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Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events

  1. Christopher J Cates1,*,
  2. Roman Jaeschke2,
  3. Stefanie Schmidt3,
  4. Montse Ferrer3

Editorial Group: Cochrane Airways Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 1 AUG 2012

DOI: 10.1002/14651858.CD006922.pub3


How to Cite

Cates CJ, Jaeschke R, Schmidt S, Ferrer M. Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD006922. DOI: 10.1002/14651858.CD006922.pub3.

Author Information

  1. 1

    St George's, University of London, Population Health Sciences and Education, London, UK

  2. 2

    McMaster University, Department of Medicine and Department of Clinical Epidemiology and Biostatistics, Hamilton, Ontario, Canada

  3. 3

    IMIM (Hospital del Mar Medical Research Institute), Health Services Research Unit, Barcelona, Spain

*Christopher J Cates, Population Health Sciences and Education, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK. ccates@sgul.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 28 MAR 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Aubier 1999

MethodsA randomised, double-blind, double-dummy, multicentre, parallel-group study over 28 weeks from May 1996 to November 1997 at 55 centres in 3 countries (Germany, France and the Netherlands). Run-in 2 weeks and follow-up 2 weeks.


ParticipantsPopulation: 503 adolescents and adults (12 to 79) years with asthma. 

Baseline Characteristics: Mean age 48 years. FEV1 73% predicted.

Concomitant ICS used by 100% of participants.

Inclusion Criteria: At least 12 years old with a documented clinical history of reversible airways disease, and received treatment with any inhaled corticosteroid continuously for 12 weeks prior to run-in. FEV1 % predicted between 50% to 100%, At the end of the 2-week run-in period were symptomatic (symptom score 2 or more on at least 4 of the last 7 consecutive days), had a mean morning PEF that was > 50% and < 85% of the maximum PEF 15 min after administration of inhaled salbutamol 400 mcg. 

Exclusion Criteria: taking long-acting beta2-agonists.


Interventions
  1. Fluticasone propionate/salmeterol 500/50 mcg BD
  2. Fluticasone propionate 500 mcg + salmeterol 50 mcg BD
  3. Fluticasone propionate 500 mcg BD


Delivery was Diskus device.


OutcomesPrimary outcome: Mean morning PEF during weeks 1 to 12.

The paper reports "The incidence of drug-related adverse events was similar for the three treatments".

Full SAE data from web report. One death from bronchial carcinoma on salmeterol and fluticasone (separate inhalers). This death was not included in Jaeschke 2008b as the patient stopped taking study medication to allow for elective surgery and died of surgical complications, but was still in the trial and had intended to restart treatment post-operatively.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk403/503 (80%) completed the study

Selective reporting (reporting bias)Low riskFull data on GlaxoSmithKline website

Bailey 2008

MethodsA randomised, double-blind, multicenter, parallel-group study over 52 weeks from November 2004 to April 2007 at 59 centers in the USA.  Run-in: 2 weeks on usual ICS and then 4 weeks on fluticasone 250 mcg twice daily.


ParticipantsPopulation: 475 adolescents and adults (12 to 65) years of African descent with persistent asthma, and symptomatic while taking low dose ICS.

Baseline Characteristics: Mean age 32 years. FEV1 85% predicted. Concomitant ICS used by 100% of participants.

Inclusion Criteria:12 years or older with a documented clinical history of persistent asthma for at least six months and had been symptomatic using ICS (FP 200 mcg daily or equivalent) for at least 4 weeks before entering the run-in period. FEV1 % predicted between 60% and 90%, with at least 12% reversibility following 2 to 4 puffs of albuterol. 

Exclusion Criteria:  Participants were only included in the 52-week study period if on the 2 week run-in taking low dose ICS twice daily, they showed FEV1 at least 60% predicted and in the last 7 days of run-in they had at least 4 days with albuterol use or were symptomatic. They were excluded if they had an exacerbation in the 4 weeks on fluticasone 250 mcg twice daily.


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg Diskus BID
  2. Fluticasone propionate 100 mcg Diskus BID alone.


OutcomesPrimary outcome was rate of asthma exacerbations.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low risk"Double blind treatment period"

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk70/239 lost to follow-up on combined treatment and 85/236 on fluticasone alone

Selective reporting (reporting bias)Low riskFull data on GlaxoSmithKline website (SFA103153SFA103153)

Bateman 2001

MethodsA randomised, double-blind, double-dummy, multicenter, parallel-group study over 12 weeks from March 1998 to June 1999  at 69 centers in 10 countries.  Run-in 2 weeks and 2 weeks follow-up.


ParticipantsPopulation: 497 adolescents and adults (12 to 79) years with documented clinical history of reversible airways obstruction.

Baseline Characteristics: Mean age 40 years. FEV1 76% predicted. Concomitant ICS used by 100% of participants.

Inclusion Criteria:12 years or older with a documented clinical history of reversible airway obstruction, a smoking history of less than 10 pack-years and been using ICS (beclomethasone dipropionate, budesonide or flunisolide 400-500 mcg day or FP 200-250 mcg day) for at least 4 weeks before entering the run-in period. FEV1 % predicted at least 50%.  

Mean PEF over the last 7 days of the run-in period of between 50% and 85% measured after inhalation of salbutamol (400 mg). Had to be symptomatic, i.e. have a cumulative total symptom score (daytime plus night-time) greater than 8 for the last 7 days of the run-in period, and be taking salbutamol up to 800 mcg day.  

Exclusion Criteria:  Received a long-acting beta2-agonist or oral beta2-agonist within 2 weeks of the run-in period, changed asthma medication, had a lower respiratory tract infection within 4 weeks of the run-in period or had an acute asthma exacerbation requiring hospitalisation within 12 weeks of study entry. Other exclusion criteria included prior treatment with oral, depot or parenteral corticosteroids or combination therapy (containing a beta2-agonist and/or ICS).


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg HFA MDI
  2. Fluticasone propionate/salmeterol  100/50 mcg Diskus
  3. Fluticasone propionate 100 mcg CFC MDI


OutcomesPrimary efficacy variable was the mean morning PEF over the 12-week treatment period.

A serious adverse event was described as any event which was fatal, life-threatening, disabling or incapacitating, or which required or prolonged hospitalisation.

Paper reports: "During treatment, serious adverse events were reported by three patients (2%) in each group. These included asthma exacerbations (n.5), breast neoplasia (n.1) and events associated with the gastrointestinal system (n.2) and ear, nose and throat (n.1). The only serious adverse events considered by the investigator to be drug-related were asthma exacerbations in two patients (one each in the fluticasone propionate/salmeterol MDI and Diskus groups)."

SFCB3022 reports 5 patients with asthma SAE in fluticasone propionate/salmeterol groups (333 pts) and none on fluticasone propionate alone (165 pts).


NotesBateman reports 4 asthma hospitalisations in fluticasone propionate/salmeterol groups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk430/497 (87%) completed the study

Selective reporting (reporting bias)Low riskFull data on GlaxoSmithKline website

GOAL 2004

MethodsA randomised, double-blind, multicentre, stratified, parallel-group study over 12 months from December 2000 to December 2002 in 326 centres in Europe, North America, Latin America and Asia Pacific. Run-in 4 weeks.


ParticipantsPopulation: 3416 adolescents and adults (9 to 83) with uncontrolled asthma.  

Baseline Characteristics: Mean age 40 years. FEV1 77% predicted. Concomitant ICS not previously used in stratum 1, low dose in stratum 2 and medium to high dose in stratum 3 at baseline. 

Inclusion Criteria:12 years old or more and less than 80 years old with at least a 6-month history of asthma, bronchodilator reversibility by an increase of at least 15%  in FEV1 over baseline (and 200 mL) based on FEV1 measured pre- and post-inhalation of any short-acting beta2-agonist within the last six months or to demonstrate reversibility at Visit 1, Visit 2, or between Visit 1 and Visit 2 using 200-400 mcg of salbutamol/albuterol. 

Eligible for Stratum 1 of the study if had not received ICS for at least 6 months prior to Visit 1. For Stratum 2, if receiving ≤500 mcg BDP or equivalent daily, Stratum 3, receiving > 500 and ≤ 1000 mcg BDP or equivalent daily.

During 2 or more of the 4 weeks prior to Visit 2, subjects should have failed to achieve the criteria for 'Well-Controlled' asthma. 

Exclusion Criteria:  assessed as having Well-Controlled asthma on more than 3 of the 4 weeks during run-in, change in regular asthma medication; emergency visits due to asthma; treatment with systemic corticosteroids; respiratory tract infection; more than 3 days of morning PEF less than 50% predicted; non-compliance with the diary record card.


Interventions
  1. Fluticasone propionate/salmeterol 100/50, 250/50 or 500/50 mcg BD (by strata)
  2. Fluticasone propionate 100, 250 or 500 mcg BD (by strata)


Delivery was Diskus device


OutcomesThe primary efficacy variable was the proportion of subjects who achieved 'Well-Controlled' asthma with the fluticasone propionate/salmeterol combination compared with fluticasone propionate alone during Phase I of the study.

Paper states that "Serious adverse events were observed during the double-blind period in 4% and 3% of patients in the salmeterol/fluticasone and fluticasone arms, respectively". Web report gives the number of patients (67 and 53 respectively).

Website reports 2 deaths on fluticasone propionate (both myocardial infarction) and 3 deaths on fluticasone propionate/salmeterol (2 myocardial infarction and 1 pneumonia). No asthma-related deaths are reported.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was done telephonically from a computer-generated allocation schedule balanced per stratum and per country

Allocation concealment (selection bias)Unclear riskNot reported  

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk2890/3416 (85%) completed the study

Selective reporting (reporting bias)Low riskFull data on GlaxoSmithKline website

Godard 2008

MethodsA randomised double-blind 24 week multicenter study at 124 centers in France. 8 week open run-in on SFC (50/250 mcg twice daily).


ParticipantsPopulation: 308 adults (18+) years with asthma controlled on ICS (1000 mcg CFC beclomethasone equivalent daily) and LABA. 

Baseline Characteristics: Mean age 44 years. FEV1 90% predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: Currently receiving ICS at a dose of 1000 mcg daily of inhaled beclomethasone dipropionate (BDP) or equivalent and LABA.  Asthma controlled on a stable dose for at least 4 weeks were entered into run-in, and then entered into full study if asthma was well-controlled (as defined in GOAL) in last two weeks of 8-week run-in on fluticasone propionate/salmeterol.

Exclusion Criteria: Patients were excluded from entry into the run-in period if they had a smoking history of 10 pack-years or more, a respiratory tract infection during the last 4 weeks prior to the initial clinic visit (V1), acute asthma exacerbation requiring emergency room treatment or hospitalisation within 4 weeks prior to V1, and/or use of oral/parenteral corticosteroids during the last 4 weeks prior to V1 (12 weeks for depot corticosteroids), or any change in their asthma maintenance treatment in the previous 4 weeks.


Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD
  2. Fluticasone 250 mcg  BD
  3. Fluticasone propionate/salmeterol 100/50 mcg BD (not analysed in this review)


Delivery device Diskus


OutcomesThe primary efficacy endpoint was the variation in mean morning PEF over the first 12 weeks of the treatment period compared to the last 2 weeks of the run-in period (baseline).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind randomised 24-week study"

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
High riskUneven withdrawals (18/159 on fluticasone propionate/salmeterol and 30/159 on fluticasone)

Selective reporting (reporting bias)Low riskFull SAE data reported in paper

Ind 2003

MethodsA randomised, double-blind, double-dummy, multicenter, parallel-group study over 28 weeks from January 1995 to December 1996 at 99 centers in Canada, Denmark, Iceland, Ireland, Italy and the United Kingdom. Run-in 4 weeks


ParticipantsPopulation: 502 adolescents and adults (16 to 75) years with asthma poorly controlled on current ICS.  

Baseline Characteristics: Mean age 45 years. FEV1 2.3L. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: Currently receiving ICS at a dose of 1000 to 1600 mcg daily of inhaled beclomethasone dipropionate (BDP) or equivalent.  Asthma poorly controlled (demonstrated by a PEF of < 85% of maximal achievable PEF after inhaling 400 mcg salbutamol) and had experienced at least 2 exacerbations of asthma in the last year that required a change in asthma therapy. Therefore, over the last 10 days of the baseline period had to demonstrate an average morning PEF which was < 90% of their maximal achievable PEF measured at screening and a diurnal variation in PEF of at least 15%. They also had to have asthma symptoms on at least 4 of the last 7 days or nights of the baseline period.

Exclusion Criteria: Receiving continuous oral corticosteroids, any serious uncontrolled systemic disease or participation was deemed unsuitable

by the physician, had to demonstrate a period variation in PEF of at least 15% (highest evening value-lowest morning value as a percentage of highest

PEF) over the last 10 days and/or nights of the run-in period and to have sub-optimal PEF, with average PEF over the last 10 days of the run-in not exceeding 90% of post-bronchodilator PEF (measured at visit 1).


Interventions
  1. Fluticasone propionate 250 mcg + salmeterol 50 mcg BD
  2. Fluticasone propionate 250 mcg BD
  3. Fluticasone propionate 500 mcg BD


Delivery was MDI (fluticasone propionate 500 arm not used in this review).


OutcomesThe primary efficacy variables were: mean morning PEF; incidence and severity of asthma exacerbations.

No SAE information found in paper publication. Full SAE data on web report. One fatal pneumothorax on salmeterol and fluticasone (separate inhalers).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk432/502 (86% completed study)

Selective reporting (reporting bias)Low riskFull data on GlaxoSmithKline website

Katial 2011

MethodsA 52-week, randomised, double-blind, parallel-group study of fluticasone propionate/salmeterol combination product 250/50 mcg BID and fluticasone propionate (FP) Diskus 250 BID in treatment of subjects with asthma. 61 centers in North and South America, Canada and the Philippines from May 2007 to May 2009.


ParticipantsPopulation: 621 adults and adolescents (12+) years with asthma that was not controlled on ICS at low dose (with or without LABA), or at medium dose without LABA. Clinical diagnosis of asthma, defined by the ATS, for ≥ 6 months before screening.

Baseline Characteristics: Mean age 38 years. FEV1 74% predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: Subjects were required to have treatment with a low-to-medium dose of ICS or combination inhaled corticosteroid/long-acting beta2 –agonist (ICS/LABA) controller medications if the ICS was a low dose for ≥ 4 weeks before screening.

Subjects must have reported being symptomatic while taking their controller medication in the 4 weeks before screening.

Exclusion Criteria: Life-threatening asthma in the 12 months before screening, seasonal or exercise induced asthma without other manifestations of persistent asthma, or concurrent respiratory disease or any other significant concurrent condition/disease.

Subjects were excluded if they had worsening asthma in the 4 weeks before screening including an emergency room visit, hospitalisation, or use of oral/ parenteral corticosteroid. Concurrent use of medications that could have affected the course of asthma or interacted with study medication was prohibited.


Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD
  2. Fluticasone 250 mcg  BD


Delivery device Diskus


OutcomesPrimary outcome was FEV1 over a 52 treatment week period. SAE data fully reported in the published paper and GlaxoSmithKline web report (ADA109055).


NotesClinicalTrials.gov identifier NCT00452699 (Identical design to Kerwin 2011)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind"

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
High risk81/306 withdrew on fluticasone propionate/salmeterol and 73/315 on fluticasone propionate. Of these 14 and 4 respectively withdrew due to adverse events or lack of efficacy.

Selective reporting (reporting bias)Low riskSAE data fully reported

Kavuru 2000

MethodsRandomized, double-blind, double-dummy, parallel-group placebo-controlled study over 12 weeks at 42 centers in the USA. Run-in 2 weeks single blind placebo.


ParticipantsPopulation: 356 adolescents and adults (12 to 70) years with asthma.

Baseline Characteristics: Mean age 37 years. FEV1 64% predicted.

Concomitant ICS used by 100% of participants in group 1 and 0% of participants in group 2. 

Inclusion Criteria:  At least 12 years old and a medical history of asthma (as defined by the ATS) of at least 6 months duration. FEV1 % predicted between 40% to 85%,bronchodilator reversibility by an increase of at least 15%  in FEV1 over baseline 30 minutes after two puffs (180 mcg)  of inhaled albuterol.

Stratified into 2 groups according to type of asthma therapy used at enrolment. 

Exclusion Criteria: History of life-threatening asthma; hypersensitivity reaction to sympathomimetic drugs or corticosteroids; smoking within the previous year or a history of > 10 pack-years; use of oral, inhaled or injectable corticosteroid therapy within the previous month; use of intranasal corticosteroid therapy except for Flonase (GlaxoWellcome Inc.); use of daily oral corticosteroid treatment within the previous 6 months; use of any other prescription or over-the-counter medication that could have affected the course of asthma or interacted with sympathomimetic amines; abnormal chest x-ray films; clinically significant abnormal 12-lead electrocardiograms (ECGs); or a history of significant concurrent disease (e.g., glaucoma, diabetes, hypertension).


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD
  2. Fluticasone 100 mcg  BD


Delivery was Diskus inhaler


OutcomesMean morning pre-dose FEV1 at endpoint; area under the 12-hour serial FEV1 curve relative to baseline [AUC(bl)] after I week of treatment (mean FEV1 AUC); and probability of remaining in the study over time without withdrawal due to lack of efficacy.

Paper reports no serious drug-related adverse events, and reports two serious adverse events that led to withdrawal. Website records 2 events on Fluticasone propionate/salmeterol and 1 event on fluticasone propionate. (Unclear whether the 2 fluticasone propionate/salmeterol events were in separate patients, so treated as one patient).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk142/182 (78%) completed the study

Selective reporting (reporting bias)Low riskData on GlaxoSmithKline website

Kerwin 2011

MethodsA 52-week, randomised, double-blind, parallel-group study of fluticasone propionate/salmeterol combination product (fluticasone propionate/salmeterol) 250/50 mcg BID and fluticasone propionate (FP) Diskus 250 BID in treatment of subjects with asthma. 76 centers in North and South America, Canada and the Philippines from May 2007 to April 2009.


ParticipantsPopulation: 628 adults and adolescents (12+) years with asthma that was not controlled on ICS at low dose (with or without LABA), or at medium dose without LABA. Clinical diagnosis of asthma, defined by the ATS, for ≥ 6 months before screening.

Baseline Characteristics: Mean age 40 years. FEV1 74% predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: Subjects were required to have treatment with a low-to-medium dose of ICS or combination inhaled corticosteroid/long-acting beta2 –agonist (ICS/LABA) controller medications if the ICS was a low dose for ≥ 4 weeks before screening.

Subjects must have reported being symptomatic while taking fluticasone propionate/salmeterol Diskus 100 mcg twice daily in the 4 weeks before screening.

Exclusion Criteria: Life-threatening asthma in the 12 months before screening, seasonal or exercise induced asthma without other manifestations of persistent asthma, or concurrent respiratory disease or any other significant concurrent condition/disease.

Subjects were excluded if they had worsening asthma in the 4 weeks before screening including an emergency room visit, hospitalisation, or use of oral/ parenteral corticosteroid. Concurrent use of medications that could have affected the course of asthma or interacted with study medication was prohibited.


Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD
  2. Fluticasone 250 mcg  BD


Delivery device Diskus


OutcomesPrimary Outcome was FEV1 over a 52 treatment week period. SAE data fully reported in the published paper and GlaxoSmithKline web report (ADA109057).


NotesClinicalTrials.gov identifier NCT00452348 (Identical in design to Katial 2011).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind therapy"

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk79/310 withdrew on fluticasone propionate/salmeterol and 84/318 withdrew on fluticasone, but balanced withdrawals for adverse events of lack of efficacy.

Selective reporting (reporting bias)Low riskFull SAE data reported in paper and GlaxoSmithKline web report

Koenig 2008

MethodsA randomised, double-blind, multicenter, parallel-group study over 40 weeks from February 2003 to October 2004 at 55 sites (50 in the USA, 3 in Latin America, 2 in Latvia). Run-in 2 weeks.


ParticipantsPopulation: 466 adolescents and adults(12 to 81) with asthma.  

Baseline Characteristics: Mean age 34 years. FEV1 78% predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: 12 years of age or older, with a diagnosis of asthma, as defined by the ATS, for at least 3 months prior to visit 1, must have been treated with a short-acting beta2-agonist, an anticholinergic, or an allowed ICS at a fixed dosing regimen (within an allowed total daily dose) for at least 4 weeks prior to the screening visit. FEV1 % predicted between 60% to 95%, bronchodilator reversibility by an increase of at least 12%  in FEV1 over baseline within 30 minutes of inhalation 2 puffs of inhaled albuterol (180 mcg).

Exclusion Criteria: Pregnancy, life-threatening asthma, hospitalisation attributable to asthma within the last 6 months, current smoker or a more than10 pack-year history of smoking, a recent (within 2 weeks) upper or lower respiratory tract infection, or significant concurrent diseases. Medications that could confound the evaluation of the study treatments or treatment strategies were prohibited before and throughout the study, including inhaled (up to 250 mcg fluticasone propionate allowed prior to randomisation), oral, or parenteral corticosteroids (with the exception of protocol defined use of oral corticosteroids following second consecutive assignment to the highest dose of fluticasone propionate/salmeterol), theophylline or other bronchodilators, leukotriene modifiers, anticholinergics, cromolyn, and nedocromil.


Interventions
  1. Fluticasone propionate/salmeterol 100/50, 250/50 or 500/50 mcg BD (BHR strategy)
  2. Fluticasone propionate 100, 250 or 500 mcg (BHR strategy)
  3. Fluticasone propionate 100, 250 or 500 mcg (Reference strategy) - data were not used from this arm


Delivery was Diskus device


OutcomesPrimary efficacy variable was the average inhaled corticosteroid treatment dose over the treatment period.

Paper reports "There were no non-fatal serious adverse events in any treatment group that were considered to be drug related. One patient in the fluticasone propionateBHR treatment group died due to convulsions and cardiac arrest following deep vein thrombosis."

Web report indicates one patient with SAE related to asthma on fluticasone propionate/salmeterolBHR and one patient with ear infection and sinusitis on fluticasone propionateBHR.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk321/466 (69%) completed the study

Selective reporting (reporting bias)Low riskFull data on GlaxoSmithKline website

Koopmans 2006

MethodsA randomised, double-blind, single-centre, parallel-group study over 12 months from September 2000 to December 2003 in the Netherlands. Run-in 4 weeks.

A study to compare the long-term effects on airway inflammation of Seretide versus Flixotide in adult subjects with asthma


ParticipantsPopulation: 54 adults (19 to 59) with mild to moderate persistent allergic asthma. 

Baseline Characteristics: Mean age 32 years. FEV1 89% predicted. Concomitant ICS used by 100% of participants (Median dose 600 mcg/day).  

Inclusion Criteria: Aged between 18 and 50 years with reversible airways obstruction, informed consent, allergic to house dust mite, PC20 histamine < 8 mg/mL, FEV1 greater than 70% predicted.  

Exclusion Criteria: serious concurrent disease likely to interfere with the study, lower respiratory tract infection, or use of antibiotics in the previous 4 weeks.


Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD
  2. Fluticasone propionate 250 mcg BD


Delivery was Diskus device


OutcomesThe primary efficacy variables were the percentage of eosinophils and eosinophil cationic protein (ECP) in induced sputum (baseline and after allergen challenge) at randomisation and 1, 3 6, 9 and 11 months later.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk50/54 (93%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

Li 2010

MethodsA randomised, double-blind, double-dummy, 12 week parallel-group study evaluating the safety of fluticasone propionate/salmeterol 100/50 mcg HFA (2 inhalations of 50/25 mcg) twice daily compared with fluticasone propionate 100 mcg HFA (2 inhalations of 50 mcg) twice daily in subjects 4-11 years of age with persistent asthma. Ran from February 2007 to February 2008.

25 centers in North America, 13 centers in Latin America , and 18 centers in Europe.


ParticipantsPopulation: 350 children (age 4 to 11 years) with persistent asthma who were symptomatic on an ICS.

Baseline characteristics: 22% were aged 4 to 5 years and 78% 6 to 11 years. Spacers were used by 78% of children at baseline.

Inclusion criteria: Male and female subjects 4 to 11 years of age diagnosed with asthma requiring ICS for control of asthma symptoms for at least 1 month prior to screening. Subjects 6 to 11 years of age were required to have an FEV1 ≥ 60% of predicted value and subjects 4 and 5 years of age were required to have a clinic AM PEF ≥ 60% of predicted value at the screening visit. Subjects also had to demonstrate reversibility ≥ 12% over baseline to albuterol or have historical documentation of ≥ 12% reversibility within 24 months prior to the screening visit.

Exclusion criteria: life-threatening asthma or hospitalised for asthma ≥ twice in the past year.


Interventions1. Fluticasone propionate/salmeterol 100/50 mcg HFA (administered as 2 inhalations of 50/25 mcg ex-valve strength via HFA MDI), twice daily

2. Fluticasone propionate 100 mcg HFA ex-valve strength, HFA (administered as 2 inhalations ex-valve strength of 50 mcg via HFA MDI), twice daily

Delivery was via MDI (with spacer if inhalation technique was not well coordinated).


OutcomesAdverse events and serious adverse events on treatment. There were no fatal events, and 1 patient on fluticasone propionate/salmeterol had a head injury occurring after a fall (reported on the GSK website 25 Sept 2008, study ID SFA106484, but not found in the paper publication).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind, double dummy"

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk93% completed

Selective reporting (reporting bias)Low riskData on GSK website

Lundback 2006

MethodsA randomised, double-blind, parallel-group study over 12 months from August 1997 to December 2002 in Sweden. Run-in 2 months.

An interventional 3 year study for asthma control - In what way and in what kind of population is it possible to get asthmatic patients free from symptoms, keep the patients in work, restore a normal lung function, diminish hyperreactivity and normalise quality of life?


ParticipantsPopulation: 282 adults (18 to 70) with mild to moderate persistent asthma. 

Baseline Characteristics: Mean age 40 years. FEV1 93% predicted. Concomitant ICS used by 68% of participants. 

Inclusion Criteria: Clinically representative mild to moderate asthma, symptoms, or use of rescue medication at least twice a week, required to have airway hyperreactivity (AHR) demonstrated by methacholine challenge with a PC20 (the concentration required to provoke a 20% reduction in FEV1) < 8 mg/mL. If AHR was not demonstrated via methacholine challenge then one of the following: diurnal variability in PEF of at least 20% on > 3 days during the last 14 days of the run-in; at least 30% difference between the highest and lowest PEF reading during any 7 days in the run-in period; or an increase of at least 15% in FEV1 or PEF after salbutamol inhalation (0.8 mg). 

Exclusion Criteria: taking daily doses of ICS greater than 1200 mcg, had experienced one or more life-threatening exacerbation requiring hospitalisation during the previous 12 months, were hypersensitive to beta-agonists or ICS, were pregnant or lactating or had a respiratory tract infection during the 4 weeks prior to run-in.


Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD
  2. Fluticasone propionate 250 mcg BD
  3. Salmeterol 50 mcg BD


Delivery was Diskus device (arm three was not used in this review).


OutcomesThe primary efficacy variable was the requirement for an increased dose of study medication.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk263/282 (93%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

Malone 2005

MethodsA randomised, double-blind, active-controlled, multicenter, parallel-group study over 12 weeks from April 2002 to January 2003 at 79 centres (66 in the USA and 13 in Canada). Run-in 2 weeks. 


ParticipantsPopulation: 203 children (4 to 11) years with persistent asthma.

Baseline Characteristics: Mean age 8 years. FEV1 mean 80% predicted. (6-11 years) PEF mean 87% predicted. (4-5 years).

Concomitant ICS used by 100% of participants.  

Inclusion Criteria: 4-11 years of age diagnosed with asthma (ATS definition), who required physician-prescribed treatment for at least 2 months and taking an inhaled corticosteroid for asthma for at least one month prior to visit 1.

FEV1 % predicted between 50% to 95% (6-11 years), am PEF % predicted between 50% to 95% (4-5 years). Bronchodilator reversibility by an increase of at least 12%  in FEV1 (6-11 years) or am PEF (4-5 years) over baseline within 30 minutes of 2-4 actuations of albuterol (180-360 mcg) or to have historical documentation of 12% or greater reversibility within the previous year. 

Exclusion Criteria: History of life-threatening asthma,  hospitalisation due to asthma twice or more in the previous year, significant concurrent disease (e.g. cystic fibrosis, malignancy or immunologic compromise), recent upper or lower respiratory tract infection, current chickenpox or recent exposure to chickenpox in a nonimmune patient, severe milk protein allergy, hypersensitivity to beta2-agonist, sympathomimetic or corticosteroid therapy, clinically significant abnormal laboratory test results.


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD
  2. Fluticasone propionate 100 mcg BD


Delivery was Diskus device.


OutcomesThis was a safety study and no primary efficacy endpoint was identified.

No SAE occurred in this study.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk168/203 (83%) completed the study

Selective reporting (reporting bias)Low riskFull data on GSK website

Murray 2004

MethodsA randomised, double-blind, active-controlled, multicenter, parallel-group study over 12 weeks from November 1999 to September 2000 at 33 centres in the USA. Run-in 2 weeks, single blind placebo.


ParticipantsPopulation: 267 adolescents and adults (12 to 73) years with persistent asthma. 

Baseline Characteristics: Mean age 34 years. FEV1 66% predicted. Concomitant ICS used by 0% of participants.  

Inclusion Criteria: 12 years or older with a 6 month history of asthma and must have been treated with as-needed, short-acting, inhaled beta2-agonists alone during the previous month with no oral or inhaled corticosteroid use within 1 month or long-acting beta-agonist within 72 hours of study entry.

FEV1 % predicted between 40% to 85%, bronchodilator reversibility by an increase of at least 15% in FEV1 over baseline within 30 minutes of inhalation of 2 puffs (180 mcg) of albuterol. 

Exclusion Criteria: Pregnancy and/or lactation, life-threatening asthma, hospitalisation attributable to asthma twice or more in the last year, current smoker or a more than 10 pack-year history of smoking, significant concurrent diseases including a recent upper or lower respiratory tract infection. Medications prohibited before and throughout the study included inhaled, oral or parenteral corticosteroids, theophylline or other bronchodilators, anticholinergics, leukotriene modifiers, cromolyn and nedocromil.


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD
  2. Fluticasone propionate 100 mcg BD


Delivery Diskus


OutcomesTwo primary efficacy variables were defined: (1) mean change from baseline in AM predose FEV1 at endpoint for fluticasone propionate/salmeterol 100/50 compared to salmeterol 50, (2) area under the serial FEV1curve at treatment week 12 relative to treatment day 1 baseline for fluticasone propionate/salmeterol 100/50 compared to fluticasone propionate 100.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTreatment assignments were generated in blocks of 6 by a computer-based random codes system

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk228/267 (85%) completed the study

Selective reporting (reporting bias)Low riskFull data on GSK website

Nathan 2006

MethodsParallel group multicentre study over 12 weeks.


Participants365 adults and adolescents randomised. Age range: 12 to 82 years, mean FEV1 68% predicted. Inclusion criteria: Fluticasone propionate 440-660 mcg/d for at least 3 months prior to study entry; FEV1 40-85%; reversibility >=15%


InterventionsCombination HFA fluticasone propionate/salmeterol 110/42 BID (220/84) versus CFC salmeterol 42 BID (84) versus CFC fluticasone 110 BID (220) versus HFA placebo. Inhaler devices: MDI. Run-in: 2 weeks
This review only includes data from the salmeterol and placebo arms.
Co-interventions: ICS at usual dose was an inclusion criterion, but appears to have been withdrawn in the salmeterol and placebo arms of the study.


OutcomesThe paper publication mentions one drug-related SAE (an upper gastrointestinal bleed from the placebo group).
Website: SAS30004. No fatal SAE. No SAE on fluticasone propionate/salmeterol or fluticasone propionate.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk243/365 (67%) completed the study, no SAE events occurred

Selective reporting (reporting bias)Low riskFull data on GSK website

NCT01192178

MethodsRandomized, double-blind, 16 week parallel-group study in paediatric subjects from 02 August 2010-16 December 2010 at 39 centers in the USA.


ParticipantsPopulation: 339 children (age 4 to 11 years) with persistent asthma who were symptomatic on an inhaled corticosteroid (ICS).

Baseline characteristics: 22% were aged 4 to 5 years and 78% 6 to 11 years. Spacers were used by 78% of children at baseline.

Inclusion criteria: Male and female subjects 4 to 11 years of age diagnosed with asthma requiring an ICS for control of asthma. Subjects were required to have an AM PEF ≥ 70% of predicted value at the screening visit. Subjects also had to have a history of at least 1 exacerbation of asthma during the previous respiratory viral season, that required the use of out-patient systemic corticosteroids or an urgent-care visit, emergency room visit, or hospitalisation.

Exclusion criteria: life-threatening asthma, unstable asthma, evidence of concurrent respiratory disease, history of any upper or lower respiratory tract infection within 4 weeks of randomisation that required the use of an antibiotic or accompanied by worsening asthma, or other clinically significant medical conditions.


Interventions1, Fluticasone propionate/salmeterol Diskus 100/50 mcg, one inhalation twice daily

2. Fluticasone propionate Diskus 100 mcg, one inhalation twice daily, for 16 weeks.


OutcomesPrimary outcome: number of exacerbations of asthma during the double blind period. There were no deaths and two children suffered SAEs on fluticasone propionate/salmeterol (one was status asthmaticus) and on child suffered an SAE (syncope) on fluticasone propionate.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Low risk"Double blind"

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk86% completed treatment in both groups

Selective reporting (reporting bias)Low riskFull data on GSK website

Nelson 2003

MethodsRandomized, double-blind, active-controlled, parallel-group study over 12 weeks at 33 centres in the USA. Run-in 2 weeks, (run-in was single blind placebo).


ParticipantsPopulation: 283 adolescents and adults  (12 to 77) years with asthma.  

Baseline Characteristics: Mean age 32 years. FEV1 66% predicted.

Concomitant ICS used by 0% of participants. 

Inclusion Criteria: At least 12 years old and a medical history of asthma (as defined by the ATS) requiring asthma pharmacotherapy for at least 6 months, FEV1 % predicted between 40% to 85%, bronchodilator reversibility by an increase of at least 15%  in FEV1 over baseline within 30 minutes after 2 inhalations of inhaled albuterol (180 mcg)  

Exclusion Criteria: History of life-threatening asthma; hypersensitivity reaction to sympathomimetic drugs or corticosteroids; smoking within the previous year or a history of > 10 pack-years; use of oral, inhaled or injectable corticosteroid therapy within the previous month; use of intranasal corticosteroid therapy except for Flonase (GlaxoWellcome Inc.); use of daily oral corticosteroid treatment within the previous 6 months; use of any other prescription or over-the-counter medication that could have affected the course of asthma or interacted with sympathomimetic amines; abnormal chest x-ray films; clinically significant abnormal 12-lead electrocardiograms (ECGs); or a history of significant concurrent disease (e.g., glaucoma, diabetes, hypertension).


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg HFA BD
  2. Fluticasone propionate 100 mcg CFC BD
  3. Salmeterol 502 mcg CFC BD (not considered in this review)


Delivery was MDI.


OutcomesPrimary efficacy measures were area under the serial FEV1 curve for 12 hours following administration of study medication and change from baseline at endpoint in morning pre-dose  FEV1.

The paper reports "no serious drug related adverse events".


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk257/283 (91%) completed the study

Selective reporting (reporting bias)Low riskFull data on GSK website

Pearlman 2004

MethodsRandomized, double-blind, active-controlled, parallel-group study over 12 weeks at 36 centers in the US and 1 center in Puerto Rico.


ParticipantsN = 360. Fluticasone propionate/salmeterol arm N = 92, fluticasone propionate arm N = 89.
Population: Males and females 12 years of age or older, with a diagnosis of asthma using the ATS definition were screened. All subjects were required to have a FEV1 of 40% to 85% predicted normal and > 15% reversibility following 2 puffs of ventolin at screening. The study population was stratified according to whether or not subjects were treated with ICS or inhaled beta2-agonists at screening (salmeterol or short-acting beta2-agonists only). Subjects treated with ICS must have been treated for at least 3 months prior to Visit 1 and receiving a daily dose of: 252-336 mcg beclomethasone dipropionate, 600-800 mcg triamcinolone acetonide, 1000 mcg flunisolide, 400-600 mcg budesonide, 176 mcg fluticasone propionate inhalation aerosol or 200 mcg fluticasone propionate inhalation powder for at least one month prior to Visit 1 with no change in regimen. Eligible subjects using only, as-needed, short-acting beta-agonist therapy were required to have received treatment for at least 1 week prior to Visit 1 and have a 7 day total symptom score >7 for the 7 days prior to Visit 2. Eligible subjects using salmeterol at baseline were required to have received salmeterol and as-needed, short-acting beta2-agonists only for at least one week prior to Visit 1.

No details on distribution between the groups provided. Participants described as symptomatic. Baseline medication: prn SABA alone: 142; salmeterol: 84; ICS: 134 (37%).


Interventions1. Fluticasone propionate/salmeterol 100/50 mcg BD

2. Fluticasone 100 mcg BD

The other arms were not used for this review.


OutcomesPaper reports no serious drug-related adverse events.
Website: SAS3003. No fatal SAE in the fluticasone propionate/salmeterol or fluticasone propionate group. One tachyarrhythmia on fluticasone propionate.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk279/360 (77%) completed study

Selective reporting (reporting bias)Low riskData on GSK website

Renzi 2010

MethodsA 24 week, multicentre, randomised, double-blind, parallel group trial to compare the efficacy and tolerability of salmeterol/fluticasone propionate (ADVAIR®) Diskus inhalation device 50/100 mcg bid with fluticasone propionate Diskus inhalation device 100 mcg bid as initial maintenance treatment in adult and adolescent subjects with symptomatic, persistent asthma not controlled on short-acting bronchodilators alone.


ParticipantsPopulation: 532 adults and adolescents (12+) years with a documented history of asthma treated with SABA only.

Inclusion Criteria: Male and female patients aged > 12 years with a documented history of asthma treated with SABA only and with FEV1 > 80% predicted were eligible for recruitment to the 2-week run-in period. They were recruited to the trial if they were symptomatic for the last 7 days of run-in on SABA alone.

Exclusion Criteria: Key exclusion criteria were the use of asthma controller

medications in the previous month or systemic corticosteroids in the previous 12 weeks; exacerbation requiring either emergency room treatment in the previous 6 weeks or hospitalisation in the previous 12 weeks; and smoking history of > 10 pack years.


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD
  2. Fluticasone 100 mcg  BD


Delivery device Diskus


OutcomesChange in morning PEF over 24 weeks. SAE fully reported in paper and GSK web report (SAS40068).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"Double blind"

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk53/262 lost to follow-up on fluticasone propionate/salmeterol and 46/270 on fluticasone propionate (Withdrawn due to adverse events 6 and 11 respectively)

Selective reporting (reporting bias)Low riskSAE fully reported in paper and GSK web report (SAS40068)

Rojas 2007

MethodsA randomised, double-blind, multicenter, parallel-group study over 12 weeks from February 2003 to September 2003 at 48 centres worldwide (Argentina (4), Czech Republic (8), France(9), Israel (4), Italy (9), Poland(4), Slovakia (6), Turkey (4)). Run-in 2 weeks.


ParticipantsPopulation: 362 adolescents and adults (12to 78) years with moderate persistent asthma.

Baseline Characteristics: Mean age 41 years. FEV1 72% predicted. Concomitant ICS used by 0% of participants.  

Inclusion Criteria:12 to 80 years with a documented clinical history of persistent asthma for at least 6 months and currently receiving inhaled short-acting beta2-agonists alone. FEV1 % predicted between 60% and 80%, bronchodilator reversibility by an increase of at least 15%  in FEV1 over baseline after 400 mcg salbutamol, or a mean morning PEF during the last 7 days of the run-in of less than 85% of the post-bronchodilator value, and a daytime symptom score of at least 2 on at least 4 of the last 7 days of the run-in.

Exclusion Criteria: Taken corticosteroids within 12 weeks, leukotriene receptor antagonists within 4 weeks or long acting inhaled or oral beta2-agonists, sodium cromoglycate, nedocromil sodium, ketotifen, methylxanthines, or inhaled anticholinergics within 2 weeks of entering the study, or had an acute asthma exacerbation requiring hospital treatment within 6 weeks, or had a respiratory tract infection within 4 weeks of entering the study, or a smoking history of more than10 pack-years.


Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD
  2. Fluticasone propionate 250 mcg BD


Delivery was Diskus inhaler


OutcomesPrimary efficacy variable was mean morning PEF.

Paper reports: "Only three serious adverse events occurred and none were considered related to study treatment."


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk350/362 (97%) completed the study

Selective reporting (reporting bias)Low riskFull data on GSK website

SAM30007

MethodsA randomised, double-blind, multi centre, parallel-group study over 30 weeks from September 2000 to May 2002 at 5 centres in Denmark. Run-in 2 weeks.

A comparative investigation of the corticosteroid-saving potential of the combination therapy fluticasone propionate and salmeterol (SERETIDE) compared with fluticasone propionate alone, given to adult asthmatic subjects, when reducing the inhaled corticosteroid dose from an initially high level of 500 mcg bd.


ParticipantsPopulation: 61 adults (18 + ) with stable asthma.  

Baseline Characteristics: Mean age 37 years. FEV1 not reported % predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: At least18 years old with a clinical diagnosis of stable asthma, treated with 1500-2000 mcg of budesonide, beclomethasone dipropionate or flunisolide, or 750 to 1000 mcg of fluticasone propionate for at least 10 weeks prior to the study. FEV1 % predicted at least 60%, need to  be able to use the data capture method (electronic diary, AM-2) correctly. 

Exclusion Criteria: not reported


Interventions
  1. Fluticasone propionate/salmeterol 500/50, 250/50 or 100/50 mcg BD
  2. Fluticasone propionate 500, 250 or 100 mcg BD


OutcomesThe primary efficacy endpoint was the minimum dose at which the subject’s asthma remained controlled ? the minimum acceptable dose (MAD).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk55/61 (90%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

SAM40004

MethodsA multicentre, randomised, double-blind, placebo-controlled parallel group study to compare the effect on airway inflammation and remodelling of treatment with salmeterol/fluticasone propionate combination product (50/100 mcg strength) bd via the Accuhaler inhaler, or fluticasone propionate 100 mcg bd via the Accuhaler inhaler or placebo via the Accuhaler inhaler for 16 weeks, followed by double-blind treatment for 52 weeks with the salmeterol/fluticasone propionate combination product (50/100 mcg strength) bd via the Accuhaler inhaler or fluticasone propionate 100 mcg bd via the Accuhaler inhaler, in adults with reversible airways obstruction (SIRIAS - Seretide in Inflammation and Remodelling In Asthma Study).


ParticipantsPopulation: 63 adults (18 to 50) with mild asthma. 

Baseline Characteristics: Mean age 32 years. FEV1 unknown % predicted. Concomitant ICS used by unknown % of participants, but all withdrawn during the run-in period.  

Inclusion Criteria: Aged 18 to 50 years with a history of reversible airways obstruction, to have received short-acting beta2- agonist alone or Beclometasone dipropionate or budesonide at a constant daily dose of up to 400 mcg per day (excluding any CFC-free formulation) or fluticasone propionate at a constant daily dose of up to 200 mcg per day via any device for at least 4 weeks prior to the first visit. In addition subjects were to have had a fall in FEV1 of at least 20% with a histamine challenge test at the first visit and have a post-bronchodilator FEV1 of > 60% of predicted normal. To be randomised subjects had to have a fall in FEV1 of at least 20% with a standardised histamine challenge test, AND at least one of the following criteria: have recorded symptoms on at least 4 of the last 7 days of the preventer-free run-in period; have recorded using their inhaled short-acting beta2 -agonist on at least 2 occasions on at least 4 of the last 7 days of the preventer-free run-in period; have a period variation of at least 10% over the last 7 days of the preventer-free run-in period. 

Exclusion Criteria: not reported.


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD throughout
  2. Placebo initially and then fluticasone propionate/salmeterol 100/50 mcg BD
  3. Fluticasone propionate 100 mcg BD throughout


Delivery as DPI.


OutcomesOutcome: The primary efficacy endpoint was the  level of airway hyper-reactivity (as measured by histamine PC20) and response of the induced airway spasm to bronchodilator (post-bronchodilator FEV1)

SAE data were used for the 52 week extension period as reported. There were no SAEs reported in the 16 week initial period.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
High risk37/63 (59%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

SAM40008

MethodsA multicentre, randomised, double-blind, parallel group comparison of the efficacy of SERETIDE* bd and fluticasone propionate bd (Both Via Diskus*/ACCUHALER*, Inhaler) when tapering the inhaled corticosteroid dose in asthmatic adults.

Carried out over 26 weeks from May 2000 to July 2001 at 34 centres in 10 countries (Australia, Estonia, Finland, France, Germany, Israel, Latvia, New Zealand, Spain, the United Kingdom)


ParticipantsPopulation: 186 adults (18+) with persistent asthma. 

Baseline Characteristics: Mean age 50 years.  FEV1 unknown % predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: 18 years or older with documented evidence of asthma within the previous 2 years and who were receiving 1500 to 2000 mcg/day of BUD or equivalent ICS, excluding fluticasone propionate, for at least 3 months prior to the start of baseline. 

Exclusion Criteria: not reported


Interventions
  1. Fluticasone propionate/salmeterol 500/50 mcg BD
  2. Fluticasone propionate 500 mcg BD


Delivery as DPI.


OutcomesThe primary efficacy endpoint was the minimum acceptable daily dose of ICS.


NotesHigh drop-out rate. Only 8% completed the study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
High riskonly 14/186 (8%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

SAM40012

MethodsA  randomised, double-blind, double-dummy, multi centre, parallel-group study over 24 weeks from June 2000 to June 2001 at 38 centres in 7 countries (Bulgaria, Hungary, Israel, Poland, Russia, Spain, the United Kingdom). Run-in 2 weeks.

A comparison of three treatments : 1) salmeterol/fluticasone propionate (SFC) (50/100 mcg strength) bd via Diskus/ACCUHALER inhaler, 2) fluticasone propionate 200 mcg bd via Diskus/ACCUHALER inhaler, 3) fluticasone propionate 100 mcg bd via Diskus/ACCUHALER inhaler in children aged 4-11 years with asthma.


ParticipantsPopulation: 548 children (4 to 11) with asthma.

Baseline Characteristics: Mean age 8 years.  FEV1 not reported % predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: Aged 4-11 years, inclusive, with documented evidence of asthma and receiving BDP, BUD or equivalent at a dose of 400-500 mcg/day or fluticasone propionate at a dose of 200-250 mcg/day for at least 4 weeks before Visit 1. Recorded a symptom score (i.e. total score of daytime and night-time scores) on the electronic daily record card of at least 2 on at least 3 of the last 7 consecutive days of the run-in period and had a mean morning PEF (calculated from the last 7 days of the run-in period) of between 50% and 85% of the PEF measured 15 minutes after administration of 400 mcg of salbutamol at the randomisation visit. In addition, subjects had to have recorded at least 70% of data into their electronic daily record cards. 

Exclusion Criteria: not reported.


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD
  2. Fluticasone propionate 100 mcg BD
  3. Fluticasone propionate 200 mcg BD


Delivery was Diskus device (third arm not used in this review)


OutcomesThe primary efficacy endpoint was the percentage of combined symptom-free days and nights during weeks 1-24.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk513/548 (94%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

SAM40031

MethodsA one year, randomised, double-blind, parallel-group comparison of the efficacy of Seretide (fluticasone propionate/salmeterol combination Accuhaler) and Flixotide(fluticasone propionate Accuhaler) when down-titrating the inhaled corticosteroid dose in asthmatic adults who have previously received Seretide 500/50 mcg twice daily for at least 4 weeks

A study over 52 weeks from March 2002 to February 2006 at 3 centres in Australia.


ParticipantsPopulation: 82 adolescents and adults (18 to 80) with asthma. 

Baseline Characteristics: Mean age 47 years. FEV1 unknown % predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: Aged between 18 and 80 years with a clinical diagnosis of asthma according to ATS criteria for at least 6 months prior to enrolment, currently receiving fluticasone propionate/salmeterol, either via dry powder inhaler or metered dose inhaler (with or without spacer) at a dose of 500/50 mcg bd or 250/25mc 2 inhalations bd for a minimum of 4 weeks prior to enrolment. 

Exclusion Criteria: not reported


Interventions
  1. Fluticasone propionate/salmeterol 500/50, 250/50 or 100/50 mcg BD (Reduced incrementally)
  2. Fluticasone propionate 500, 250 or 100 mcg BD (Reduced incrementally)


Delivery was DPI.


OutcomesThe primary efficacy endpoint was the average daily fluticasone propionate dose (mcg/day) from week 0 to completion/withdrawal, including study medication and exacerbation medication.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk60/82 (73%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

SAM40065

MethodsA randomised, double-blind, double-dummy, multicentre, parallel-group study for 40 weeks from January 2003 to October 2004 at 44 centres (United States (39), Brazil (3), Bulgaria (2)). Run-in 2 weeks.

A comparison of asthma control using bronchial hyper responsiveness as an additional guide to long-term treatment in adolescents and adults receiving either fluticasone propionate/salmeterol Diskus BID or fluticasone propionate Diskus BID (or placebo BID if asymptomatic).


ParticipantsPopulation: 449 adults (12 + years) with asthma. 

Baseline Characteristics: Mean age 34 years. FEV1 not reported % predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: 12 years of age or older, with a diagnosis of asthma, as defined by the ATS, for at least 3 months prior to visit 1 and must have been treated with a short-acting beta2-agonist, an anticholinergic, or an allowed ICS at a fixed dosing regimen (within an allowed total daily dose) for at least 4 weeks prior to the screening visit. FEV1 % predicted between 60% to 95%, bronchodilator reversibility by an increase of at least 12% in FEV1 over baseline within 30 minutes following 2 puffs of albuterol inhalation aerosol at the screening visit.  Documentation of historical reversibility within 24 months was allowed. 

Exclusion Criteria: History of life-threatening asthma, current unstable asthma, current respiratory tract infection or clinically significant concurrent disease that would put the subject at risk during the study if the condition exacerbated.


Interventions
  1. Fluticasone propionate/salmeterol 100/50, 250/50 or 500/50 mcg BD
  2. Fluticasone propionate 100, 250 or 500 mcg BD (BHR strategy)
  3. Fluticasone propionate 100, 250 or 500 mcg  BD (Reference strategy)


Delivery was Diskus device (third arm not used in this review)


OutcomesThe primary efficacy endpoint was the average ICS treatment dose over the treatment period.


NotesSAE data included run-in.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk322/449 (72%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

SAS30021

MethodsA stratified, randomised, double-blind, placebo-controlled, parallel-group study for 12 weeks from November 2001 to February 2004 at 164 centres (United States (153), Latin America(11))

A Stratified, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 12-Week Trial Evaluating the Safety and Efficacy of the Fluticasone Propionate/salmeterol Diskus Combination Product 100/50 mcg Once Daily Versus Fluticasone Propionate Diskus 100 mcg Once Daily and Placebo in Symptomatic Pediatric Subjects (4-11 Years) With Asthma


ParticipantsPopulation: 908 children(4 to 11) with asthma. 

Baseline Characteristics: Mean age 8 years. FEV1 not reported % predicted. Concomitant ICS used by 0% of participants.  

Inclusion Criteria: 4-11yrs of age with a diagnosis of asthma for at least 6 months and treated with short-acting beta2-agonists only or non-ICS controller medications for at least one month prior to screening. FEV1 % predicted between 50% to 85%, bronchodilator reversibility by an increase of at least 15% in FEV1 over baseline within 30 minutes following 2 puffs of albuterol at screening. At the randomisation visit, subjects were required to demonstrate AM PEF reproducibility of +15% of the screening visit pre-albuterol PEF, demonstrate a PM PEF 50 to 90% of predicted normal, and have either an asthma symptom score of at least 2 on 4 or more days in the week prior to randomisation, or have used albuterol on at least 4 days in the week prior to randomisation.

Exclusion Criteria: Not reported


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg QD
  2. Fluticasone propionate 100 mcg QD


Delivery was Diskus device


OutcomesThe primary efficacy endpoint was the change from Baseline in % predicted PM Peak Expiratory Flow (PEF) over Weeks 1-12


NotesOnce daily dose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk715/908 (79%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

SAS30022

MethodsA randomised, double-blind, placebo-controlled, parallel-group study for 12 weeks from November 2001 to June 2003 at 121 centres. (US (103), Canada (18)).

A trial evaluating the efficacy and safety of the fluticasone propionate/salmeterol Diskus combination product 250/50 mcg once daily versus fluticasone propionate/salmeterol Diskus combination product 100/50 mcg twice daily versus fluticasone propionate Diskus 250 mcg once daily versus placebo in symptomatic adolescent and adult subjects with asthma that is not controlled on short acting beta2-agonists alone


ParticipantsPopulation: 844 adolescents and adults (12 + years ) with asthma that was not controlled on short-acting beta2-agonists alone. 

Baseline Characteristics: Mean age 33 years. FEV1 not reported % predicted. Concomitant ICS used by 0% of participants.

Inclusion Criteria: 12 years of age or older with a diagnosis of asthma for at least 3 months and treated with short-acting beta2-agonists only for at least 1 month prior to screening. FEV1 % predicted between 50% to 85%, bronchodilator reversibility by an increase of at least 15% in FEV1 over baseline within 30 minutes following 2 puffs of albuterol at screening.

At the randomisation visit, subjects were required to demonstrate FEV1 reproducibility of ±15% of the screening visit pre-ventolin FEV1, demonstrate a PM PEF 50 to 90% of predicted normal, and have either an asthma symptom score of at least 2 on 4 or more days in the week prior to randomisation, or have used ventolin on at least 4 days in the week prior to randomisation. 

Exclusion Criteria: not reported


Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg QD
  2. Fluticasone propionate/salmeterol 100/50 mcg BD
  3. Fluticasone propionate 250 mcg QD


(Second arm not used in this review)


OutcomesPrimary outcome/efficacy variable was the change from baseline in % predicted PM PEF over weeks 1 to 12.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk698/844 (83%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

SAS30023

MethodsA randomised, double-blind, multicentre, placebo-controlled, parallel-group study over 12 weeks from April 2002 to April 2003 at 69 centres in 9 countries (Australia, France, UK, Hungary, Ukraine, Italy, Philippines, Thailand, Russia).

A study to compare the efficacy and tolerability of fluticasone propionate/salmeterol combination (SERETIDE/VIANI/ADVAIR) 88/42 mcg once daily in the morning with fluticasone propionate 88 mcg once daily in the morning and placebo (short-acting beta2-agonist as required only) once daily in the morning, all via the HFA MDI as initial maintenance therapy in mild asthmatic subjects.


ParticipantsPopulation: 464 adolescents and adults (12 to 80) with mild asthma. 

Baseline Characteristics: Mean age 34 years. FEV1 not reported % predicted. Concomitant ICS used by 0% of participants. 

Inclusion Criteria: a documented clinical history of asthma for at least 6 months who were currently receiving short-acting beta2-agonists alone.

Exclusion Criteria: Not reported.


Interventions
  1. Fluticasone propionate/salmeterol 50/25 mcg two puffs once daily
  2. Fluticasone propionate 50 mcg two puffs once daily


Delivery was MDI device with HFA propellant.


OutcomesThe primary efficacy endpoint was the morning PEF.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk433/464 (93%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

SAS40036

MethodsA randomised, double-blind, double-dummy, multicenter, parallel-group study for 16 weeks from October 2001 to May 2003 at 85 centres in the United States. Run-in 2 weeks.


ParticipantsPopulation: 331 adolescents and adults(15+ years old) with persistent asthma.

Baseline Characteristics: Mean age 41 years. FEV1 not reported (% predicted). Concomitant ICS used by 100% of participants.  

Inclusion Criteria: 15 years of age or older, with a diagnosis of asthma, as defined by the ATS, for at least 6 months prior to visit 1 and must have been treated with an allowed ICS at a fixed dosing regimen (within an allowed total daily dose) for at least four weeks prior to the screening visit. FEV1 % predicted between 40% to 85%, bronchodilator reversibility by an increase of at least 12% in FEV1 over baseline within 30 minutes following 2 to 4 puffs of albuterol inhalation aerosol at the screening visit. Documentation of historical reversibility within 24 months was allowed. 

Exclusion Criteria: Not reported 


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD
  2. Fluticasone propionate 100 mcg BD


Delivery was Diskus device (other arms of trial not considered for this review)


OutcomesThe primary efficacy endpoint was the mean change from baseline at endpoint in morning PEF


NotesNo SAEs at all reported in double blind phase of the study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk243/331 (73%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

SAS40037

MethodsA randomised, double-blind, double-dummy, multicenter, parallel-group study for 16 weeks from October 2001 to May 2003 at 87 centres in the United States. Run-in 2 weeks.


ParticipantsPopulation: 331 adolescents and adults (15+ years old) with persistent asthma.

Baseline Characteristics: Mean age 41 years. FEV1 not reported (% predicted). Concomitant ICS used by 100% of participants.  

Inclusion Criteria: 15 years of age or older, with a diagnosis of asthma, as defined by the ATS, for at least 6 months prior to visit 1 and must have been treated with an allowed ICS at a fixed dosing regimen (within an allowed total daily dose) for at least 4 weeks prior to the screening visit. FEV1 % predicted between 40% to 85%, bronchodilator reversibility by an increase of at least 12% in FEV1 over baseline within 30 minutes following 2 to 4 puffs of albuterol inhalation aerosol at the screening visit. Documentation of historical reversibility within 24 months was allowed. 

Exclusion Criteria: Diagnosed with life-threatening asthma, hospitalised for asthma within the previous 6 months, had a concurrent respiratory disease, or had intermittent or seasonal asthma alone, had a respiratory tract infection or used antibiotics for the treatment of a suspected or diagnosed respiratory tract infection within 14 days of visit 1.


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD
  2. Fluticasone propionate 100 mcg BD


Delivery was Diskus device (other arms of trial not considered for this review)


OutcomesThe primary efficacy endpoint was the mean change from baseline at endpoint in morning PEF.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk230/322 (71%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

SAS40068

MethodsA randomised, double-blind, multicenter, parallel-group study for 24 weeks from October 2002 to February 2004 at 58 centres in Canada.

A trial to compare the efficacy and tolerability of salmeterol/fluticasone propionate (ADVAIR) Diskus inhalation device 50/100 mcg bid with fluticasone propionate Diskus inhalation device 100 mcg bid as initial maintenance treatment in adult and adolescent subjects with symptomatic, persistent asthma not controlled on short-acting bronchodilators alone.


ParticipantsPopulation: 532 adolescents and adults(12+ years ) with symptomatic, persistent asthma. 

Baseline Characteristics: Mean age 35 years. FEV1 not reported % predicted. Concomitant ICS used by 0% of participants.  

Inclusion Criteria: 12 years of age or older with symptomatic, persistent mild asthma (defined as FEV1 at least 80% predicted and over the last 7 consecutive days of run-in, had an asthma symptom score of 2, or more on at least 3 days or disruptions of normal sleep patterns on 2 or more occasions, or had used rescue bronchodilator medication on 4 or more days), and treated with inhaled short-acting bronchodilators alone 

Exclusion Criteria: Taken any other asthma therapy (e.g. ICS, leukotriene modifiers, inhaled long-acting beta2-agonists) within 1 month prior to screening, had a smoking history of 10 pack-years or more, or had an acute asthma exacerbation requiring emergency room treatment within the last 6 weeks or hospitalisation within the last 12 weeks prior to screening.


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD
  2. Fluticasone propionate100 mcg BD


Delivery was Diskus device


OutcomesThe primary efficacy endpoint was the change from baseline in daily record card (DRC) mean morning PEF over 24 weeks.

One death due to aorta hypoplasia and ventricular hypertrophy on fluticasone.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk433/532 (81%) completed the study

Selective reporting (reporting bias)Low riskData in GSK website

SFA103153

MethodsA randomised, double-blind,multicenter, parallel-group study for 52 weeks from November 2004 to April 2007 at 59 centres in the United States. Run-in 4 weeks.


ParticipantsPopulation: 475 adolescents and adults(12 to 65) of African descent with persistent asthma. 

Baseline Characteristics: Mean age 32 years. FEV1 78% predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: Subjects were of African descent, 12 to 65 years of age with persistent asthma, and were symptomatic while taking an ICS.

Exclusion Criteria: Not reported. 


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD
  2. Fluticasone propionate 100 mcg BD


Delivery was Diskus device


OutcomesThe primary efficacy endpoint was asthma exacerbation rate per subject per year.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk320/475 (67%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

SFCF4026

MethodsA randomised, double-blind, multicenter, parallel-group study for 24 weeks from May 2002 to November 2003 at 124 centres in France. Run-in 8 weeks.

Maintenance of asthma control in adults: comparison of three therapeutic strategies in patients whose asthma is controlled by a medium dose of inhaled corticosteroid and a long-acting inhaled beta2-agonist.


ParticipantsPopulation: 476 adolescents and adults(18+ years) with asthma.

Baseline Characteristics: Mean age 45 years. FEV1 not reported % predicted. Concomitant ICS used by 100% of participants.

Inclusion Criteria: 18 years of age or older with a documented history of asthma (for at least 6 months) and whose asthma was controlled with the current treatment (inhaled corticosteroid at a dose of 1000 mcg of CFC beclomethasone dipropionate or equivalent and a long-acting beta2-agonist at recommended dose) at stable dose for at least 4 weeks prior to the run-in period. Randomized if fulfilled the following criteria: at least 2 of the following: diurnal symptoms at least 2 days per week, use of rescue short-acting bronchodilator no more than 2 days per week and no more than 4 occasions per week, PEF at least 80 % predicted every day. Plus all the following criteria: no night-time awakenings due to asthma, no exacerbations, no emergency visits, no treatment-related adverse events enforcing a change in asthma therapy. 

Exclusion Criteria: For entry in the run in period:smoking history of ten pack-years or more, respiratory tract infection during the last 4 weeks prior to visit 1 (the last 2 weeks after amendment number 1), acute asthma exacerbation requiring emergency room treatment or hospitalisation within 4 weeks prior to visit 1, use of oral/parenteral corticosteroids during the last 4 weeks prior to visit 1 or any change in maintenance treatment, use of depot corticosteroid within 12 weeks of visit 1. For entry into the treatment period: changes in asthma medication (excluding study rescue medication), use of oral/parenteral or depot corticosteroids, respiratory tract infection, insufficient asthma control, according to daily record card, asthma control questionnaire and investigator’s judgement to allow a reduction in maintenance treatment.


Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD
  2. Fluticasone propionate/salmeterol 100/50 mcg BD
  3. Fluticasone propionate 250 mcg BD


Delivery was Diskus device (arm two not used in this review)


OutcomesThe primary efficacy endpoint was the morning PEF over the first 12 weeks of the treatment period.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk413/476 (87%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

Shapiro 2000

MethodsMulticentre study, USA


Participants349 adults and adolescents randomised (4 treatment arm study; fluticasone propionate/salmeterol: 84; fluticasone propionate: 84. Data from 13 participants excluded from the analysis due to poor procedure at one site).

Inclusion criteria: ≥ 12 years; ATS defined asthma of ≥ 6 months duration requiring pharmacotherapy for at least 6 months; FEV1 between 40 and 85% predicted; ≥ 15% increase in FEV1 30 mins after 2 puffs of albuterol; use of ICS 12 weeks prior to the study.

Exclusion criteria: Females with negative pregnancy tests; life-threatening asthma; hypersensitivity to sympathomimetic drugs/steroids; smoking within previous year; smoking history of > 10 pack-years; use of oral/injectable steroid therapy within 1 month of study; use of daily oral steroids within 6 months prior to the study; use of any prescription or over the counter medication that could have affected asthma or course of treatment; abnormal chest x-ray; clinically significant abnormal 12-lead electrocardiogram or history of concurrent disease.


Interventions1. Fluticasone propionate/salmeterol 250/50 bd

2. Fluticasone 250 bd

Third arm not used in this review


Outcomes83% completed study in fluticasone propionate/salmeterol arm and 73% in fluticasone propionate arm.
Paper reports "no serious drug-related adverse events. Two patients treated with salmeterol withdrew from the study because of adverse events; however, these adverse events were considered by the investigator to be unrelated to study drug (bilateral subcapsular cataracts and postsurgical infection)."
Website SFCA3003: no fatal adverse events. No serious adverse events in fluticasone propionate/salmeterol arm; one in fluticasone propionate arm (Asthma exacerbation).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk131/168 (78%) completed the study

Selective reporting (reporting bias)Low riskFull data on GSK website

SLGF75

MethodsA randomised, double-blind, multicenter, parallel-group study for 12 weeks from January 1998 to December 1998 at 7 centres in Italy. Run-in 4 weeks, follow-up 2 weeks.

Salmeterol plus low-dose fluticasone propionate versus high-dose fluticasone propionate in naive patients with mild to moderate asthma: effects on pulmonary function, and inflammatory markers of induced sputum


ParticipantsPopulation: 46 adolescents and adults(16 to 65 ) with mild to moderate asthma.

Baseline Characteristics: Mean age 39 years. FEV1 unreported % predicted. Concomitant ICS used by 0% of participants.  

Inclusion Criteria: performed on three study visits.

Pre-study visit: all subjects with asthma disease for at least 6 months, 

Visit 2: 16 to 65 years old with asthma at moderate level (score of severity at least 6), did not use anti-inflammatory drugs for last month before visit 1, FEV1 % predicted at least 60%, eosinophils at least 5% in induced sputum. 

Visit 4: bronchial asthma assessed up to 6 (severity classes value) and with persistence of eosinophils at least 5% (or at least 3% in sites where an amendment was applicable) in induced sputum.

Exclusion Criteria: Inhaled steroids or cromones in last 3 months, more than 1 short course of oral steroids in last 3 months or 1 short course of oral steroids in last month before pre-study visit; respiratory tract infection in the last 1 month pre-study visit, with lung or other important disease, or on beta-blocker therapy; hypersensitivity to beta2-agonist and suspected to abuse drug or alcohol.


Interventions
  1. Fluticasone propionate 100 + salmeterol 50 mcg BD
  2. Fluticasone propionate 100 mcg BD
  3. Fluticasone propionate 250 mcg BD


Delivery was Diskus (third arm not used in this review)


OutcomesThe primary efficacy endpoint was the daily morning PEF.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk42/46 (91%) completed the study

Selective reporting (reporting bias)Low riskData on GSK website

Strand 2004

MethodsA randomised, double-blind, comparative, multicenter, parallel-group study over 12 weeks from May 2001 to September 2002  at 45 centres in Denmark. Run-in 2 weeks.


ParticipantsPopulation: 150 adults with persistent asthma 

Baseline Characteristics: Mean age 39 years. PEF 80% predicted. Concomitant ICS used by 0% of participants. 

Inclusion Criteria: At least 18 years old and an asthma medical history of at least 3 months, either diurnal PEF variation ?20% on at least 2 days or one of the following must have been determined within 3 years prior to baseline: FEV1 reversibility ?15% in response to bronchodilator, provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) less than 4 mg/mL, diurnal PEF variation at least 20%; mean relief medication (albuterol) use at least 1 episode/week; and day or night symptom score 1 or more at least once/week. 

Exclusion Criteria: Upper or lower respiratory tract infection or middle ear infection within 1 month prior to visit 1; other lung diseases than asthma; known or suspected other diseases or situations likely to affect the outcome of the study results;  known serious cardiovascular disease, diabetes mellitus, untreated hypokalaemia, or thyrotoxicosis; use of long-acting bronchodilators, ICS, or other long-acting asthma medication within 2 months prior to visit 1; use of daily oral corticosteroid treatment within 2 months of visit 1 or oral corticosteroid therapy within 1 month prior to visit.


Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD
  2. Fluticasone propionate 100 mcg BD


OutcomesThe primary efficacy variable was symptom-free days and nights.

"1 patient in the fluticasone propionate/salmeterol group and 2 patients in the fluticasone propionate group had a serious adverse event. None of these serious adverse events was considered related to the study drug."

One death reported on the website in the fluticasone propionate/

arm but no cause given.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk126/150 completed study

Selective reporting (reporting bias)Low riskFull data from GSK website

van Noord 2001

MethodsA randomised, double-blind, double-dummy, multicenter, placebo-controlled, parallel-group study over 3 months from December 1997 to March 1999 at 61 centres in 13 countries. Run in 2 weeks.


ParticipantsPopulation: 509 adolescents and adults (12 to 82) years with moderate to severe asthma.

Baseline Characteristics: Mean age 47 years. FEV1 72% predicted. Concomitant ICS used by 100% of participants.

Inclusion Criteria:12 years old or more with a documented clinical history of reversible airways obstruction and symptomatic on ICS therapy (beclomethasone dipropionate, budesonide or flunisolide at a dose of 1500 to 2000 mcg/day or fluticasone propionate 750 to 1000 mcg day) for at least 4 weeks before the start of the study. FEV1 % predicted between 50% to 100%.

During the last 7 days of the run-in period, required to have had a mean morning PEF of > 50% and < 85% of PEF measured 15 minutes after administration of 400 mcg of salbutamol at the randomisation visit, and a cumulative total symptom score (daytime plus night-time) in the daily record card of at least 8.  

Exclusion Criteria: Received a long-acting beta2-agonist or oral beta2-agonist with 2 weeks of the run-in period, changed asthma medication, had a lower respiratory tract infection in the 4 weeks preceding the run-in period or had an acute asthma exacerbation requiring hospitalisation in the 12 weeks preceding study entry. 


Interventions
  1. Fluticasone propionate/salmeterol 500/50 mcg HFA BD via MDI
  2. Fluticasone propionate/salmeterol 500/50 mcg HFA BD via Diskus
  3. Fluticasone propionate 500 mcg  CFC BD via MDI


OutcomesPrimary efficacy variable was the mean morning PEF over the 12-week treatment period.

Paper reports eight patients with SAE in fluticasone propionate/salmeterol groups and 2 on fluticasone propionate. These included 3 asthma exacerbations. Web report indicates that 2 of these were on fluticasone propionate/salmeterol and one on fluticasone propionate.

One death report on fluticasone propionate/salmeterol via MDI due to leukaemia


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, double-dummy

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk447/509 (88%) completed the study

Selective reporting (reporting bias)Low riskFull data on GSK website

Wallin 2003

MethodsA randomised, double-blind, parallel-group study over 12 weeks. Run-in 2 to 4 weeks.


ParticipantsPopulation: 56 asthmatics, previously not well-controlled on ICS 

Baseline Characteristics: Mean age 42 years. FEV1 88% predicted.

Concomitant ICS used by 100% of participants. 

Inclusion Criteria: Asthma symptoms on 6 or more days or 4 or more nights; need for rescue salbutamol on 6 or more days or 4 or more nights; greater than 20% variation between AM and PM PEF on 4 or more days; pulmonary function, one or more of: at least 15% increase in FEV1 15 mins after inhalation of 400 to 800 mcg salbutamol, at least 15% increase in PEF 15 mins after inhalation of 400 to 800 mcg salbutamol compared to the mean AM PEF values in the preceding week, more than 20% variation between AM and PM PEF on at least 4 consecutive days, PC20 methacholine < 4 mg/mL.

Exclusion Criteria: Not reported as such


Interventions
  1. Fluticasone propionate 200 + salmeterol 50 mcg BD
  2. Fluticasone propionate 200 mcg BD
  3. Fluticasone propionate 500 mcg BD (not used in this review)


Delivery was Diskus device


OutcomesPrimary end points were submucosal eosinophil and mast cell counts.

No information in paper but no SAEs reported on GSK website


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed

Incomplete outcome data (attrition bias)
All outcomes
Low risk46/56 (82%) completed the study

Selective reporting (reporting bias)Low riskSAE data on GSK website

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Adinoff 1998Not randomised to ICS

Adolfsson 2005Dose response study

Bateman 1998Device comparison

Bateman 2006Higher dose ICS in control arm

Baumgarten 20024 week study

Bergmann 2004Higher dose ICS in control arm

Bjermer 2000Salmeterol versus LTRA

Bjermer 2003Salmeterol versus LTRA

Bleecker 2006Salmeterol versus salmeterol/fluticasone

Bleecker 2007Review

Bleecker 2008Salmeterol versus LTRA

Bracamonte 2005Device comparison

Busse 2006Cross-over study

Calhoun 2001Salmeterol versus LTRA

Chapman 1999Device comparison

Condemi 1999Higher dose ICS in control arm

Cook 1998Higher dose ICS in control arm

D'Urzo 20016 week duration

Del 2001Salmeterol versus LTRA

Deykin 2007Comparison between different combined inhalers

Didier 1997No ICS control arm

Dorinsky 2004Comparison between different combined inhalers

Faurschou 19943 week cross-over study

Fish 2001Salmeterol versus LTRA

Fujimoto 2006Salmeterol versus tolobuterol

GlaxoSmithKline 2004Higher dose ICS in control arm

GlaxoSmithKline 2005aSalmeterol versus LTRA

GlaxoSmithKline 2005bHigher dose ICS in control arm

GlaxoSmithKline 2005cDevice comparison

GlaxoSmithKline 2005dHigher dose ICS in control arm

GlaxoSmithKline 2005eCross-over study

Greening 1994Higher dose ICS in control arm

Grutters 19998 week duration

House 20042 week duration

Ilowite 2004Salmeterol versus LTRA

Isabelle 2001Device comparison

Jarjour 2006FSC compared to higher dose FP

Johansson 2001Different ICS in control arm

Juniper 2002Different ICS in control arm

Kelsen 1999Higher dose ICS in control arm

Koopmans 2005Single dose study

Lazarus 2001Not randomised to ICS

Lemanske 2001Not randomised to ICS

Lotvall 2006Single dose study

Lundback 2000Different ICS in control arm

Martinat 2003Device comparison

Murray 1999Higher dose ICS in control arm

Nan 2004Different ICS in control arm

Nathan 2001Review of SAS30003 and SAS30004

Nelson 2000Salmeterol versus LTRA

Nelson 2001Salmeterol versus LTRA

O'Byrne 2005Different ICS in control arm

O'Connor 2004Salmeterol versus LTRA

Pauwels 1998Different ICS in control arm and salmeterol given in both groups

Pearlman 19994 week study

Peters 2007Higher dose ICS in control arm

Reddel 2010Down-titration study designed to allow uneven fluticasone dose between the two arms of the trial

Ringdal 2003Salmeterol versus LTRA

Rosenthal 1999No randomisation to ICS

Russell 1995No randomisation to ICS

SAM30002FSC compared to Budesonide at higher dose

SAM30013FSC compared with higher dose fluticasone

SAM40116Patients with asthma and COPD compared to higher dose fluticasone

SAS30015FSC compared to BDP

Schermer 2007Higher dose ICS in control arm

Schlosser 1998Device comparison

Scott 2005Device comparison

SLGA5021FSC comparison with higher dose fluticasone

Tonnel 2004Device comparison in acute asthma

Van den 2000Device comparison

Van Noord 1999Higher dose ICS in control arm

Vermetten 1999Higher dose ICS in control arm

Woolcock 1996Higher dose ICS in control arm

You-Ning 2005Device comparison

Zhong 2002Device comparison

Zhong 2005Comparison to different ICS in control arm

 
Characteristics of ongoing studies [ordered by study ID]
NCT01462344

Trial name or titleA 6-month Safety and Benefit Study of Inhaled Fluticasone Propionate/ Salmeterol Combination Versus Inhaled Fluticasone Propionate in the Treatment of 6,200 Pediatric Subjects 4-11 Years Old With Persistent Asthma

MethodsThe purpose of this study is to assess whether the risk of serious asthma-related events (asthma-related hospitalizations, endotracheal intubations, and deaths) in children 4-11 years old taking inhaled fluticasone propionate/salmeterol combination is the same as those taking inhaled fluticasone propionate alone.

The target enrolment is 6200 subjects. The expected completion date for accrual and the study remains unchanged from August 2016 and February 2017 respectively.

ParticipantsInclusion Criteria:

  1. Consent to participate in the study
  2. Age 4-11 years old
  3. Male or eligible female - Female subjects should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation
  4. Asthma diagnosis for at least 6 months
  5. Ability to answer questions regarding asthma control and use a metered dose inhaler and Diskus
  6. A history of clinical varicella infection or recipient of a varicella vaccine in countries where the product label includes a warning regarding more serious chickenpox infections in patients using corticosteroids.
  7. History of at least once occurrence of asthma exacerbation within the prior 12 months
  8. Currently being treated for asthma and no change in asthma therapy for the last 4 weeks (Eligible subjects include: subjects with use of short-acting beta-agonist, leukotriene receptor antagonist, theophylline, or cromolyn whose asthma is not well-controlled; subjects on low-dose ICS monotherapy whose asthma is not well-controlled; subjects on low-dose ICS and one or more adjunctive therapy whose asthma is either controlled or not well-controlled asthma; subjects on medium-dose ICS monotherapy whose asthma is either controlled or not well-controlled; and subjects on medium-dose ICS and one or more adjunctive therapy whose asthma is well-controlled)


Exclusion Criteria:

  1. History of life-threatening asthma
  2. Unstable asthma
  3. Current use of high-dose ICS or ICS/LABA therapy to treat asthma symptoms
  4. Concurrent respiratory disease: Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, cystic fibrosis, bronchopulmonary dysplasia, or other severe respiratory abnormalities other than asthma.
  5. Respiratory infection
  6. Subjects with only exercise-induced asthma
  7. An asthma exacerbation within the last 4 weeks or more than 4 separate exacerbations in the last 12 months
  8. Hospitalization for asthma within 4 weeks or more than 2 hospitalizations within the last 12 months
  9. Other current evidence of clinically significant uncontrolled disease/conditions of any body or organ system
  10. Neurological or psychiatric disease or history of drug or alcohol abuse of a subject or his/her guardian which in the opinion of the investigator could interfere with the subject's proper completion of the protocol requirements
  11. Participation in an interventional study or used any investigational drug for any disease state within the last 30 days
  12. Any adverse reaction including immediate or delayed hypersensitivity to any beta-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy, or vehicle contained within these medication
  13. Severe hypersensitivity to cow's milk proteins
  14. Administration of prescription or over the counter medications that would significantly affect the course of asthma, or interact with sympathomimetic amines such as: anti-IgE (omalizumab), anticonvulsants (barbiturates, hydantoins, carbamazepine); polycyclic antidepressants, beta-adrenergic blockers; phenothiazines, monoamine oxidase inhibitors, or diuretics
  15. Potent cytochrome P450 3A4 (CYP3A4) inhibitors within the last 4 weeks (e.g., ritonavir, ketoconazole, itraconzole)
  16. Affiliation with investigator's site, including a immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.
  17. A Child in Care (CiC) is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 twice daily
  2. Fluticasone propionate/salmeterol 250/50 twice daily
  3. Fluticasone propionate 100 twice daily
  4. Fluticasone propionate 250 twice daily


Delivery Device Diskus

OutcomesPrimary Outcomes

  • Time to first event in the composite endpoint of serious asthma-related outcomes (asthma-related hospitalizations, endotracheal intubations, or deaths) over the 6-month study treatment period
  • Time to first asthma exacerbation

Starting dateNovember 2011

Contact informationGSKClinicalSupportHD@gsk.com

NotesAs of April 24, 2012, 313 subjects have been randomised. The target enrolment is 6200 subjects. The expected completion date for accrual and the study remains unchanged from August 2016 and February 2017 respectively.

NCT01475721

Trial name or titleSAS115359, a Safety and Efficacy Study of Inhaled Fluticasone Propionate/Salmeterol Combination Versus Inhaled Fluticasone Propionate in the Treatment of Adolescent and Adult Subjects With Asthma

MethodsThe purpose of this study is to assess whether the risk of serious asthma-related events (asthma-related hospitalizations, endotracheal intubations, and deaths) in adolescents and adults (12 years of age and older) taking inhaled fluticasone propionate/salmeterol combination is the same as those taking inhaled fluticasone propionate alone.

ParticipantsInclusion Criteria:

  • Provided consent to participate in the study
  • Male or female, 12 years of age and older
  • Clinical diagnosis of asthma for at least 1 year prior to the randomisation
  • Clinic PEF of greater than or equal to 50% of predicted normal value
  • Subject must be appropriately using one of the treatments for asthma listed in the protocol
  • Subject must be able to complete the asthma control questionnaire, daily questions about asthma, and use a Diskus inhaler
  • Subject must have history of at least 1 asthma exacerbation including one of the following in the year prior to randomisation:
  • requiring treatment with systemic corticosteroids
  • an asthma-related hospitalisation


Exclusion Criteria:

  • History of life threatening asthma defined for this protocol as asthma episode that required intubation and/or was associated with hypercapnea requiring non-invasive ventilatory support
  • Concurrent respiratory disease other than asthma
  • Current evidence of, or ever been told by a physician that they have chronic bronchitis, emphysema, or chronic obstructive pulmonary disease.
  • Exercise induced asthma (as the only asthma-related diagnosis) not requiring daily asthma control medicine
  • Presence of a bacterial or viral respiratory infection that is not resolved at randomisation
  • An asthma exacerbation requiring systemic corticosteroids within 4 weeks of randomisation or more than 4 separate exacerbations in the 12 months preceding randomisation
  • More than 2 hospitalizations for treatment of asthma in the 12 months preceding randomisation
  • Subject must not meet unstable asthma severity criteria as listed in the protocol
  • Potent cytochrome P450 3A4 (CYP3A4) inhibitors within the last 4 weeks (e.g., ritonavir, ketoconazole, itraconzole)
  • Pregnancy, breast-feeding or planned pregnancy during the study
  • A Child in Care (CiC) is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 twice daily
  2. Fluticasone propionate/salmeterol 250/50 twice daily
  3. Fluticasone propionate/salmeterol 500/50 twice daily
  4. Fluticasone propionate 100 twice daily
  5. Fluticasone propionate 250 twice daily
  6. Fluticasone propionate 500 twice daily


Delivery Device Diskus

OutcomesPrimary Outcome Measures:

  • Time to first event in the composite endpoint of serious asthma related events (i.e. asthma-related hospitalisation, asthma-related endotracheal intubation, or asthma-related death) over the 6-month treatment period
  • Time to first severe asthma exacerbation

Starting dateNovember 2011

Contact informationGSKClinicalSupportHD@gsk.com

NotesAs of April 24, 2012, 552 subjects have been randomised. The target enrolment is 11,664 subjects. The expected completion date for accrual and the study remains unchanged from August 2016 and February 2017 respectively.

 
Comparison 1. Regular salmeterol in addition to regular inhaled corticosteroids

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All cause mortality4015309Peto Odds Ratio (Peto, Fixed, 95% CI)0.90 [0.31, 2.60]

    1.1 Adults and adolescents
3513447Peto Odds Ratio (Peto, Fixed, 95% CI)0.90 [0.31, 2.60]

    1.2 Children
51862Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 All cause non-fatal SAE4015309Peto Odds Ratio (Peto, Fixed, 95% CI)1.15 [0.92, 1.44]

    2.1 Adults and adolescents
3513447Peto Odds Ratio (Peto, Fixed, 95% CI)1.15 [0.91, 1.44]

    2.2 Children
51862Peto Odds Ratio (Peto, Fixed, 95% CI)1.20 [0.37, 3.91]

 3 All cause SAE (fatal and non-fatal)4015309Peto Odds Ratio (Peto, Fixed, 95% CI)1.14 [0.91, 1.42]

    3.1 Adults and adolescents
3513447Peto Odds Ratio (Peto, Fixed, 95% CI)1.13 [0.91, 1.42]

    3.2 Children
51862Peto Odds Ratio (Peto, Fixed, 95% CI)1.20 [0.37, 3.91]

 4 Asthma-related SAE4015309Peto Odds Ratio (Peto, Fixed, 95% CI)1.11 [0.65, 1.91]

    4.1 Adults and adolescents
3513447Peto Odds Ratio (Peto, Fixed, 95% CI)1.12 [0.65, 1.94]

    4.2 Children
51862Peto Odds Ratio (Peto, Fixed, 95% CI)0.99 [0.06, 15.85]

 
Summary of findings for the main comparison. Serious adverse events

Regular salmeterol in addition to regular inhaled corticosteroids compared to regular inhaled corticosteroids for chronic asthma

Patient or population: Adults and children with chronic asthma

Settings: Community

Intervention: Regular salmeterol in addition to regular inhaled corticosteroids (ICS)

Comparison: Regular ICS

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Regular ICSRegular salmeterol in addition to regular ICS

Adults and adolescents

All cause mortality
Follow-up: mean 34 weeks
10 per 10,00019 per 10,000
(3 to 26)
OR 0.9
(0.31 to 2.6)
13,447
(35)
⊕⊕⊕⊝
moderate2

All cause non-fatal SAE
Follow-up: mean 34 weeks
21 per 1000124 per 1000
(19 to 30)
OR 1.15
(0.91 to 1.44)
13,447
(35)
⊕⊕⊕⊝
moderate2

Asthma-related SAE
Follow-up: mean 34 weeks
4 per 100014 per 1000
(2 to 7)
OR 1.12
(0.65 to 1.94)
13,447
(35)
⊕⊕⊕⊝
moderate2

Children

All cause mortalitysee commentsee commentsee commentsee commentNo deaths occurred in children, so risks of mortality cannot be assessed in this age group.

All cause non-fatal SAE
Follow-up: mean 15 weeks
5 per 100016 per 1000
(2 to 21)
OR 1.2
(0.37 to 3.91)
1862
(5)
⊕⊕⊕⊝
moderate2

Asthma-related SAE
Follow-up: mean 15 weeks
1 per 100011 per 1000
(0 to 17)
OR 0.99
(0.06 to 15.85)
1862
(5)
⊕⊕⊕⊝
moderate2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Mean control event rate
2 Imprecision (-1). Downgraded one level due to wide confidence intervals
 
Table 1. Dose of salmeterol and fluticasone

Study IDAge of Participants (Years)N on FSCN on ICSDaily dose of fluticasone (mcg)Daily dose of salmeterol (mcg)Combined InhalerSeparate InhalersDuration (weeks)

Aubier 199912+338165100010028

Bailey 200812+23923620010052

Bateman 200112+1709170720010052

GOAL 200412+333165200/500/100010012

Godard 200818+15915950010024

Ind 200316+33616050010028

Katial 201112+30631550010052

Kavuru 200012+31031820010052

Kerwin 201112+929050010012

Koenig 200812+156156200/500/100010040

Koopmans 200618+17317750010012

Lundback 200618+10110250010012

Malone 20054 to 11888920010012

Murray 200412+949120010012

Nathan 200612+17116822010016

Nelson 200312+959720010012

Pearlman 200412+928920010012

Renzi 201012+26227020010024

Rojas 200712+18018250010012

SAM3000718+2932200/500/100010030

SAM4000418+422120010052

SAM4000818+9393100010026

SAM400124 to 1118118120010024

SAM4003118+4141200/500/100010052

SAM4006512+150150200/500/100010040

SAS300214 to 113043041005012

SAS3002212+2102125005012

SAS3002312+1511551005012

SAS4003615+17215920010016

SAS4003715+16116120010016

SAS4006812+26227020010024

SFA10315312+23923620010052

SFCF402618+15915950010024

Shapiro 200012+848450010012

SLGF7516+141720010012

Strand 200418+787220010012

van Noord 200112+337172100010012

Wallin 200312+181940010012

 FSC (salmeterol/fluticasone), ICS (inhaled corticosteroid)
 
Table 2. Mortality

Study IDTreatment armCause of death (in adults)

Aubier 1999salmeterol and fluticasone

(separate inhalers)
Bronchial carcinoma (one death)

GOAL 2004salmeterol/fluticasoneMyocardial infarction (two deaths) and pneumonia (one death)

GOAL 2004fluticasoneMyocardial infarction (two deaths)

Ind 2003salmeterol and fluticasone

(separate inhalers)
Pneumothorax (one death)

Kerwin 2011salmeterol/fluticasoneCardiac disease (one death)

Kerwin 2011fluticasoneBreast cancer (one death)

Koenig 2008fluticasoneCardiac arrest and deep vein thrombosis (one death)

Renzi 2010fluticasoneCardiac arrest (one death)

SAS40068fluticasoneVentricular hypertrophy and aortic hypoplasia (one death)

Strand 2004fluticasoneUnknown cause (one death)

van Noord 2001salmeterol/fluticasoneLeukaemia (one death)