Original Research

Original Research
COPD
The Efficacy and Safety of Combination
Salmeterol (50 ␮g)/Fluticasone
Propionate (500 ␮g) Inhalation Twice
Daily Via Accuhaler in Chinese Patients
With COPD*
Jin-Ping Zheng, MD, FCCP; Lan Yang, MD; Ya Mei Wu, MD;
Ping Chen, MD, FCCP; Zhong Guang Wen, MD; Wen-Jie Huang, MD; Yi Shi, MD;
Chang-Zheng Wang, MD; Shao-Guang Huang, MD; Tie-ying Sun, MD; Guang-Fa
Wang, MD; Sheng-Dao Xiong, MD; and Nan-Shan Zhong, MD, FCCP
Background: Few studies of the efficacy and safety of therapy with combinations of salmeterol/
fluticasone propionate (SFCs) have been conducted in Chinese patients with COPD, and the benefits
of combination therapy in nonsmoking patients with COPD are, to our knowledge, not known.
Study objectives: The aims were to establish the efficacy and tolerability of the therapy with SFC
(salmeterol, 50 ␮g/fluticasone, 500 ␮g, twice daily) in the management of Chinese COPD patients and
to investigate the effectiveness of SFC in nonsmokers with COPD.
Methods and patients: This was a randomized, double-blind, placebo-controlled, parallel-group,
multicenter study. Changes in prebronchodilator and postbronchodilator FEV1, quality of life
determined by the St. George Respiratory Questionnaire (SGRQ) scores, relief bronchodilator
use, nighttime awakenings, and frequency of exacerbations of COPD were measured in patients
randomized to receive SFC (n ⴝ 297) or placebo (n ⴝ 148). Never-smokers, former smokers, and
current smokers accounted for 11.7%, 66.7%, and 21.6%, respectively, of the study population.
Results: After 24 weeks, the mean changes in prebronchodilator and postbronchodilator FEV1 were
180 mL (95% confidence interval [CI], approximately 91 to 268; p < 0.001) and 65 mL (95% CI,
approximately 14 to 115; p ⴝ 0.012), respectively, greater for the SFC group than that for the placebo
group. The differences in response to treatment were significant (all p < 0.0001) in former or current
smokers but not in never-smokers (p > 0.05). The mean improvement in the total SGRQ score for the
SFC group was 5.74 (p < 0.01) greater than that for the placebo group. SFC significantly reduced the
frequency of nighttime awakenings and the use of relief bronchodilator. The adjusted ratio of
exacerbations of COPD for the SFC group relative to the placebo group was 0.61 (95% CI,
approximately 0.45 to 0.84; p < 0.01). There were no significant differences between the SFC and
placebo groups in safety measures.
Conclusions: SFC therapy achieved sustained improvement in lung function, quality of life, and
control of symptoms, and was well tolerated in Chinese patients. Greater improvements in lung
function were found only for COPD patients with a history of smoking.
Trial registration: http://ctr.gsk.co.uk/Summary/fluticasone_salmeterol/studylist.asp Identifier: No.
SCO100540.
(CHEST 2007; 132:1756 –1763)
Key words: COPD; fluticasone propionate; inhaled corticosteroid; long-acting ␤2-agonist; salmeterol
Abbreviations: CI ⫽ confidence interval; FP ⫽ fluticasone propionate; ICS ⫽ inhaled corticosteroid; LABA ⫽ long-acting
␤2-adrenoceptor agonist; SAL ⫽ salmeterol; SFC ⫽ combination of salmeterol/fluticasone propionate; SGRQ ⫽ St. George
Respiratory Questionnaire; TRISTAN ⫽ Trial of Inhaled Steroids and Long-Acting ␤2-Adrenoceptor Agonists
ver the past 2 decades, there has been a dramatic
O increase
in tobacco consumption in China; approximately 67% of men and 4% of women ⬎ 15
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years of age are currently smokers.1 There are ⬎ 320
million Chinese smokers, representing about one
third of all smokers worldwide. COPD, which preOriginal Research
dominantly develops in individuals with a significant
smoking history, is a leading and rising cause of
mortality worldwide.2 In south China, the prevalence
of COPD is reported to be 9.4% for those ⱖ 40 years
of age3 and is expected to rise as the full impact of
the increase in the numbers of Chinese smokers
manifests itself. In 2002, the World Health Organization Global Burden of Disease Project4 ranked
COPD as second in its list of the 20 leading causes of
death in China.
COPD is characterized by inflammation and airflow obstruction5,6 with chronic progressive symptoms and impaired health status,7 particularly in
those persons who experience episodes of acute
symptom exacerbation.8 The use of combination
therapy involving a long-acting ␤2-adrenoceptor agonist (LABA), such as salmeterol (SAL), and inhaled
corticosteroid (ICS), such as fluticasone propionate
(FP), to reduce airflow obstruction and improve
health outcomes in COPD patients has been supported by a number of studies,9 –12 including the
12-month Trial of Inhaled Steroids And Long-Acting
␤2-Adrenoceptor Agonists (TRISTAN).13 The complementary actions of the LABA and ICS components work together to produce clinical benefits.
Therapy with a combination of SAL/FP (SFC) has
been shown to reduce exacerbations and to improve
lung function and health status to a significantly
greater extent than those with either FP or SAL
*From the Guangzhou Institute of Respiratory Disease (Drs. Zheng
and Zhong), First Affiliated Hospital of Guangzhou Medical College, Guangzhou, People’s Republic of China; First Affiliated Hospital (Dr. Yang), Xi’An Jiao Tong University, Xi’An, People’s Republic of China; First Affiliated Hospital (Dr. Wu), Chongqing
Medical University, Chongqing, People’s Republic of China;
Shenyang People’s Liberation Army General Hospital (Dr.
Chen), Shenyang, People’s Republic of China; Beijing People’s
Liberation Army 304 Hospital (Dr. Wen), Beijing, People’s
Republic of China; Nanjing People’s Liberation Army General
Hospital (Dr. Shi), Nanjing, People’s Republic of China; Xinqiao
Hospital (Dr. C.-Z. Wang), Chongqin, People’s Republic of
China; Ruijing Hospital (Dr. S.-G. Huang), Shanghai, People’s
Republic of China; Beijing Hospital (Dr. Sun), Beijing, People’s
Republic of China; First Affiliated Hospital of Beijing University
(Dr. G.-F. Wang), Beijing, People’s Republic of China; Tongji
Hospital (Dr. Xiong), Wuhan, People’s Republic of China; and
Guangzhou People’s Liberation Army General Hospital (Dr.
W.-J. Huang), Guangzhou, People’s Republic of China.
All authors contributed equally to this article.
The study was funded by GlaxoSmithKline China.
The authors have reported to the ACCP that no significant
conflicts of interest exist with any companies/organizations whose
products or services may be discussed in this article.
Manuscript received December 15, 2006; revision accepted
August 17, 2007.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: N. S. Zhong, MD, FCCP, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical College, Guangzhou 510120, People’s Republic
of China; e-mail: [email protected]
DOI: 10.1378/chest.06-3009
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monotherapy. In addition, SFC has demonstrated an
ability to restore responsiveness to relief medication
in patients with COPD, in whom cigarette smoking
was associated with a blunted vasodilator response to
inhaled salbutamol.14
Although cigarette smoking is one of the most
important risk factors for the development of COPD,
it is not the only risk factor. Environmental toxic
gases, air pollution, and indoor biomass fuel pollutants have also been reported to induce COPD.15 In
most studies published in the last few years, only
those persons with a history of heavy smoking (smoking index, ⬎ 20 pack-years9,10 or 10 pack-years13,16)
were enrolled in the study. However, in the real world,
some patients with COPD were never-smokers.
Whether or not these never-smokers would benefit
from SFC therapy is not known.
Few studies have examined ethnic differences in
response to COPD treatment (eg, SFC therapy in
Chinese COPD patients). Drug metabolism can be
influenced by, among others things, genetic and environmental factors. For some drugs (eg, theophylline,
warfarin, and corticosteroids), the mean response of
Chinese patients is known to be substantially
different from that of other ethnic groups. Differences in the frequency of ␤2-adrenergic receptor
polymorphisms in black, white, and Chinese populations have been proposed to account for observed
differences in ␤2-adrenergic responsiveness between
ethnic groups.17 Adherence to therapy with ICSs
could also be associated with race-ethnicity and
other factors.18 We therefore initiated the present
study in order to investigate the efficacy and safety of
SFC in Chinese patients with COPD, including
never-smokers.
Materials and Methods
Patients
We recruited outpatients 40 to 79 years of age in whom COPD
had been diagnosed, as defined by the European Respiratory
Society19 and the Global Initiative for Chronic Obstructive Lung
Disease,15 distributed evenly in 12 hospitals (Guangzhou Institute of Respiratory Disease, south China; First Affiliated Hospital, Xi’An Jiao Tong University, Xi’An, northwest China; First
Affiliated Hospital, Chongqing Medical University, Chongqing,
southwest China; Shenyang People’s Liberation Army General
Hospital, Shenyang, northeast China; Beijing People’s Liberation
Army 304 Hospital, Beijing, north China; and Guangzhou People’s Liberation Army General Hospital, Guangzhou, south
China). Patients were recruited regardless of their smoking
history. All patients had a baseline FEV1 after bronchodilation
that was approximately 25 to 69% of predicted normal values, a
postbronchodilation FEV1/FVC ratio of ⬍ 70%, and poor reversibility of airflow obstruction, defined as an increase of ⬍ 10% of
the normal predicted FEV1 value 30 min to 2 h after the
inhalation of 400 ␮g of salbutamol. Predicted FEV1 values were
CHEST / 132 / 6 / DECEMBER, 2007
1757
selected from the European Committee of Coal and Steel
predictions20 and adjusted for people of Chinese ethnicity according to the recommendation of Zheng and Zhong.21
The specific study exclusion criteria were as follows: the
presence of concurrent respiratory disorders other than COPD; a
requirement for regular or long-term oxygen therapy (⬎ 12 h/d);
the use of oral corticosteroids or ICSs (beclomethasone dipropionate or equivalent, ⬎ 1,000 ␮g daily) or antibiotics in the 4
weeks before the 2-week run-in period; the use of ␤-blockers
(except topical betaxolol for glaucoma and celiprolol for hypertension, provided the dosage did not exceed 200 mg/d); a
moderate-to-severe COPD exacerbation or lower respiratory
tract infection during the run-in period; and any significant
medical condition or disease that would place the patient at risk
or interfere with the study evaluation. This study was conducted
in compliance with the protocol and principles of the Declaration
of Helsinki (1996) and was approved by the State Food and Drug
Administration of China and the local ethics committees at all
sites. All participants provided written informed consent.
100-mL difference in FEV1 between treatment groups at the 5%
significance level with 90% power. We therefore planned a study
enrollment of 500 patients in order to randomize 420 (SFC
group, 280 patients; placebo group, 140 patients). Predose and
postdose FEV1 and changes from baseline and SGRQ scores
were analyzed using repeated-measures analysis of covariance.
Covariates used for analyses were age, sex, smoking status,
baseline value, and study center. Interactions of treatment with
all covariates were tested for predose and postdose FEV1. FEV1
values at the end of the study were analyzed by the lastobservation-carried-forward method. For nighttime awakenings
and the use of a relief bronchodilator, median data were analyzed
for each time interval and were compared between treatment
groups using the van Elteren extension to the Wilcoxon rank sum
test. The rate of COPD exacerbations was calculated using
maximum likelihood-based analysis, assuming a negative binomial distribution with time on treatment as an offset variable and
adjusting for the effects of age, sex, smoking status, baseline
FEV1, and study center.
Study Design
This was a randomized, double-blind, placebo-controlled,
parallel-group, multicenter study. There was a 2-week run-in
period to the study; a 24-week treatment period with clinic visits
at weeks 0, 2, 4, 8, 12, 16, 20, and 24; and a 2-week posttreatment
follow-up period. During the run-in period, patients stopped
taking ICSs and LABAs. Inhaled salbutamol was used as relief
medication and regular COPD treatment (with no change in dose
for 1 month prior to screening and during the study), including
inhaled short-acting anticholinergics, methylxanthines, mucolytics, and sodium cromoglycate, nedocromil sodium, and antihistamine, was permitted throughout the study. If patients had
clinically stable symptoms during the run-in period, they were
randomized to receive therapy with SFC (FP, 500 ␮g; SAL, 50 ␮g)
or placebo twice daily for 24 weeks via a dry-powder inhaler
(ACCUHALER; GlaxoSmithKline R&D; Greenford, UK/DISKUS;
GlaxoSmithKline; Research Triangle Park, NC). Randomization
was stratified at week 0 by smoking status (ie, current, former, or
never-smoker), which was recorded at each subsequent visit.
The primary efficacy end point was prebronchodilator FEV1
when patients had abstained from using all bronchodilators for at
least 6 h, and from study medication for at least 12 h. Other
efficacy end points included postbronchodilator FEV1 (recorded
30 min to 2 h after the inhalation of salbutamol, 400 ␮g),
supplemental salbutamol use, nighttime awakenings, health status (assessed at weeks 0, 8, 16, and 24 by the St. George
Respiratory Questionnaire [SGRQ]), and exacerbations of COPD
(defined as a worsening of symptoms that required treatment
with antibiotics or oral corticosteroids and/or hospitalization).
All lung function measurements were performed at the same
time of day using the same spirometer; at each visit the highest of
three technically acceptable measurements of FEV1 taken before
and 30 min to 2 h after the inhalation of salbutamol, 400 ␮g, via
a spacer (Volumatic; GlaxoSmithKline R&D) were recorded.
Patients daily recorded the use of salbutamol for relief of
symptoms, the number of nighttime awakenings due to COPD
symptoms, and any changes in medication.
In terms of the safety assessment, participants were questioned
about the occurrence of adverse events at each clinic visit.
Hematology, urinalysis, biochemistry, and 12-lead ECG measurements were made at weeks 0 and 24; vital signs and
oropharyngeal examination results were recorded at each visit.
Statistical Analysis
Based on the results of the TRISTAN study,13 we estimated
that 348 evaluable patients would be needed in order to detect a
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Results
Study Population
Of the 510 patients screened in this study, 445
were randomized and treated (SFC group, 297
patients; placebo group, 148 patients). A total of 52
patients (12% from the SFC group; 11% from the
placebo group) were dropped from the study. The
reasons for discontinuation from the SFC and placebo groups were adverse events (SFC group, 3.7%;
placebo group, 2.7%), not meeting inclusion criteria
(SFC group, 2.0%; placebo group, 2.0%), consent
withdrawn (SFC group, 1.7%; placebo group, 0.7%),
lost to follow-up (SFC group, 2.0%; placebo group,
0.7%), protocol violations (SFC group, 0.7%; placebo group, 2.7%), lack of efficacy (SFC group,
0.7%; placebo group, 2.0%), exacerbation of COPD
(SFC group, 0.3%; placebo group, 0.0%), and other
reasons (SFC group, 1.0%; placebo group, 0.0%).
Demographic and disease characteristics at screening are provided in Table 1. There was no statistically
significant difference between the two groups with
regard to baseline smoking status and lung function,
duration of COPD, vital signs, and laboratory test
results. Although 11% of patients in the SFC arm
and 14% in the placebo arm were never-smokers, the
remainder of the patients had a significant smoking
history with a median of 30 to 35 pack-years. Treatment compliance over the 24-week study period was
high and comparable across the treatment groups
(SFC group, 96%; placebo group, 95%).
Lung Function
Prebronchodilator FEV1: A significantly greater increase in the mean (⫾ SD) prebronchodilator FEV1
was observed at the end of the study (1,240 ⫾ 606 mL)
compared with baseline (1,063 ⫾ 377 mL; p ⬍ 0.001)
Original Research
Table 1—Demographics and Characteristics at Screening*
SFC Group
(n ⫽ 297)
Variables
Sex
Male
Female
Age, yr
Mean ⫾ SD
Range
Height, cm
Mean, ⫾ SD
Range
Weight, kg
Mean ⫾ SD
Range
BMI
Mean ⫾ SD
Range
Prior use of COPD medications, %
ß2-adrenoreceptor agonists
Xanthines
Anticholinergics
Duration of COPD, %
⬎ 5 yr
⬎ 15 yr
Smoking status
Nonsmoker
Former smoker
Current smoker
Smoking history, pack-yr
Median
Range
Spirometry
Mean FEV1, mL
Mean FEV1 % predicted
Patients with FEV1 ⬍ 50% predicted
Mean FEV1/FVC
Mean reversibility
269 (90.57)
28 (9.43)
Placebo Group
(n ⫽ 148)
128 (86.49)
20 (13.51)
66.04 ⫾ 8.16
Approximately 41–80
66.60 ⫾ 7.66
Approximately 40–79
167 ⫾ 7
Approximately 142–185
166 ⫾ 7
Approximately 151–181
64 ⫾ 11
Approximately 40–97
62 ⫾ 11
Approximately 37–90
22.95 ⫾ 3.45
Approximately 14.20–34.37
22.59 ⫾ 3.48
Approximately 14.82–32.66
30
8
11
22
19
11
83
37
81
36
32 (11)
203 (68)
62 (21)
30
Approximately 0.20–120
1,063
47
59%
0.41
5.2%
20 (14)
94 (64)
34 (23)
35
Approximately 0.30–150
1,030
47
59%
0.41
5.0%
*Values are given as No. (%), unless otherwise indicated. BMI ⫽ body mass index.
in the SFC group, but not in the placebo group
(1,022 ⫾ 383 vs 1,030 ⫾ 366 mL, respectively;
p ⬎ 0.05). Significantly greater increases in predose
FEV1 were observed throughout the study during
treatment with SFC compared to placebo (Fig 1). After
adjusting for the effects of center, age, sex, baseline
smoking status, and FEV1, the mean change in FEV1
from baseline was higher in the SFC group than in the
placebo group (difference, 180 mL; 95% confidence
interval [CI], approximately 91 to 268 mL; p ⬍ 0.0001)
after 24 weeks of treatment.
Adjusted changes in prebronchodilator FEV1 between baseline and 24 weeks of treatment according to
smoking status are shown in Table 2. Prebronchodilator
FEV1 increased significantly in all nonsmoking, exsmoking, and smoking subgroups treated with SFC;
however, no significant changes were found in the
placebo group. The differences in response to treatment
between the SFC and placebo groups were significant (all
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p ⬍ 0.01) in COPD patients with a history of smoking (ie,
former and current smokers) but did not reach significance (p ⫽ 0.3592) in never-smokers.
2-h Postbronchodilator FEV1: The mean baseline postbronchodilator FEV1 values were
1,218 ⫾ 379 and 1,178 ⫾ 384 mL, respectively, in
the SFC and placebo groups (the difference was
not statistically significant). After 24 weeks of
treatment, the mean elevation in postdose FEV1
from baseline was 99 mL in the SFC group and 28
mL in the placebo group (p ⬍ 0.01). Significantly
greater increases in postdose FEV1 were observed
throughout the study during treatment with SFC
compared to placebo (Fig 2). After adjusting for
the effects of center, age, sex, baseline smoking
status, and FEV1, the mean change in postdose
FEV1 from baseline was 65 mL higher (95% CI,
approximately 14 to 115 mL; p ⫽ 0.012) in the
CHEST / 132 / 6 / DECEMBER, 2007
1759
Figure 1. Improvement in predose FEV1 from baseline with
SFC therapy compared to placebo (n ⫽ 445).
SFC group than in the placebo group after 24
weeks of treatment.
Use of Relief Medication and Symptom-Free Days
Significant reductions in the overall salbutamol
use (ie, the number of inhalations per day per
patient) were observed during treatment with SFC
compared to placebo. Salbutamol use decreased in
the SFC group as the study progressed (median total
daily use for each 4-week interval from baseline to 24
weeks, 40, 37, 32.5, 35.5, 32, and 30 puffs, respectively) but did not change significantly in the placebo
group (median total daily use was 60, 62, 62.5, 68, 65,
and 63 puffs, respectively) [Fig 3].
The number of nighttime awakenings requiring
salbutamol use was lower for the SFC group than for
the placebo group. The percentage of days free from
nighttime awakenings was consistently higher in the
SFC group than in the placebo group (p ⬍ 0.05).
Health Status
The baseline mean overall SGRQ scores were 44.8
for the SFC group and 44.5 for the placebo group.
These scores decreased (ie, improved) for both groups
over the 24-week study period; however, at the end of
the study, the mean change in total score was 5.74 U
Figure 2. Improvement in postdose FEV1 from baseline with
SFC therapy compared to placebo (n ⫽ 445).
(95% CI, approximately 2.79 to 8.69; p ⫽ 0.0001)
greater for the SFC group (Fig 4). There was a
statistically and clinically significant improvement in
the overall quality of life of patients in the SFC group
relative to the control group. Among patients with
more severe disease (postdose FEV1, ⬍ 50% predicted), even greater improvements in the overall
SGRQ scores for the SFC group relative to the control
group of 4.043, 5.192, and 6.847 U, respectively (all
p ⬍ 0.05), were recorded at 8, 16, and 24 weeks.
However, there was no significant difference in the
SGRQ scores at 24 weeks between the SFC and
control groups in patients with moderate disease (ie,
postdose FEV1, ⱖ 50% predicted). In addition, an
analysis of the symptom score component of the SGRQ
showed that, after 24 weeks of treatment, the mean
change in symptom score from baseline was 9.67 U
(95% CI, approximately 5.55 to 13.79 U) greater in the
treatment group than that in the control group. For the
activity and impact components, the mean changes
from baseline were 4.83 and 5.23 U, respectively,
greater for the treatment group at the end of the study.
All of the differences were clinically and statistically
significant.
Table 2—Changes in Prebronchodilator FEV1 Between Baseline and 24 Weeks After Beginning Treatment
According to Smoking Status*
SFC Group
Placebo Group
Smoking Status
Patients, No.
Change of Pre-FEV1 From Baseline
Patients, No.
Change of Pre-FEV1 From Baseline
p Value
Never-smoker
Former smoker
Current smoker
32
203
62
0.261 ⫾ 0.078†
0.177 ⫾ 0.035†
0.112 ⫾ 0.037†
20
94
34
0.141 ⫾ 0.099
0.006 ⫾ 0.052
⫺0.085 ⫾ 0.048
0.3592
0.0068
0.0022
*Values are given as the mean ⫾ SD, unless otherwise indicated.
†p ⬍ 0.01 compared with baseline.
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Original Research
(95% CI, approximately 0.58 to 1.44) in the placebo
group; the rate ratio was 0.54 (95% CI, approximately
0.29 to 0.99).
Safety
Figure 3. Median overall use of salbutamol as relief medication
for patients in the SFC group compared to the placebo group.
Other Efficacy Measures
The annual rates for exacerbations of COPD
needing to be treated with antibiotics, systemic
corticosteroids, or hospitalization, and the total occurrence rates were 0.68, 0.16, 0.10, and 0.81,
respectively, for the SFC group, and 1.15, 0.48, 0.13,
and 1.35, respectively, for the placebo group. Exacerbations requiring antibiotic treatment were the
most common for both groups. The total risk of
exacerbations was reduced by 39% for the SFC group
compared with the placebo group (rate ratio, 0.61; 95%
CI, approximately 0.45 to 0.84; p ⫽ 0.0021). The average number of exacerbations of COPD per year for
those with an FEV1 of ⬎ 50% predicted were 1.03
(95% CI, approximately 0.79 to 1.33) in the SFC group
and 1.61 (95% CI, approximately 1.18 to 2.21) in the
placebo group; the rate ratio of SFC to placebo was
0.64 (95% CI, approximately 0.42 to 0.96). For those
with an FEV1 of ⬍ 50% predicted, the average number
of exacerbations of COPD per year was 0.49 (95% CI,
approximately 0.33 to 0.74) in the SFC group and 0.91
A total of 246 patients (SFC group, 56%; placebo
group, 55%) experienced at least one adverse event
during the study (Table 3). The nature and incidence
of adverse events were similar across the SFC and
placebo groups, including 1% of persons in both
groups who experienced oropharyngeal candidiasis.
The incidence of at least one drug-related adverse
event was 11% in the SFC group and 7% in the
placebo group. Adverse events resulted in withdrawal from the study in 4% of patients (SFC group)
and 3% of patients (placebo group). Three patients
experienced tetter in each group, but no skin bruising was reported in this study.
Two patients in the SFC group died during the
study, one due to acute exacerbations of COPD and
chronic renal failure, and the other due to combined
cholestatic jaundice, abdominal carcinoma, and asphyxia (bile inhalation). Neither death was considered by the investigators to be related to the study
drug. The incidence of serious adverse events was low
(placebo group, 7%; SFC group, 8%). No significant
differences were found in ECG abnormalities between
the SFC and placebo groups. No treatment-related
effects on vital signs or cardiac rate were observed.
Discussion
In agreement with the results of previous studies,9,10,13,22,23 we found that, compared with placebo,
SFC significantly improved lung function and relieved clinical symptoms in our cohort of Chinese
patients. SFC effectively and promptly increased
predose and postdose FEV1. After 24 weeks of
treatment, the mean changes in predose and postdose FEV1 were 180 and 65 mL, respectively, higher
in the SFC group compared to the placebo group.
Prebronchodilator FEV1 increased by about 16% in
the SFC group, though poor reversibility of airflow
obstruction had been found in these COPD patients
Table 3—Incidence of Adverse Events > 10%*
Figure 4. Adjusted mean change in total SGRQ score from
baseline for the SFC group vs the placebo group.
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Adverse Event
SFC
Group (n ⫽ 297)
Placebo
Group (n ⫽ 148)
Any event
Nasopharyngitis
URTI
165 (56)
53 (18)
32 (11)
81 (54)
28 (19)
14 (9)
*Values are given as the No. (%). URTI ⫽ upper respiratory tract
infection.
CHEST / 132 / 6 / DECEMBER, 2007
1761
before the study. This indicates that regular treatment with ICSs and LABAs can indeed improve lung
function, but to a lesser extent than is observed in
asthma patients, in whom postdose FEV1 can improve by ⬎ 200 mL. Hanania et al10 also have
reported a similar improvement in predose FEV1
(16.6% over baseline) in the SFC group. As demonstrated previously, the nature and incidence of adverse events were similar for the SFC and placebo
groups in our study.
In our study, 52 of the participants (11.7%) were
never-smokers. As shown in Table 2, prebronchodilator FEV1 increased significantly in all patients
treated with SFC regardless of smoking status, but
not in persons treated with placebo. However, the
differences in prebronchodilator FEV1 response between the SFC and placebo groups were not significant in never-smokers. This might indicate that SFC
therapy is more effective in smokers. Because the
number of never-smokers was small, a further study
with a larger sample size is needed to address these
effects.
The number of nighttime awakenings was lower in
the SFC group, and the percentage of days without
nighttime awakenings was higher in the SFC group
than in the placebo group. We found, as have
previous studies,9,13 that SFC effectively reduced the
use of relief bronchodilators compared to placebo.
In addition, SFC improved patients’ overall healthrelated quality of life and well being. After 24 weeks of
treatment, clinically and statistically significant improvements over placebo were achieved for the SGRQ
total score as well as all the domain scores. Moreover,
this effect was more pronounced among patients in the
SFC group with more severe COPD (postdose FEV1,
⬍ 50% predicted), who had an improvement in total
mean SGRQ score at 24 weeks of 6.85 U (95% CI,
approximately 3.06 to 10.64), which was both statistically and clinically significant. In contrast, there was no
significant difference in improvement in SGRQ scores
between the two treatment groups at 24 weeks for
patients with moderate COPD (postdose FEV1,
ⱖ 50% predicted).
The degree of improvement was more significant
than that reported in the TRISTAN trial13 (SGRQ
total score improved by 2.2 U) and the Towards a
Revolution in COPD Health16 (SGRQ total score
improved by 3.1 U), which compared therapy with
SFC to that with placebo. Most of the participants in
the TRISTAN and Toxoplasmosis, Other, Rubella,
Cytomegalovirus, and Herpes studies were white.
In our 24-week study, acute exacerbation was
observed as a secondary outcome. The risk of exacerbation was reduced by 39% in the SFC group.
Very similarly, a 39% reduction in exacerbation risk
was also seen in the TRISTAN study,13 except that
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study was conducted over 1 year. Other 24-week
studies of exacerbation risk have been reported, such
as those of Collet et al24 and Niewoehner et al25;
however, optimally, the study period should be ⱖ 1
year. Our data also showed that more frequent exacerbations of COPD were found in patients with severe
obstruction, and that SFC therapy reduced the exacerbation rate both in patients with an FEV1 of ⬍ 50%
predicted and FEV1% of ⱖ 50% predicted; however,
the reduction in exacerbation rate was greater in the
former group (SFC/placebo rate ratio, 0.54) compared
to the latter (SFC/placebo rate ratio, 0.64).
The absolute changes in lung function induced by
SFC treatment, which were similar in our study to
those observed by previous groups,9,13 happened
rapidly, being noticeable after only 2 weeks of
treatment. These changes could be sufficient to
allow improvement in exercise tolerance, and to
reduce the perceived severity of an exacerbation and
hence the number of episodes reported. It is also
likely that the broad-spectrum antiinflammatory activity of the SFC therapy had a role in significantly
reducing the rate of exacerbations.26
The efficacy of half-year SFC therapy in the management of Chinese COPD patients seems to be
remarkable. One explanation might be that the majority of patients were steroid naı¨ve and had not previously
received any regular treatment or participated in a
clinical trial. Ethnic differences in response to SFC
therapy might also be a contributing factor. For instance, Zhou et al27 showed that low-dose administration of theophylline significantly reduced the time to
first exacerbation, and improved SGRQ total, activity,
and impact scores in Chinese patients with COPD,
which has not been reported in white patients. Significant differences in theophylline pharmacokinetics constants were demonstrated between American and Chinese children with asthma28; therefore, recommended
doses of aminophylline were approximately 4 to 7
mg/kg/d lower in Chinese children who were approximately 9 to 16 years of age.
As in other studies conducted using the same SFC
regimen,9,13 we found that the nature and incidence
of adverse events were similar across the SFC and
placebo groups. However, higher dosages of corticosteroids are always a safety concern. Chen and
colleagues29 reported that, for persons with mild
asthma, the inhalation of beclomethasone dipropionate, 400 ␮g/d for a year, which was generally
considered safe in whites, tended to reduce height
growth and serum cortisol level after adrenocorticotropic hormone stimulation was reduced significantly
compared with low-dose beclomethasone dipropionate inhalation (200 ␮g/d) as well as steroid-naı¨ve
patients. A lower FP dosage (250 ␮g) may retain the
benefits of improving pulmonary function and qualOriginal Research
ity of life while relieving symptoms of COPD.10
Further studies are necessary to confirm the efficacy
of the lower dose of ICSs in Chinese patients.
We conclude that SFC therapy composed of an
ICS and a LABA (ie, SAL, 500 ␮g/FP, 50 ␮g) was
effective in Chinese patients with COPD by increasing predose and postdose FEV1, reducing the number of nighttime awakenings and the use of relief
bronchodilator, improving quality of life, and decreasing the rate of exacerbations of COPD. The
combination therapy was also well tolerated in these
patients. A greater improvement in lung function was
found in COPD patients with a history of smoking, but
a larger sample size is needed to further investigate
these results.
ACKNOWLEDGMENT: The authors thank the SCO100540
investigators, study site personnel, and the patients who participated
in the study, as well as editorial assistance from Elsevier/Excerpta
Medica.
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