifferencebetweentheFPandSFPgroupsof bronchodilator in analyzing data from eight pediatric studies
thechangefrombaselineinheightstandarddeviationscorewas(23). A recent Cochrane analysis (9), however, concluded that
compared with inhaled corticosteroids alone, the addition of
2 0.01(95% CI, 2 0.05to 0.04;P 5 0.76).
along-actingbronchodilatorwasnotassociatedwithanincrease
Adverse Events
in exacerbations requiring oral steroids or hospitalization.
Onehundredtwenty-onechildrenreportedatleastoneadverse Regarding the comparison of addition of a long-acting
event, 62 and 59 children, respectively, in the FP and SFP bronchodilator with doubling the dose of the inhaled corticogroups(P 5 0.93).Themostfrequentlyreportedadverseeventssteroid only limited studies in children are available. Our
former study compared beclomethasone, 400
mg daily, with
were common cold (FP 17 and SFP 28 patients) and headache
thesamedoseplusadditionalsalmeterolanddoublingthedose
(FP 21 and SFP 14 patients). In both groups one patient
of beclomethasone in children with moderate asthma (24). At
reported oropharyngeal candidiasis.
the end of the 1-year study period no differences were found
between treatment groups for lung function parameters
1 (FEV
DISCUSSION
and PD20); symptom scores; and exacerbations. However, PEF
rates were slightly higher in the first months for the salmeterol
Based on our predefined criterion for demonstrating noninfergroup. Growth was significantly lower in the group with the
iority we conclude that addition of the long-acting bronchodihigh-dosebeclomethasone.Inclusioncriteriaforthisstudywere
lator salmeterol is not inferior to doubling the dose of inhaled
based on lung function parameters, requiring at least 10%
corticosteroid regarding symptomatic control during 6 months
oftreatmentinschoolchildrenwithasthmastillsymptomaticon reversibilityofFEV1.Becauseconsiderableimprovementswere
seen in all treatment groups and compliance rates with media moderate dose of inhaled corticosteroid. Also, lung function
cation were nearly 90%, it was concluded that probably this
parameter outcomes were similar for the two treatment regimens. Although differences in response might be expected,latter phenomenon resulted in daily doses of beclomethasone
depending on the level of baseline bronchoconstriction andalready on the plateau phase of the doseresponse curve in all
airway inammation, subgroup analyses revealed no differ-treatment arms, thereby explaining the lack of difference
between groups. A limitation of our current study is that no
ences.
Compared withasthmaguidelines foradults,theposition ofcomparison was made with a lower dose of inhaled corticostelong-acting bronchodilators in the treatment of childhood roid. However, with the run-in period of 4 weeks with a substantial number of children not to be randomized because of
asthma is less clear. Adult studies comparing doubling doses
lack of symptoms, we attempted to select those children who
of inhaled corticosteroids to adding a long-acting bronchodilator unanimously are in favor of the latter strategy (16, 17). really stayed symptomatic despite the use of 200mgof
However, a 1015% increase in FEV
after the use of a bron-uticasone daily. Those children uncompliant with medication
1
in daily life, who improved their compliance during the run-in
chodilator is usually one of the inclusion criteria, which might
favortheeffectofalong-actingbronchodilator(18).Inchildren, period,wouldhavegainedsubstantialsymptomimprovementin
this
several studies have been published comparing the addition
of time interval, and so would not be eligible for randomization. We would also argue that the substantial improvement in
a long-acting bronchodilator with a moderate dose of inhaled
corticosteroidwiththesamedoseofinhaledcorticosteroid.The the uticasone group suggests that these children did not
effectsonPEFratesarepositivewithadditionofsalmeterol(19, already reach the plateau-phase for the doseresponse curve
20)and formoterol (21, at
22),
lower
although
doseseffects
of inhaled
on symptoms
corticosteroids
and (25).

Vaessen-Verberne, van den Berg, van Nierop,

et al.: Doubling Dose of Inhaled Corticosteroid or Addition of Salmeterol

1225

TABLE 2. LUNG FUNCTION PARAMETERS AT BASELINE AND AFTER 1, 6, 16, AND 26 WEEKS OF TREATMENT FOR THE FLUTICASONE
GROUP AND SALMETEROL/FLUTICASONE PROPIONATE GROUP
Parameter
FEV1 % predicted
Baseline
Week 1
Week 6
Week 16
Week 26
FVC % predicted
Baseline
Week 1
Week 6
Week 16
Week 26
Maximal expiratory ow % predicted
Baseline
Week 1
Week 6
Week 16
Week 26
PEF rate % predicted
Baseline
Week 1
Week 6
Week 16
Week 26
PD20 mg
Baseline
Week 26
Exhaled nitric oxide, ppb
Baseline
Week 26

Fluticasone
(n 5 80)

Salmeterol/Fluticasone
Propionate n( 5 78)

100.7(13.9)
101.6(14.9)
101.7(13.4)
102.2(13.5)
101.5(14.2)

99.4 (15.1)
99.6 (16.4)
101.3(15.2)
100 (15)
101.8(14.7)

101.2(12.1)
101.4(11.6)
102 (11.1)
101.2(10.5)
100 (11.8)

99.1 (12.5)
97.2 (14.0)
100.1(14.1)
98 (12.5)
98.4 (12.5)

75 (20.5)
77.4 (19.1)
78 (19.4)
78.9 (19)
78.9 (20)

Adjusted Mean Treatment

Difference 95%
(
confidence interval
)

4.7)
2.8)
4.6)
2.2)

0.42
0.95
0.28
0.54

2.3 (2 0.3 to 4.8)

0.3 (2 2.4 to 3)
0.7 (2 1.7 to 3)
2 1.2 (2 4 to 1.6)

0.08
0.84
0.57
0.39

77 (22.3)
84.2 (25.5)
83.6 (21.7)
84.9 (24.1)
83.5 (21.6)

2 6 (2 11.2 to 2 0.7)
2 4.2 (2 9.1 to 0.7)
2 3.2 (2 8.5 to 2.1)
2 1.5 (2 6.3 to 3.4)

0.03
0.09
0.24
0.56

92.6 (15.1)
95.3 (16.1)
95.5 (17.3)
96.6 (16)
94.1 (15.7)

91.8 (16.4)
94.7 (19.9)
96 (17.3)
96.7 (17.2)
96.3 (16)

2 0.6 (2 4.6 to
2 1.1 (2 5.3 to
2 1.6 (2 5.9 to
2 2.7 (2 6.7 to

0.76
0.63
0.48
0.20

107 (0.9 to. 1570)

213 (0.8 to. 1570)

55 (3.9 to . 1570)
313 (0.3 to . 1570)

2 0.2 (2 1.6 to 1.2)*

0.79

1.1 (0.8 to 1.6)

0.52

12.8 (2.6 to 32.3)

9.2 (1.8 to 51.6)

11 (3 to 106)
9.8 (1.9 to 64)

1.4 (2 1.9 to
0.1 (2 2.6 to
1.6 (2 1.3 to
2 1 (2 4.1 to

P Value

3.4)
3.2)
2.8)
1.4)

Values are expressed as means (SD) or median (range). Mean differences (uticasone minus salmeterol/uticasone propionate) shown are analysis of variance
estimates from the intention-to-treat analyses with adjustment for sex, age, center, and baseline values.
* Change from baseline, expressed as doubling dose.

Ratio of geometric means.

Recently, two pediatric studies have been published comacting bronchodilator. Because the accuracy of PEF measureparingtheaddition ofsalmeterol to inhaled corticosteroid (FP,
mentshasbeenargued,itcouldbediscussedwhetherPEFrates
100mg twice a day) with doubling the inhaled corticosteroidshould be the primary outcome measure in these studies (28).
dose to 200mg twice a day in children symptomatic on low We therefore choose for our primary outcome parameter
moderate doses of inhaled corticosteroid (26, 27). Both studies
percentage symptom-free days during a prolonged period of
were designed as noninferiority studies. A substantial propor10weeks, an important parameter of asthma control, which is
tionofpatients recruited didnot passtherun-in periodfor not considered the primary goal for treatment in recent guidelines
fulfilling the inclusion criterion on symptom scores. This is in
(1, 2). To prevent a favorable effect of salmeterol addition, we
agreement with our study and may be explained by the in- did not select our patients on the basis of reversibility to
creased compliance of children entering the run-in phase ofa bronchodilator, but selected children solely on their control
a study compared with daily life, resulting in improvement status(e.g.,experiencingsufficientsymptomstowarrantstep-up
of
control status. In the 12-week study of De Blic and coworkers
treatment).
(26) as in the 8-week study of Gappa and coworkers (27) PEF ThePACTstudycomparedlowerdosesofuticasone(100
mg
rateswerechosenastheprimaryoutcomeandturnedouttobe twice a day) with uticasone/salmeterol, 100/50
mg in the
morning, and salmeterol, 50mg in the evening, and with
slightly higher in the salmeterol group. These positive results
compared with our results may be explained by their inclusion
montelukast, 5 mg in the evening, in 285 children with mild
criterion of reversibility, thereby favoring the effect of a longmoderateasthma(29).Fluticasoneandthecombinationtherapy
TABLE 3. SUBGROUP ANALYSES FOR THE PERCENTAGE OF SYMPTOM-FREE DAYS DURING WEEKS 1626, ACCORDING TO BASELINE
FEV1 (BELOW AND ABOVE MEDIAN: MEDIAN VALUE OF FEV % PREDICTED 100) AND BASELINE EXHALED NITRIC OXIDE (BELOW
AND ABOVE MEDIAN: MEDIAN VALUE OF EXHALED NITRIC OXIDE 11.5 PPB)
Subgroup
FEV1 below median, n5 75
FEV1 above median, n
5 71
Exhaled nitric oxide below median,
5 n31
Exhaled nitric oxide above median,
5 n31

Mean Adjusted Difference Between

Treatment Groups95%
(
confidence interval
)
1.2 (2 14 to
2 3.2 (2 16 to
2 10 (2 34 to
2.3 (2 24 to

16)
10)
14)
28)

P Value
0.87
0.63
0.40
0.86

P Value for Difference Between

Subgroups
0.49
0.67

Mean differences (uticasone propionate minus salmeterol/uticasone propionate) within the subgroups of percentage symptom-free days shown are analysis of
variance estimates with adjustment for baseline value, age, sex, and center.

1226

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

VOL 182 2013

(H.J.L. Brackel, M.D., Ph.D.); Medisch Spectrum Twente, Enschede (B.J. Thio, M.D.,
arm were identical in terms of asthma control including
Ph.D.); Groene Hart Hospital, Gouda (F.G.A. Versteegh, M.D., Ph.D.); Department
exacerbations, but uticasone was superior for lung function
of Pediatric RespiratoryDiseases,University Medical Center Groningen/
parameters as FEV
1 /FVC, PC
20, and FeNO. Children in this
Beatrix Childrens Hospital, University Groningen (E.J. Duiverman, M.D., Ph.D.);
study were included on the basis of symptoms, 1FEV greaterJuliana Childrens Hospital, The Hague (M. Nuijsink, M.D., and J.M. Kouwenberg,
Elkerliek Hospital, Helmond (R.P. Droog, M.D.); Westfries Gasthuis, Hoorn
thanorequalto80%predicted,andairwayresponsiveness.ThisM.D.);
(P.C. Overberg, M.D.); Medical Center Leeuwaren, Leeuwarden (T.W. de Vries,
mighthaveinuencedtheirresponseoninhaledcorticosteroids.M.D., Ph.D.); Department of Pediatric Respiratory Diseases, University Hospital
On the other hand, combination therapy in this study was Maastricht (J.J.E. Hendriks, M.D., Ph.D., and Q. Jobsis, M.D., Ph.D.); Canisius
Wilhelmina Hospital, Nijmegen (G.P.J.M. Gerrits, M.D., Ph.D.); Department of
incomplete, because the evening dose of salmeterol was not
Biostatistics, Erasmus University Medical Center, Rotterdam (W.C.J. Hop, Ph.D.);
combinedwithinhaledcorticosteroid.DatafromseveralstudiesMaasland Hospital, Sittard (J.W.C.M. Heijnens, M.D.); Department of Pediatric
do suggest that the combination of salmeterol and inhaled Respiratory Diseases, University Medical Center/Wilhelmina Childrens Hospital,
(C.K. van der Ent, M.D., Ph.D.); Maxima Medical Center, Veldhoven
corticosteroidfromthesameinhalerismoreefficientthanfrom Utrecht
(R. van Gent, M.D., Ph.D.); and Isala Klinieken, Zwolle (P.L.P. Brand, M.D., Ph.D.)
separate inhalers, thereby suggesting a synergistic effect of
allthe
from the Netherlands.
combination therapy (30).
A triple crossover study comparing step-up treatment with
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