Gaining Optimal Asthma controL Research Articles

Global Initiative for Asthma 2016–derived asthma control with fluticasone propionate and salmeterol: A Gaining Optimal Asthma Control (GOAL) study reanalysis

BackgroundIn 2004, the landmark Gaining Optimal Asthma Control (GOAL) study demonstrated that most patients can achieve asthma control through sustained treatment and that adding a long-acting β2-adrenoreceptor agonist to an inhaled corticosteroid (ICS) is more effective than ICS alone in this regard. Definitions of asthma control have since evolved, and the consequent implications for the GOAL study findings are unclear. ObjectiveTo evaluate the efficacy of fluticasone propionate and salmeterol and fluticasone propionate alone in achieving and maintaining asthma control, as derived from the Global Initiative for Asthma (GINA) 2016 report. MethodsIn total, 3416 patients were stratified by prior medication (ICS-naive [stratum 1], low-dose ICS [stratum 2], or medium-dose ICS [stratum 3]) and randomized to receive fluticasone propionate and salmeterol or fluticasone propionate. The primary end point was the proportion of patients achieving well-controlled or partly controlled asthma; secondary end points included the proportion of patients achieving well-controlled asthma. Control was evaluated during the last 4 weeks of each dose titration. ResultsIn all strata, more patients achieved well-controlled or partly controlled asthma with fluticasone propionate and salmeterol vs fluticasone propionate alone (stratum 1: 91% vs 85%; P = .003; stratum 2: 86% vs 82%; P = .07; and stratum 3: 76% vs 66%; P < .001), as well as patients with well-controlled asthma (stratum 1: 64% vs 56%; P = .005; stratum 2: 59% vs 41%; P < .001; and stratum 3: 40% vs 22%; P < .001). ConclusionA markedly higher proportion of patients with uncontrolled asthma in each stratum achieved control according to GINA 2016 criteria compared with the original study criteria. The proportion of patients achieving control remained greater with fluticasone propionate and salmeterol than with fluticasone propionate alone.

COST-effectiveness of salmeterol/fluticasone propionate combination (Advair®) in uncontrolled asthma in Canada

To evaluate the cost-utility of the treatment with a long acting beta-agonist (LABA) and inhaled corticosteroid (ICS) combination inhaler [salmeterol xinafoate (SAL)/fluticasone propionate (FP) combination inhaler (SFC) (Advair(®))] to continuing on current ICS dose (no ICS dose change) or increased ICS dose [fluticasone propionate (FP)] in patients with uncontrolled asthma in Canada. A cost-utility analysis was conducted from a Canadian public healthcare perspective with a one year time horizon. In the no FP dose change scenarios, remaining on daily low (FP 100ugBID) or medium (FP 200-250ugBID) or high dose (FP 500ugBID) was considered. In the increased FP dose scenarios, doubling the FP dose from low to medium dose and from medium to high dose regimens were considered. A decision model was developed with two health states: "symptom free" or "with symptoms". Clinical efficacy was based on a meta-analysis of relevant randomized controlled trials. Over the one year time horizon the percentage with symptom free days (SFD) was used as the measure of differential treatment scenario effectiveness. Drug costs and non-drug costs were incorporated into the analysis. Utilities, derived from EQ5D scores and health services resource use based on patient diaries for 'symptom free' and 'with symptoms' were based on regression analyses of individual patient data from the Gaining Optimal Asthma controL (GOAL) trial. Costs were assessed by assigning unit cost for each health services resource use for each patient. The incremental cost-utility ratios (ICUR) for SFC vs no FP dose change or increased FP dose were estimated using descriptive statistics. Uncertainty was assessed by deterministic and probabilistic sensitivity analysis (PSA). Over one year, SFC resulted in an incremental cost per patient of $544-$655 compared to no FP dose change and $47-$380 per year compared to increased FP dose. SFC results in incremental QALYs per patient of 0.0100-0.0149 compared to no FP dose change and 0.0136-0.0152 compared to increased FP dose. The one year ICURs were $43,000 to $54,400 per QALY gained for SFC compared to no FP dose change and $25,000 to $3500 per QALY gained compared to increased FP dose scenarios. The probability of SFC being cost-effective at $50,000 per QALY gained was greater than 75% compared to increased FP dose scenarios and compared to no dose change for patients on low or medium dose FP. The results were robust to changes in assumptions within the model. In Canadian patients with inadequately controlled asthma on FP, it is cost-effective to use SFC for patients 12 years and over compared to doubling their FP dose. It is also cost-effective to use SFC for patients on low or medium dose FP compared to remaining on the current FP dose in patients with uncontrolled asthma.

Transcultural and Measurement Evaluation of the Asthma Quality-of-Life Questionnaire

Objective This analysis compared Asthma Quality-of-Life Questionnaire (AQLQ) data from across 16 countries (17 languages) to evaluate suitability to combine data in analyses. Study Design AQLQ data from the Gaining Optimal Asthma Control study was used for the analyses; 1832 patients had an overall AQLQ score at baseline and week 12. The original North American English version, for Canadian patients only, was the reference language (RL). AQLQ scores range from 1-7, where a high score indicates no impairment. Values within 0.5 of the RL were considered comparable. Results The number of patients varied from 27 (Canadian French) to 257 (Mandarin Chinese). Mean age ranged from 27.6 (Spain Spanish) to 52.9 years (Norway Norwegian). Mean overall AQLQ score (SD) at baseline in the RL was 4.59 (0.94). All but 3 languages reported scores within 0.5 of the RL. Mean change from baseline in the overall AQLQ score in the RL was 0.89 (1.06). Baseline overall AQLQ scores were all within 0.5 of the RL. Cronbach alpha ranged from 0.93 to 0.97 (RL 0.94). Correlation with baseline Asthma Control Questionnaire (ACQ) and the forced expiratory volume in 1 second (FEV 1) ranged from −0.76 to −0.58 (RL −0.69) and −0.02 to 0.41 (RL 0.08), respectively. Similarly, correlations with change from baseline for ACQ and FEV 1 ranged from −0.83 to −0.61 (RL −0.77) and −0.11 to 0.56 (RL 0.03). Effect sizes were all >0.50, ranging from 0.59 (Norway Norwegian) to 1.10 (New Zealand English) (RL 0.85). Conclusions The finding that internal consistency, construct validity, and responsiveness were demonstrated across languages and similar to the RL supports the combining of data for analyses.

Measuring asthma control: a comparison of three classification systems

There are various ways to classify asthma control; however, no classification is universally accepted. This retrospective analysis compared asthma control as assessed by the Asthma Control Questionnaire (5-item version; ACQ-5), Global Initiative for Asthma (GINA) or Gaining Optimal Asthma Control (GOAL) study criteria. Pooled data at the final study week (n = 8,188) from three budesonide/formoterol maintenance and reliever therapy studies which measured ACQ-5 were stratified according to GINA or GOAL criteria and ACQ-5 score distribution. The percentages of patients with a controlled/partly controlled week (GINA), totally/well-controlled week (GOAL) and range of ACQ-5 cut-off points were compared. Patients with GINA controlled, partly controlled and uncontrolled asthma had mean ACQ-5 scores of 0.43, 0.75 and 1.62, respectively. Patients with GOAL totally controlled, well-controlled and uncontrolled asthma had ACQ-5 scores of 0.39, 0.78 and 1.63. The kappa measure of agreement was 0.80 for GINA and GOAL criteria, and 0.63 for GINA controlled/partly controlled and ACQ-5 <1.00. ACQ-5 detected clinically important improvements in 49% of patients who, according to GINA criteria, remained uncontrolled at the end of the study. Asthma control measured by GINA or GOAL criteria provides similar results. GINA Controlled/Partly Controlled and GOAL Totally Controlled/Well-Controlled correspond to ACQ-5 <1.00. The ACQ-5 is more responsive to change in a clinical trial setting than a categorical scale.

Stability of asthma control with regular treatment: an analysis of the Gaining Optimal Asthma controL (GOAL) study

Uncontrolled asthma is characterized by variability. Current asthma guidelines recommend focussing on the achievement and maintenance of control but few studies have examined in detail, using composite measures of control, the stability and potential duration of control once achieved. In this post-hoc analysis of the results of the Gaining Optimal Asthma controL (GOAL) study, we examine the association between the level of asthma control achieved during the step-up phase of the study and the stability of control experienced during the maintenance phase. GOAL was a 1-year, randomized, stratified, double-blind study of 3421 patients with uncontrolled asthma, which compared salmeterol/fluticasone propionate combination with fluticasone propionate in achieving two composite, guideline-based measures of control: totally controlled and well-controlled asthma. We analysed the proportion and duration of time spent in control, the effect of treatment on asthma stability, and the impact of asthma control stability on unscheduled use of healthcare resources. In patients achieving well-controlled or totally controlled asthma, at least well-controlled asthma was maintained for a median of almost 3 and 6 months, and for more than 85% and 95% of weeks of follow-up, respectively. A high level of stability was confirmed in a Markov analysis investigating transitional probability of change in control status. Variability in control was associated with increased probability of an unscheduled healthcare resource use (odds ratio: 1.06, P < 0.001). Most patients achieving guideline-defined control can maintain at least a similar level of control with regular, stable dosing, with little likelihood of losing control.

Determinants of response to fluticasone propionate and salmeterol/fluticasone propionate combination in the Gaining Optimal Asthma controL study

During the Gaining Optimal Asthma controL study, 3416 patients with uncontrolled asthma were randomized to receive salmeterol/fluticasone propionate combination (SFC) or fluticasone propionate (FP) for 1 year. Approximately two thirds of patients achieved well-controlled (WC) asthma, and one third continued to have asthma that was not well controlled (NWC). This analysis aimed to (1) identify factors influencing treatment response and (2) assess the clinical benefits of SFC and FP in patients with NWC asthma. Logistic regression analysis was used to investigate whether covariates influenced the achievement of at least WC asthma in the study population. In patients with NWC asthma, predefined criteria were used to assess improvements in 6 clinical outcomes. Factors affecting the probability of having NWC asthma included smoking status (current vs never: odds ratio [OR], 2.757; 95% CI, 2.061-3.689; P < .0001; former vs never: OR, 1.274; 95% CI, 1.031-1.574; P = 0.0273), sex (women vs men: OR, 0.652; 95% CI, 0.527-0.806; P < .0001), history of inhaled corticosteroid use (no history vs history: OR, 0.546; 95% CI, 0.437-0.683; P < .0001), and treatment (FP vs SFC: OR, 1.972; 95% CI, 1.686-2.308; P < .0001). Of patients with NWC asthma, 86% to 96% showed improvements in 1 or more clinical outcomes. It is imperative for good asthma control that patients stop smoking. Patients who did not have at least WC asthma demonstrated clinical improvements in individual asthma outcomes. Although not all patients can achieve guideline-defined control, long-term treatment with SFC or FP is associated with clinical improvements in nearly all patients, regardless of smoking history or inhaled corticosteroid use.

Validation of a guideline-based composite outcome assessment tool for asthma control

BackgroundA global definition of asthma control does not currently exist. The purpose of this study was to validate two new guideline-based composite measures of asthma control, defined as totally controlled (TC) asthma and well controlled (WC) asthma.MethodsWe used data from 3416 patients randomised and treated in the multi-centre Gaining Optimal Asthma controL (GOAL) study. The criteria comprising the asthma control measures were based on Global Initiative for Asthma/National Institutes of Health guidelines. This validation study examined the measurement properties of the asthma control measures using data from run-in, baseline, 12 and 52 weeks. Forced expiratory volume in 1 second (FEV1) and the Asthma Quality of Life Questionnaire (AQLQ) were used as the reference criteria in the validation analysis.ResultsBoth measures had good discriminative ability showing significant differences in FEV1 and AQLQ scores between control classification both cross-sectionally and longitudinally (p < 0.001). Overall both of the composite measures accounted for more of the variance in FEV1 after 52 weeks than the individual components of each asthma control measure. Both of the reference criteria were independently related to each asthma control measure (p < 0.0001). The measures also had good predictive validity showing significant differences in FEV1 and AQLQ scores at 52 weeks by control classification at 12 weeks (p < 0.0001).ConclusionThe guideline-based composite asthma control measures of WC asthma and TC asthma have good psychometric properties and are both valid functional indices of disease control in asthma.

Extent, patterns, and burden of uncontrolled disease in severe or difficult‐to‐treat asthma

Characterization of uncontrolled asthma burden in a natural treatment setting can influence treatment recommendations and clinical practice. The objective was to characterize and compare the economic burden of severe or difficult-to-treat asthma in uncontrolled and controlled patients. Baseline patient data (age > or = 13 years; n = 3916) were obtained from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study. Disease control was assessed using two approaches: (i) applying criteria for control based on the Gaining Optimal Asthma Control study, and (ii) using the Asthma Therapy Assessment Questionnaire (ATAQ) to identify the number of asthma control problems. Assessments were performed at baseline, and at months 12 and 24. Monetary values were assigned to productivity loss and medical resource use. Direct and indirect costs were aggregated over 24 months and compared using Student's t-test for continuous measures and chi-squared for categorical variables. Throughout the study, most patients had uncontrolled asthma (83% uncontrolled; 16% inconsistent control; 1.3% controlled). Controlled patients experienced fewer work or school absences and less healthcare resource use than uncontrolled patients at all study time points. Using the multilevel ATAQ control score, asthma costs increased directly with the number of asthma control problems. Costs for uncontrolled patients were more than double those of controlled patients throughout the study (14,212 vs 6,452 US Dollars; adjusted to 2002 Dollars; P < 0.0001). This study demonstrated that few severe or difficult-to-treat asthma patients achieved control over a 2-year period and the economic consequence of uncontrolled disease is substantial.

Cost‐effectiveness of asthma control: an economic appraisal of the GOAL study

The Gaining Optimal Asthma ControL (GOAL) study has shown the superiority of a combination of salmeterol/fluticasone propionate (SFC) compared with fluticasone propionate alone (FP) in terms of improving guideline defined asthma control. Clinical and economic data were taken from the GOAL study, supplemented with data on health related quality of life, in order to estimate the cost per quality adjusted life year (QALY) results for each of three strata (previously corticosteroid-free, low- and moderate-dose corticosteroid users). A series of statistical models of trial outcomes was used to construct cost effectiveness estimates across the strata of the multinational GOAL study including adjustment to the UK experience. Uncertainty was handled using the non-parametric bootstrap. Cost-effectiveness was compared with other treatments for chronic conditions. Salmeterol/fluticasone propionate improved the proportion of patients achieving totally and well-controlled weeks resulting in a similar QALY gain across the three strata of GOAL. Additional costs of treatment were greatest in stratum 1 and least in stratum 3, with some of the costs offset by reduced health care resource use. Cost-effectiveness by stratum was 7600 pound (95% CI: 4800-10,700 pound) per QALY gained for stratum 3; 11,000 pound (8600-14,600 pound) per QALY gained for stratum 2; and 13,700 pound (11,000-18,300 pound) per QALY gained for stratum 1. The GOAL study previously demonstrated the improvement in total control associated with the use of SFC compared with FP alone. This study suggests that this improvement in control is associated with cost-per-QALY figures that compare favourably with other uses of scarce health care resources.

Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire

The 7-item Asthma Control Questionnaire (ACQ) has been validated to measure the goals of asthma management as defined by international guidelines (minimisation of day- and night-time symptoms, activity limitation, beta(2)-agonist use and bronchoconstriction). Responses are given on a 7-point scale and the overall score is the mean of the responses (0=totally controlled, 6=severely uncontrolled). The aim of this analysis was to determine the cut-point on the ACQ that best differentiates between 'well-controlled' and 'not well-controlled' for (a) clinical practice (low risk of missing 'not well-controlled') and (b) clinical trials (low risk of including 'well-controlled'). All 1323 patients who provided data sets at week 12 in the Gaining Optimal Asthma Control (GOAL) clinical trial were included in the analysis. The gold standard for 'well-controlled' was a composite based on the GINA/NIH guidelines and derived from data collected in the clinical trial diaries and clinic records. The analysis showed that the crossover point between 'well-controlled' and 'not well-controlled' is close to 1.00 on the ACQ. However, to be confident that a patient has well-controlled asthma, the optimal cut-point is 0.75 (negative predictive value=0.85). To be confident that the patient has inadequately controlled asthma, the optimal cut-point is 1.50 (positive predictive value=0.88). In conclusion, knowledge of these cut-points will enhance practising clinicians ability to identify patients whose asthma requires additional treatment, enable investigators to enroll poorly controlled patients into studies and for both clinicians and investigators to evaluate whether treatment goals are being achieved.

Goals of asthma treatment: how high should we go?

H.K. Reddel is supported by the Ann J. Woolcock Fellowship from the Asthma Foundation of NSW. In the textbook “Respiratory Diseases”, published in 1981, Crofton and Douglas 1 commenced the discussion of asthma management with the comment “It must be admitted that the treatment of asthma is largely palliative”. The chapter provides a bleak picture of high mortality, frequent symptoms,and disabling side-effects of treatment. The use of inhaled corticosteroids (ICS) and, later, long-acting β2-agonists, has produced extraordinary improvements in asthma outcomes, particularly in the burden of disease for patients. More recent attention has focussed on fine-tuning asthma treatment, the aim being to return the patient towards the disease-free state, i.e. not just to improve lung function, which has long been the preferred outcome variable for clinical trials, but to improve the whole spectrum of asthma features, summarised in the expression “asthma control”. These concepts have been addressed by Bateman et al . 2, reporting the results of the Gaining Optimal Asthma controL (GOAL) study. The GOAL study 2 arose from scientific and clinical interest in determining the proportion of asthma patients who could achieve a stringent definition of asthma control. The commercial setting within which this question was examined was a double-blind randomised controlled trial comparing salmeterol and fluticasone combination (SFC) and fluticasone propionate (FP), given b.i.d by Diskus/Accuhaler for 12 months in patients with suboptimally controlled asthma at entry. The GOAL study 2 has raised several interesting issues relating to optimal asthma management, and the way in which response to treatment should be assessed. The GOAL study 2 was planned in the late 1990s, when there was considerable interest in the potential impact of high doses of ICS, with or without long-acting β2-agonists, in achieving better outcomes in asthma. At the time, international asthma …

Can total control of asthma be achieved? The results of the GOAL study

Rationale Whether Total Control (equating to clinical remission) of asthma can be achieved has not been investigated. Gaining Optimal Asthma controL (GOAL) assessed this in a 1-year study comparing salmeterol/fluticasone (SFC) to fluticasone propionate (FP) alone. Methods Patients with uncontrolled asthma were allocated to 3 strata based upon prior medication (ICS-naïve [S1]/low-dose ICS [S2]/moderate-dose ICS [S3]), and randomized to SFC (Seretide ®/Advair ®) or FP (Flixotide ®/Flovent ®). Treatment was stepped-up every 12 weeks until Total Control was achieved (or maximum dose reached). Total Control (no symptoms, no rescue medication, no night-awakenings, no exacerbations, no emergency visits, no adverse events and normal lung function) was based on the GINA/NIH guidelines, and evaluated over the last 8 weeks of each 12 week treatment period. Results 3421 patients were randomized to treatment (mean age 40 years (SD: 16.2) and FEV 1 77% at baseline). Significantly more patients achieved Total Control with SFC compared with FP alone: S1 42% vs 31%; S2 32% vs 20%; and S3 19% vs 8%, respectively (all p<0.001). The proportion of patients achieving Total Control at the same or lower dose of ICS was significantly greater with SFC vs FP alone in each stratum; the odds ratios were: S1 1.78; S2 2.19; and S3 2.95 (all p<0.001). Conclusions These data show that the goals of the GINA/NIH guidelines can be achieved and maintained, and that this level of Total Control (equating to clinical remission) is realised in more patients with salmeterol/fluticasone than with fluticasone alone, regardless of previous treatment.

The effect of oral corticosteroids and high-dose combination therapy on achieving control of refractory asthma

Rationale The need for oral corticosteroids (OCS) in the maintenance treatment of asthma is infrequent and generally reserved for patients with refractory disease. In a sub-population of patients with refractory asthma in the Gaining Optimal Asthma controL (GOAL) study, the efficacy of adding OCS to high-dose combination therapy on achieving asthma control was assessed. Methods After 1 year, patients across all 3 strata (based on pre-study medication: ICS-naïve [S1]; low-dose ICS [S2]; moderate-dose ICS [S3]) who had not achieved Total Control on either salmeterol/fluticasone propionate (Seretide ®/Advair ®; SFC) 50/500μg bid or fluticasone (Flixotide ®/Flovent ®; FP) 500μg bid, entered an open-label phase. 10 days of oral prednisolone (0.5mg/kg/day up to 60mg/day) was administered along with 4 weeks of SFC 50/500μg bid. The achievement of Total Control and Well-Controlled asthma based on a composite measure derived from 7 goals of the GINA/NIH guidelines was assessed over 4 weeks. Results 1462 patients received OCS+SFC (803 previously on FP alone, 659 previously on SFC). The use of OCS+SFC resulted in Total Control for an additional 35, 54 and 63 patients previously on FP and an additional 25, 37, 31 patients previously on SFC (S1/S2/S3, respectively). The number of patients achieving Well-Controlled status (for each stratum) with OCS+SFC were 40, 52, 59 for patients previously on FP, and 25, 23, 39 for patients previously on SFC. Conclusions A short course of high-dose OCS to patients on SFC 50/500 resulted in few additional responders, with a higher number of responders in patients receiving OCS+SFC who had previously received FP alone.

Achieving GINA/NIH guideline-based asthma control with salmeterol/fluticasone compared with fluticasone alone: The results of the GOAL study

Rationale Whether asthma control as defined by GINA/NIH guidelines can be achieved remains unclear. The 1-year Gaining Optimal Asthma controL (GOAL) study investigated whether guideline-based control is achievable, and in what proportion of patients, with salmeterol/fluticasone compared with fluticasone alone. Methods Patients with uncontrolled asthma were stratified into 3 strata based upon prior medication (ICS-naïve [S1]/low-dose ICS [S2]/moderate-dose ICS [S3]), and randomized to either salmeterol/fluticasone propionate (Seretide®/Advair®; SFC) or fluticasone propionate (Flixotide®/Flovent®; FP). Doses were stepped up every 12 weeks until Total Control was achieved (or maximum dose reached). Well-Controlled status (derived from 7 goals of the GINA/NIH guidelines) was evaluated over the last 8 weeks of each 12-week treatment period. Results 3421 patients were randomized to treatment; mean age 40 years (SD: 16.2), FEV1 77% predicted at baseline. Significantly more patients achieved Well-Controlled asthma with SFC vs FP alone in all strata: S1: 71% vs 65% (p=0.039); S2: 69% vs 52%; and S3: 51% vs 33%, respectively (S2 and S3; p<0.001). More patients were Well-Controlled at the same or lower dose of ICS with SFC vs FP alone in each strata; the odds ratios were: S1 1.40 (p=0.003); S2 2.20 (p<0.001); and S3 2.32 (p<0.001). Conclusions Salmeterol/fluticasone treatment enabled significantly more patients to achieve GINA/NIH guideline-based asthma control at a lower dose of ICS compared with fluticasone alone, in both ICS-naïve and those already on ICS, and should therefore become the preferred treatment for all patients with uncontrolled asthma

Salmeterol/fluticasone and fluticasone alone are well tolerated over 1 year of treatment stepped-up to achieve total control: Safety results of the GOAL study

Rationale The 1-year Gaining Optimal Asthma controL (GOAL) study showed that more patients achieve guideline-defined control with salmeterol/fluticasone (SFC) than fluticasone (FP) alone. The GOAL study provides an opportunity to evaluate safety parameters following long-term treatment stepped-up to achieve total asthma control. Methods Patients with uncontrolled asthma were stratified on prior medication (S1: ICS-naïve; S2: low-dose ICS; S3: moderate-dose ICS), and randomized to SFC (Seretide ®/Advair ®) 50/100-50/500 μg bid or FP (Flixotide ®/Flovent ®) 100-500 μg bid for up to 1 year. Adverse events (AEs) were recorded at each clinic visit and 24-hour urinary free cortisols monitored in a patient subset. Results The safety population for SFC vs FP included: S1, 548 vs 550; S2, 585 vs 578; S3, 576 vs 579 patients. The overall incidence of AEs was similar across all strata for both SFC vs FP: S1, 55% vs 56%; S2, 60% vs 57%; and S3, 69% vs 67%. Drug-related AEs were seen in 10% of patients with both treatments (all strata). The incidence of serious AEs with SFC vs FP alone was low across all strata: S1 2% vs 4%; S2 3% vs 2%; and S3 6% vs 4%. The most common adverse events (incidence ≥5%; all strata) were similar for SFC and FP and were: nasopharyngitis, upper RTI headache, sinusitis and influenza. There were no significant differences between treatments in 24-hour free urinary cortisol excretion at week 52 versus baseline. Conclusions Long-term treatment with salmeterol/fluticasone or fluticasone stepped-up to achieve Total Control is safe and well tolerated.