Comparative Responses in Lung Function Measurements with Tiotropium in Adolescents and Adults, and Across Asthma Severities: A Post Hoc Analysis.

INTRODUCTION: Airway obstruction is usually assessed by measuring forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF). This post hoc study investigated comparative responses of lung function measurements in adults and adolescents (full analysis set, N = 3873) following treatment with tiotropium Respimat®. METHODS: Lung function outcomes were analysed from five phase III trials in adults (≥ 18 years) with symptomatic severe, moderate and mild asthma (PrimoTinA-asthma®, MezzoTinA-asthma® and GraziaTinA-asthma®, respectively), and one phase III trial in adolescents (12-17 years) with symptomatic moderate asthma (RubaTinA-asthma®). Changes from baseline versus placebo in FEV1, FVC, PEF and FEV1/FVC ratio with tiotropium 5 µg or 2.5 µg added to at least stable inhaled corticosteroids at week 24 (week 12 in GraziaTinA-asthma) were analysed. RESULTS: All lung function measures improved in all studies with tiotropium 5 µg (mean change from baseline versus placebo), including peak FEV1 (110-185 mL), peak FVC (57-95 mL) and morning PEF (15.8-25.6 L/min). Changes in adolescents were smaller than those in adults, and were statistically significant primarily for FEV1 and PEF, but not for FVC. CONCLUSION: Consistent improvements were seen across all lung function measures with the addition of tiotropium to other asthma treatments in adults across all severities, whereas the improvements with tiotropium in adolescents primarily impacted measures of flow rather than lung volume. This may reflect less pronounced airway remodelling and air trapping in adolescents with asthma versus adults.

Asthma is characterised by problems with the way that the lungs work, particularly narrowing of the airways. Doctors can measure the effect of asthma on someone's breathing in different ways. We looked to see whether these different methods work for different people with asthma, and whether treatment affects all measurements in a similar way. Lung function was measured after treatment with a drug that opens the airways (tiotropium), and comparisons were made between adults and adolescents with asthma. We also looked at people with severe asthma and those whose asthma was less severe. Tiotropium improved all the measures of lung function in both age groups and across severities. One measure improved more in adults than in adolescents. This may be because adolescents had better lung function at the start and thus less room for improvement, or because the adolescents had not had asthma for as long, and so may have had less long-term damage to their airways than adults.Trial Registration Numbers: NCT00772538, NCT00776984, NCT01172808, NCT01172821, NCT01316380, NCT01257230.

An adaptive design to investigate the effect of ketoconazole on pharmacokinetics of GSK239512 in healthy male volunteers.

This open label drug-drug interaction (DDI) study investigated the effect of a strong CYP3A inhibitor ketoconazole on the PK and safety profile of GSK239512. To mitigate the tolerability concerns of high GSK239512 exposures resulting from CYP3A inhibition, a 2-cohort adaptive design was used to facilitate a stepwise selection of dose levels and subject numbers. In Cohort 1, 6 subjects received a single dose of 20 µg GSK239512 alone and then 10 µg GSK239512 in combination with repeated once daily doses of 400 mg ketoconazole. The results from Cohort 1 demonstrated an approximately 1.5-fold increase in GSK239512 exposure with a good tolerability profile. This led to the adoption of a 3-session option in Cohort 2, in which 16 subjects received sequential single doses of 20 µg GSK239512 alone, 40 µg GSK239512 alone, and a single dose of 40 µg GSK239512 in combination with repeated once daily doses of 400 mg ketoconazole. The 2-cohort adaptive design proved effective in mitigating any potentially significant DDI risk to healthy subjects. Final results showed a 1.3-fold increase in GSK239512 exposure with ketoconazole, suggesting that in vivo metabolism of GSK239512 by CYP3A is unlikely to be the primary route of GSK239512 elimination.

Combined fluticasone furoate/vilanterol reduces decline in lung function following inhaled allergen 23 h after dosing in adult asthma: a randomised, controlled trial.

BACKGROUND: There is a need for preventative asthma maintenance therapy that provides lasting bronchoprotection against allergen provocation. Fluticasone furoate (FF) is a novel inhaled once-daily corticosteroid, being investigated as monotherapy for asthma and in combination with vilanterol (VI), a novel inhaled once-daily long-acting beta-agonist, for asthma and chronic obstructive pulmonary disease. METHODS: In a crossover study of 52 subjects with mild asthma, FF/VI 100/25mcg and FF 100 dosed once-daily in the evening for 28 days were compared with placebo to evaluate their capacity to provide bronchoprotection against the early asthmatic response (EAR) stimulated by an inhaled allergen challenge. Bronchoprotection was assessed by change from post-saline baseline in weighted mean (wm) forced expiratory volume in 1 s (FEV1) for the first 2 h post-allergen challenge, which was on Day 29 (22-23 h post final dose on Day 28). The EAR was also assessed using maximum percent decrease from post-saline baseline and minimum absolute FEV1; the incidence of adverse events was a secondary endpoint. RESULTS: FF/VI 100/25 and FF 100 both provided significant bronchoprotection against the EAR for all endpoints assessed. For wmFEV1 over the first 2 h post-allergen challenge, a 162 mL (95% CI, 87 to 237 mL) difference was observed between placebo and FF 100, while a 145 mL (95% CI, 69 to 222 mL) difference was observed between placebo and FF/VI 100/25 treatment. No difference between active treatments was observed (-17 mL; 95% CI, -91 to 57 mL). Both treatments were well tolerated. CONCLUSIONS: FF 100 alone and in combination with VI 25 provides significant bronchoprotection against the EAR in subjects with mild asthma. That this protection is provided at the trough of dosing, i.e. 23 h post last dose, supports the utility of FF 100 and FF/VI 100/25 as viable once-daily therapies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01128569, GSK Study number: HZA113090.