Role of the fixed combination of fluticasone and salmeterol in adult Chinese patients with asthma and COPD

Figures & data

Table 1 Pivotal and key clinical trials for FP/SAL in COPD and asthma

References	Study population	Study design and duration	Interventions and number of subjects	Primary and other endpoints	Efficacy outcomes/results	Adverse events
Hanania et al^Citation13	COPD with FEV1 40%–65% predicted, chronic bronchitis symptoms, and moderate dyspnea	R, DB, PC over 24 weeks	FP/SAL 250/50 μg DPI (n=178) versus SAL 50 μg DPI (n=177) versus FP 250 μg DPI (n=183) versus PBO (n=185)	Primary endpoint(s): morning FEV1 for FP/SAL versus SAL and 2 hours post-dose FEV1 for FP/SAL versus FP Other endpoints: PEFR, TDI, CRDQ, AECOPD	FP/SAL more effective than individual agents and PBO in lung function improvement. TDI improved in three treatment groups, not PBO group. No significant differences in secondary measures among FP, SM, and PBO.	Oropharyngeal candidiasis >6% in FP and FP/SAL groups, <3% in SM and PBO groups. Slightly higher, but no significant differences in rates of abnormal synthetic corticotropin stimulation test in FP and FP/SAL groups. Pneumonia not reported.
Calverley et al^Citation10 (TRISTAN trial)	COPD with FEV125%–70% predicted, history of AECOPD (at least one per year in previous 3 years and at least one in the last year) and chronic bronchitis symptoms	R, DB, PC, PG over 12 months	FP/SAL 500/50 μg DPI versus FP 500 μg DPI versus SAL 50 μg DPI versus PBO	Primary endpoint: mean pretreatment FEV1 (change from baseline) Other endpoints: SGRQ, AECOPD per year	FP/SAL superior to other groups in FEV1 improvement. Only FP/SAL superior to PBO for AECOPD. FP/SAL superior SGRQ score compared with FP and PBO, not SAL.	Oropharyngeal candidiasis in FP/SAL (8%) and FP (7%), SAL (2%), PBO (2%). No differences among groups in clinically significant decreases in serum cortisol concentration.
Mahler et al^Citation9	COPD with FEV1 <65% predicted and greater than 0.7 L, daily productive cough and dyspnea	R, DB, PC, PG over 24 weeks	FP/SAL 500/50 μg DPI (n=165) versus FP 500 μg DPI (n=168) versus SAL 50 μg DPI (n=160) versus PBO (n=181)	Primary endpoints: morning predose FEV1 and 2-hour post-dose FEV1 Other endpoints: PEFR, TDI, AECOPD, rescue salbutamol use, symptoms, chronic bronchitis symptoms, CRDQ	FP/SAL superior to all other treatments in morning FEV1 and superior to FP and PBO in post-dose FEV1. FP/SAL superior to other therapies in PEFR and TDI. FP/SAL superior to FP and PBO in CRDQ. No significant differences among groups in AECOPD.	Oropharyngeal candidiasis >7% in both FP groups, <1% in SAL and PBO groups. Incidence of HPA axis suppression similar among all groups. Unspecified viral respiratory tract infections >7% in FP/SAL, FP, and SAL groups, <2% in PBO group.
Calverley et al^Citation11 (TORCH trial)	Moderate to very severe COPD (FEV1 <60% predicted)	R, DB, PC, PG over 3 years	FP/SAL 500/50 μg DPI (n=1,533) versus FP 500 μg DPI (n=1,534) versus SAL 50 μg DPI (n=1,521) versus PBO (n=1,524)	Primary endpoint: all-cause mortality Other endpoints: FEV1, GRQ, and rate of AECOPD	No statistically significant differences in mortality (P=0.052). FP/SAL was superior to individual ingredients for FEV1 improvement, SGRQ, and rate of AECOPD. FP and SAL superior to placebo in AECOPD.	Candidiasis >7% in both FP/SAL and FP groups, 2% in other groups. Dysphonia >17% in FP/SAL and FP groups, <1% in other groups. Pneumonia FP/SAL (19.6%), FP (18.3%), SAL (13.3%), PBO (12.3%). No significant differences among groups in cataracts or decreases in bone mineral density.
Kavuru et al^Citation62	Asthmatics (>12 years old) with FEV1 40%–85% predicted	R, DB, PC, PG over 12 weeks	FP/SAL 100/50 μg DPI (n=178) versus SAL 50 μg MDI (n=177) versus FP 100 μg MDI (n=183) versus PBO (n=185)	Primary endpoint: FEV1 AUC, pre-dose FEV1, and worsening asthma Other endpoints: PEFR, symptoms, rescue salbutamol use, nocturnal awakenings	Greater improvement in all measures with FP/SAL than other groups.	Throat irritation, oral candidiasis, and hoarseness <4% in all groups. No cases of pneumonia reported.
Shapiro et al^Citation61	Asthmatics (>12 years old) with FEV1 40%–85% predicted, previously uncontrolled with medium doses of ICS	R, DB, PC, PG over 12 weeks	FP/SAL 250/50 μg DPI (n=84) versus FP 250 μg DPI (n=84) versus SAL 50 μg DPI (n=88) versus PBO (n=93)	Primary endpoints: % patients that withdrew due to lack of efficacy, morning FEV1, and FEV1 AUC Other endpoints: AM and PM PEFR, rescue salbutamol use, daytime, and nighttime symptom scores	FP/SAL group had lower probability of study withdrawal related to lack of efficacy than other groups. Greater improvement in other outcome measures with combination compared with individual agents.	Oropharyngeal candidiasis >4% in FP and FP/SAL groups, <3% in SM and P groups. Slightly higher, but no significant differences in rates of abnormal synthetic corticotropin stimulation test in FP and FP/SAL groups. Pneumonia not reported.
Aubier et al^Citation63	Steroid-dependent (high-dose ICS) asthmatics ≥12 years old and FEV1 50%–100% predicted	DB, DD over 28 weeks	FP/SAL 500/50 μg DPI (n=167) versus SAL 50 μg + FP 500 μg DPI (n=171) versus FP 500 μg DPI (n=165)	Primary endpoint: morning PEFR Other endpoints: daytime and nighttime asthma symptom score, rescue-free day-time and nighttime	FP/SAL and FP + SAL groups had greater improvement in all measures compared with FP group.	Hoarseness, dysphonia, throat irritation <4% of patients in all groups.
Bateman et al^Citation14	Asthmatics, ≥ 12 years old, with uncontrolled asthma	R, DB, PG, stratified study over one year Stratum 1: not on ICS, Stratum 2: 500 μg beclomethasone and Stratum 3: 500–1,000 μg beclomethasone	FP/SAL DPI versus FP DPI In each of the three stratums, doses titrated up to FP/SAL 500/50 or FP 500 μg	Primary endpoint: proportion of patients who achieved well-controlled asthma withFP/SAL versus FP Secondary endpoints: asthma control in second study phase, FEV1, dose of ICS required, AQLQ, and exacerbations	Significantly greater number of patients achieved asthma control in all stratums with FP/SAL than FP. Lower doses of ICS in FP/SAL regimen achieved asthma control compared with FP alone. FP/SAL superior to FP alone for all other measures.	Oral candidiasis <3% in both FP/SAL and FP groups. Dysphonia in 3% of FP/SAL and 2% of FP group. No significant differences in urinary cortisol levels among treatments.

Abbreviations: Am, morning; PM, afternoon; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in one second; R, randomized; DB, double-blind; PC, placebo-controlled; FP/SAL, fluticasone/salmeterol; DPI, dry powder inhaler; PBO, placebo; PEFR, peak expiratory flow rate; TDI, Transitional Dyspnea Index; CRDQ, Chronic Respiratory Disease Questionnaire; AECOPD, acute exacerbation of COPD; PG, parallel-group; SGRQ, St George’s Respiratory Questionnaire; HPA, hypothalamopituitary axis; MDI, metered dose inhaler; AUC, area under the curve; ICS, inhaled corticosteroids; DD, double-dummy; AQLQ, Asthma Quality of Life Questionnaire; SM, salmeterol.

Table 2 Clinical studies of fluticasone propionate/salmeterol in Chinese patients

References	Study population	Study design and duration	Interventions and number of subjects	Primary and other endpoints	Efficacy outcomes/results	Adverse events
You-Ning et al^Citation65	Chinese adults with moderate asthma, uncontrolled with ICS alone	R, open-label, PG over 4 weeks	FP/SAL 250/50 μg HFA MDI (n=125) versus FP/SAL 250/50 μg DPI (n=123)	Primary endpoint: morning PEFR Secondary endpoints: evening PEFR, FEV1, morning symptoms, nocturnal symptoms, and self- evaluation of status	No differences in any primary or secondary endpoints.	Voice alteration in four subjects with DPI, none with MDI. No reports of pneumonia or oral candidiasis in either group.
Zhong et al^Citation67	Chinese adults with moderate to severe asthma, uncontrolled with low-dose ICS alone	R, open-label, PG over 6 weeks	FP/SAL 100/50 μg DPI (n=199) versus budesonide 400 μg BID DPI (n=187)	Primary endpoints: morning PEFR Secondary endpoints: evening PEFR, morning symptoms, nocturnal symptoms, rescue salbutamol use	FP/SAL provided greater improvement in all breathing tests, rescue salbutamol, and symptom-free days.	Most common side effect in both groups was pharyngitis. No cases of pneumonia reported in either group.
Zheng et al^Citation54	Chinese adults with moderate to very severe COPD	R, DB, PC, PG over 24 weeks	FP/SAL 500/50 μg DPI (n=297) versus PBO (n=148)	Primary endpoints: prebronchodilator FEV1 Other endpoints: post-bronchodilator FEV1, rescue salbutamol use, health status score (SGRQ), and AECOPD	FP/SAL provided improvement in prebronchodilator FEV1~17% above PBO. Decrease in AECOPD and improvement in SGRQ with FP/SAL compared to PBO. Improvement in salbutamol rescue use and symptoms for FP/SAL versus PBO.	No differences in adverse effects between FP/SAL and placebo including 1% incidence of oral candidiasis for FP/SAL and placebo groups.
Nie et al^Citation73	Chinese adult asthmatics naïve to asthma maintenance drug therapies	R, PG over 24 weeks	FP/SAL 250/50 μg DPI (n=130) versus FP/SAL 250/50 μg DPI + THEO 200 mg/day (n=135)	Primary endpoints: AECOPD and asthma control (Asthma Control Test) Other endpoints: FEF25%–75%, PEFR, FEV1	Decrease in number of AECOPD in FP/SAL + THEO compared with FP/SAL. No difference in asthma control. Greater improvement in FEF25%–75% with FP/SAL + THEO, but no differences seen in FEV1 or PEFR.	Not reported
Gao et al^Citation70	Chinese adults with moderate to severe asthma	R, PG, DB over 24 weeks	FP/SAL 250/50 μg DPI (n=19) versus FP/SAL 250/50 μg DPI + montelukast 10 mg daily (n=19)	Primary endpoints: small airway function based on HRCT and spirometry	Addition of montelukast to FP/SAL significantly improved air trapping (RV/TLC) and HRCT measures. No effect of addition of montelukast to FP/SAL on small airway wall thickness.	Not reported

Abbreviations: FP/SAL, fluticasone/salmeterol; ICS, inhaled corticosteroid; R, randomized; PG, parallel-group; MDI, metered dose inhaler; DPI, dry powder inhaler; PEFR, peak expiratory flow rate; PC, placebo-controlled; FEV₁, forced expiratory volume in one second; DB, double-blind; PC, placebo-controlled; PBO, placebo; SGRQ, St George’s Respiratory Questionnaire; AECOPD, acute exacerbation of COPD; THEO, theophylline; FEF25%–75%, forced expiratory flow 25% to 75%; HRCT, high resolution computed tomography; RV, residual volume; TLC, total lung capacity; HFA, hydrofluoroalkane; HRCT, high-resolution computed tomography.

Table 3 Clinical studies of fluticasone propionate/salmeterol in acute exacerbations of COPD

References	Study population	Study design and duration	Interventions and number of subjects	Primary endpoints and other outcomes	Efficacy endpoints/results	Adverse events
Ferguson et al^Citation50	COPD with prebronchodilator FEV1 ≤50%, one AECOPD in last year	R, DB, PG over 52 weeks	FP/SAL 250/50 μg DPI (n=394) versus SAL 50 μg DPI (n=388)	Primary endpoint: mean annual rate of moderate/severe exacerbations of COPD Other endpoints: time to first AECOPD, AECOPD requiring oral steroids. Mean annual rate of moderate/severe exacerbations of COPD	FP/SAL superior to SAL for all AECOPD measures.	Dysphonia (5%) FP/SAL and SAL (1%), candidiasis-related events FP/SAL (6%), SAL (<1%). Pneumonia occurred more frequently in the FP/SAL group (7%) than the SAL group (2%).
Kardos et al^Citation51	COPD with prebronchodilator FEV1 ≤50%, two or more AECOPD in last year	R, DB, PG over 44 weeks	FP/SAL 500/50 μg DPI (n=507) versus SAL 50 μg DPI (n=487)	Primary endpoint: number of moderate and severe exacerbations Secondary endpoints: time to first exacerbation, prebronchodilator PEFR, post-bronchodilator FEV1, mMRC, and SGRQ	FP/SAL superior to SAL for all AECOPD measures as well as lung function, dyspnea, and health status.	Eight cases of oropharyngeal candidiasis in FP/SAL group. Twenty-three cases of suspected pneumonia were observed in the FP/SAL group and seven in the SAL group.
Wedzicha et al^Citation60 (INSPIRE trial)	Severe to very severe COPD with FEV1 <50%, mMRC ≥2, and history of AECOPD	R, DB, DD study over 2 years	FP/SAL 500/50 DPI (n=658) versus TIO DPI (n=665)	Primary endpoint: AECOPD Other endpoints: post-dose FEV1, mortality, SGRQ, and study withdrawal rate	No difference in AECOPD or FEV1 between groups. Superior SGRQ score, mortality rate, and study withdrawal rate with FP/SAL compared with TIO.	Oral candidiasis 6% in FP/SAL versus 3% in TIO group. Pneumonia 8% in FP/SAL versus 4% in TIO group. Higher cardiovascular deaths in TIO than FP/SAL group.
Magnussen et al^Citation59 (WISDOM trial)	Severe to very severe COPD	R, DB, PG study over 12 months	FP/SAL 500/50 μg DPI + TIO DPI (n=1,243) versus SAL 50 μg DPI + TIO DPI (n=1,242)	Primary endpoint: time to first moderate to severe AECOPD Other endpoints: time to first severe AECOPD, change in lung function, SGRQ, and mMRC	Exacerbations similar between groups, severe AECOPD tended to occur early after ICS withdrawal, but was not sustained. Greater decline in FEV1 and health 1 status in ICS withdrawal group.	No difference in pneumonia between two groups.

Notes: Unless specified otherwise, FP/SAL is administered twice daily and tiotropium is administered once daily at a dose of 18 μg.

Abbreviations: COPD, chronic obstructive pulmonary disease; AECOPD, acute exacerbation of COPD; FEV₁, forced expiratory volume in one second; R, randomized; DB, double-blind; PG, parallel-group; DPI, dry powder inhaler; PEFR, peak expiratory flow rate; FP/SAL, fluticasone/salmeterol; mMRC, modified Medical Research Council; SGRQ, St George’s Respiratory Questionnaire; DD, double-dummy; TIO, tiotropium; ICS, inhaled corticosteroid.

Table 4 Clinical trials comparing fluticasone propionate/salmeterol with other agents

References	Study population	Study design and duration	Interventions and number of subjects	Primary endpoints and other outcomes	Efficacy outcomes and results	Adverse events
Dahl et al^Citation66 (EXCEL trial)	Asthmatics FEV1 >50% predicted and on high-dose ICS at baseline	R, DB, DD, PG over 24 weeks	FP/SAL 250/50 μg DPI (n=694) versus budesonide/formoterol 200/6 μg DPI (n=697)	Primary endpoint: AECOPD Other endpoints: symptom-free days and nights, rescue salbutamol-free days and nights	All measures were statistically similar between the two therapies.	Most commonly reported drug-related adverse events were hoarseness/dysphonia (2% each), candidiasis of the mouth/throat (2%). No pneumonia reported.
Nelson et al^Citation68	Asthmatics (≥15 years old) with FEV1 between 50%–80% predicted, previously on low–moderate dose ICS	DB, DD, PG over 12 weeks	FP/SAL 100/50 μg DPI (n=222) versus FP 100 μg DPI + montelukast 10 mg daily (n=225)	Primary endpoint: AM PEFR Secondary endpoints: evening PEFR, FEV1, symptom-free days and nights, asthma symptom score, asthma exacerbations, rescue-free days and nights	Pulmonary function, shortness of breath, symptom-free days and nights, asthma exacerbations, and rescue free days were better with FP/SAL. No difference in chest tightness, wheeze, or overall asthma symptom scores between treatments.	Most commonly reported drug-related adverse events were hoarseness/dysphonia, candidiasis of mouth/throat, headache, and sore throat in both groups (1%–3%).
Ringdal et al^Citation69	Asthmatics (≥15 years old) with FEV1 >50% predicted, previously on ICS	R, DB, DD, PG over 12 weeks	FP/SAL 100/50 μg DPI (n=404) versus FP 100 μg DPI + montelukast 10 mg daily (n=401)	Primary endpoint: AM PEFR Secondary endpoints: evening PEFR, FEV1, symptom-free days and nights, rescue-free days and nights	All outcome measures superior with FP/SAL compared with FP + montelukast.	Adverse effects similar between treatment groups. Oral candidiasis <1% in both groups.
Hanania et al^Citation56	Moderate to severe COPD	R, DB, PC over 24 weeks	FP/SAL 250/50 μg DPI added to TIO DPI (n=169) versus TIO DPI (n=173)	Primary endpoint: trough FEV1 Other endpoints: FVC, IC, health status, AECOPD	FEV1, FVC, IC improved with triple therapy. No difference between treatments on health status and AECOPD.	Oral candidiasis 3% in FP/SAL + TIO group, <1% in TIO group. No reports of pneumonia.
Aaron et al^Citation57	Moderate to severe COPD, AECOPD within last year	R, DB, PC over one year	FP/SAL 250/50 μg DPI + TIO DPI (n=145) versus SAL 50 μg DPI + TIO DPI (n=148) versus TIO DPI (n=156)	Primary endpoint: proportion of patients experiencing AECOPD Other endpoints: mean number of AECOPD/year, hospitalizations, dyspnea, SGRQ, and FEV1	No significant differences in AECOPD or dyspnea among groups. Triple therapy improved FEV1, SGRQ, and hospitalization rates over other groups.	Hoarseness (6.2%) and oral candidiasis more common in FP/SAL + TIO group (4.1%) versus <1% in other groups for both side effects. No difference in mortality or risk of pneumonia leading to mechanical ventilation or death among groups.
Singh et al^Citation58	COPD with 30%–75% predicted FEV1 and mMRC ≥2	R, DB, DD, three-way crossover study over 3 weeks in each treatment arm	FP/SAL 500/50 μg DPI (n=37) versus FP/SAL 500/50 μg + TIO (n=31) versus TIO (n=31)	Primary endpoint: specific airways conductance. Other endpoints: FEV1, FVC, IC, TDI	Triple therapy (FP/SAL + TIO) superior to other groups in lung function measures. Triple therapy was not superior to FP/SAL for TDI.	No differences observed in adverse effects among three groups.

Note: Unless specified otherwise, FP/SAL is administered twice daily and tiotropium is administered as a dose of 18 μg.

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in one second; ICS, inhaled corticosteroid; R, randomized; DB, double-blind; DD, double-dummy; FP/SAL, fluticasone/salmeterol; PG, parallel-group; DPI, dry powder inhaler; AECOPD, acute exacerbation of COPD; AM, morning; PEFR, peak expiratory flow rate; PC, placebo-controlled; TIO, tiotropium; FVC, forced vital capacity; IC, inspiratory capacity; mMRC, Modified Medical Research Council Dyspnea Scale; SGRQ, St George’s Respiratory Questionnaire; Tio, tiotropium; TDI, transitional dyspnea index.

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