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Combination Therapy Salmeterol/Fluticasone Versus Doubling Dose of Fluticasone in Children With Asthma
Combination Therapy Salmeterol/Fluticasone Versus Doubling Dose of Fluticasone in Children With Asthma
Combination Therapy Salmeterol/Fluticasone Versus Doubling Dose of Fluticasone in Children With Asthma
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).
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METHODS
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.
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.
1223
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
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)
1224
Statural Growth
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)
4.7)
2.8)
4.6)
2.2)
0.42
0.95
0.28
0.54
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
55 (3.9 to . 1570)
313 (0.3 to . 1570)
0.79
0.52
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.
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
16)
10)
14)
28)
P Value
0.87
0.63
0.40
0.86
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
(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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1227