Addition of a 5-lipoxygenase-activating protein inhibitor to an inhaled corticosteroid (ICS) or an ICS/long-acting beta-2-agonist combination in subjects with asthma.

OBJECTIVE: To investigate the clinical benefits of 'add-on' therapy with GSK2190915 in combination with the inhaled corticosteroid (ICS) fluticasone propionate (FP) and the ICS/long-acting beta 2 agonist (LABA) combination FP/salmeterol in asthmatic subjects. METHODS: Both studies were cross-over, randomized, double-blind, double-dummy and placebo-controlled in subjects with a forced expiratory volume in 1 second (FEV1) best of >50 and ≤80% of predicted. Add-on to ICS: Subjects (n = 162) aged ≥12 years received FP 100 µg twice daily (BID) plus GSK2190915 100 mg once daily (QD); GSK2190915 300 mg QD; montelukast 10 mg QD; salmeterol 50 µg BID or placebo. Add-on to ICS/LABA: Female subjects (n = 145) aged ≥18 years received FP/salmeterol 250/50 µg BID plus GSK2190915 300 mg QD, montelukast 10 mg QD or placebo. In both studies, the primary endpoint was trough FEV1 at the end of the treatment period. Secondary endpoints included a range of objective and patient-reported measures of efficacy. RESULTS: Add-on to ICS: There was no statistically significant difference in the primary endpoint between either dose of GSK2190915 (add-on to FP) and placebo. Nominally statistically significant increases were demonstrated for GSK2190915 300 mg add-on relative to placebo for mean morning peak expiratory flow (p = 0.049), percentage of symptom-free days (p = 0.035) and percentage of symptom-free 24 h periods (p = 0.030). Add-on to ICS/LABA: There were no statistically significant differences on the primary endpoint between treatment regimens. Nominally statistically significant decreases were demonstrated in daytime (p = 0.023), night-time (p = 0.041) and 24 h (p = 0.019) short-acting beta 2 agonist usage with FP/salmeterol + GSK2190915 300 mg vs. FP/salmeterol + placebo. CONCLUSION: There was no clinically significant improvement in the primary endpoint following GSK2190915 add-on treatment; however, improvements in a range of secondary endpoints and biomarker data provided evidence of pharmacological activity. Improvements in response to background treatment may have been a limitation in both studies. TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT01156792 and NCT01248975.

Efficacy, safety and tolerability of GSK2190915, a 5-lipoxygenase activating protein inhibitor, in adults and adolescents with persistent asthma: a randomised dose-ranging study.

BACKGROUND: GSK2190915 is a high affinity 5-lipoxygenase-activating protein inhibitor being developed for the treatment of asthma. The objective of this study was to evaluate GSK2190915 efficacy, dose-response and safety in subjects with persistent asthma treated with short-acting beta2-agonists (SABAs) only. METHODS: Eight-week multicentre, randomised, double-blind, double-dummy, stratified (by age and smoking status), parallel-group, placebo-controlled study in subjects aged ≥12 years with a forced expiratory volume in 1 second (FEV1) of 50-85% predicted. Subjects (n = 700) were randomised to receive once-daily (QD) oral GSK2190915 (10-300 mg), twice-daily inhaled fluticasone propionate 100 µg, oral montelukast 10 mg QD or placebo. The primary endpoint was mean change from baseline (randomisation) in trough (morning pre-dose and pre-rescue bronchodilator) FEV1 at the end of the 8-week treatment period. Secondary endpoints included morning and evening peak expiratory flow, symptom-free days and nights, rescue-free days and nights, day and night-time symptom scores, day and night-time rescue medication use, withdrawals due to lack of efficacy, Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores. RESULTS: For the primary endpoint, there was no statistically significant difference between any dose of GSK2190915 QD and placebo. However, repeated measures sensitivity analysis demonstrated nominal statistical significance for GSK2190915 30 mg QD compared with placebo (mean difference: 0.115 L [95% confidence interval: 0.00, 0.23], p = 0.044); no nominally statistically significant differences were observed with any of the other doses. For the secondary endpoints, decreases were observed in day-time symptom scores and day-time SABA use for GSK2190915 30 mg QD versus placebo (p ≤ 0.05). No dose-response relationship was observed for the primary and secondary endpoints across the GSK2190915 dose range studied; the 10 mg dose appeared to be sub-optimal. GSK2190915 was associated with a dose-dependent reduction in urinary leukotriene E4. The profile and incidence of adverse events were similar between treatment groups. CONCLUSION: Efficacy was demonstrated for GSK2190915 30 mg compared with placebo in day-time symptom scores and day-time SABA use. No additional improvement on efficacy endpoints was gained by administration of GSK2190915 doses greater than 30 mg. GSK2190915 was well-tolerated. These results may support further studies with GSK2190915 30 mg. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01147744.

The CONCEPT trial: a 1-year, multicenter, randomized,double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma.

BACKGROUND: A patient-driven, adjustable maintenance dosing (AMD) approach to asthma therapy, in which the dose is adjusted by patients according to the severity of their symptoms, has recently been compared with fixed-dose therapy in open-label studies. OBJECTIVE: This study used a double-blind, double-dummy design to compare the efficacy of 2 treatment approaches: stable dosing of salmeterol/fluticasone propionate (SAL/FP) and AMD of formoterol/budesonide (FOR/BUD). METHODS: This was a 1-year, multicenter, randomized, double-blind, double-dummy study in adult patients with symptomatic asthma that was not controlled by therapy with 200 to 500 microg/d inhaled corticosteroid (ICS) plus a long-acting beta2 agonist, or with >500 to 1000 microg/d ICS alone. Patients were randomized to receive 1 inhalation of SAL/FP 50/250 microg BID or 2 inhalations of FOR/BUD 6/200 microg BID, both delivered via dry powder inhaler devices. After 4 weeks of stable dosing in both groups, eligible patients continued the study for an additional 48 weeks, receiving either a stable dose of SAL/FP or AMD of FOR/BUD. According to the AMD treatment plan, patients initially halved their dose and subsequently stepped up or down as indicated by the presence or absence of nocturnal awakenings due to asthma, frequency of rescue medication use, and changes in morning peak expiratory flow (PEF). The primary end point was the percentage of symptom-free days. Other parameters included daily asthma symptom scores, morning PEF, percentage of days free of rescue medication use, daily rescue medication use, percentage of nighttime awakenings due to asthma, percentage of weeks with well-controlled asthma, and number of exacerbations requiring oral corticosteroids or emergency department (ED) visits/hospitalizations. Tolerability was assessed in terms of adverse events spontaneously reported or elicited at clinic visits. RESULTS: The intent-to-treat population comprised 688 patients (344 per treatment arm) with a mean age of 45 years and a mean baseline forced expiratory volume in 1 second 81% of the predicted normal value. After 4 weeks' stable dosing, 581 patients (295 SAL/FP, 286 FOR/BUD) continued beyond visit 3 into the remaining 48-week treatment period. Over weeks 1 through 52, patients receiving stable dosing of SAL/FP had a significantly greater percentage of symptom-free days compared with those receiving AMD of FOR/BUD (median, 58.8% vs 52.1%, respectively; P = 0.034). The incidence of asthma exacerbations requiring oral steroids or an ED visit/hospitalization was 47% lower with SAL/FP compared with FOR/BUD (adjusted annual mean rate, 0.18 vs 0.33; P = 0.008). During weeks 5 through 52, patients in the FOR/BUD AMD group used a mean of 1.8 inhalations/d (equivalent to BUD 360 microg/d), and 235 (82.2%) patients stepped down to 1 inhalation/d. Mean (SD) daily ICS exposure over 52 weeks was 463 (81) microg FP and 480 (238) microg BUD in the respective treatment arms. CONCLUSIONS: In this adult population with persistent asthma, stable dosing of SAL/FP 50/250 microg BID resulted in significantly greater increases in symptom-free days, days free of rescue medication, and morning PEE, as well as almost halving the exacerbation rate, compared with AMD of FOR/BUD 6/200 microg. The results suggest that there is a minimum daily amount of maintenance therapy necessary to prevent exacerbations in adults with persistent asthma.