This Phase II, randomized, parallel group study was conducted as part of US regulatory requirements to identify the most appropriate dose of the long-acting muscarinic antagonist glycopyrronium ...bromide (GB) for use in a single-inhaler triple-therapy combination with the inhaled corticosteroid beclomethasone dipropionate plus the long-acting β
2
-agonist formoterol fumarate. Eligible subjects were adults with COPD and post-bronchodilator forced expiratory volume in 1 s (FEV
1
) 40-80% predicted. Subjects were randomized to receive inhaled double-blind GB 6.25, 12.5, 25 or 50 µg or placebo, all twice daily (BID), or open-label tiotropium 18 µg once daily for six weeks. The primary objective was to evaluate the efficacy of GB versus placebo in terms of FEV
1
area under the curve between 0 and 12 h at Week 6. Of 733 subjects randomized, 682 (93.0%) completed the study. For the primary endpoint, all GB doses were superior to placebo (p < 0.05), with a dose-response up to 25 µg BID, and 25 and 50 µg BID both superior to 6.25 µg BID (p < 0.05). Results for the secondary spirometry endpoints were consistent with the primary endpoint. Overall, the efficacy of GB 25 and 50 µg BID was broadly consistent with that of tiotropium. The incidence of adverse events, both overall and for the most common preferred terms, was low and similar in all treatment groups, including placebo (overall, 22.3-29.3%). Based on the totality of the efficacy and safety data, the optimal GB dose is 25 µg BID.
Vilanterol (GW642444M) (VI) is a novel, inhaled, long-acting β(2) agonist with inherent 24-h activity under development as a once-daily combination therapy with an inhaled corticosteroid for COPD and ...asthma. This study assessed the dose response, efficacy, and safety of VI at doses of 3 to 50 μg in patients with moderate to severe COPD.
Six hundred two patients (intent-to-treat) were randomized (double-blind) to VI 3, 6.25, 12.5, 25, or 50 μg or placebo once daily for 28 days. The primary end point was change from baseline in trough FEV1 at the end of the 28-day treatment period. Secondary end points included 0- to 24-h weighted mean FEV(1) on days 1 and 28 and time to increases of ≥ 100 mL or ≥ 12% from baseline FEV(1) on day 1. Safety assessments included adverse events, vital signs, ECG assessment, and clinical laboratory tests.
VI once daily for 28 days significantly improved trough FEV(1) in a dose-dependent manner vs placebo. Clinically relevant treatment differences of ≥ 130 mL in trough and 0- to 24-h weighted mean FEV(1) were observed with VI 25- and 50-μg doses vs placebo. All doses of VI were associated with a low incidence of treatment-related adverse events/serious adverse events, with no suggestion of effects on BP, pulse rate, QT intervals corrected for heart rate calculated by Fridericia formula, or blood glucose and potassium levels.
VI 25 and 50 μg once daily provided both statistically and clinically relevant 24-h improvements in lung function in patients with COPD compared with placebo. All doses of VI had a safety and tolerability profile similar to placebo.
In this article, I examine how a territorial imaginary conflating culture, territory, nation, and security allows "elites of statecraft" in Europe to frame citizenship and integration policy as ...(inter)national security matters. Focusing on post-Soviet Estonia, I argue that this imaginary legitimized the denial of citizenship to Soviet-era Russian speakers and enabled the government's integration policy objective of creating the "Estonian cultural domain." Drawing on historical, archival, and ethnographic research, I demonstrate how the invocation of national security justified these events and how the territorial imaginary structured the making of integration policy from the 1991 reestablishment of independence to E.U. accession in 2004.
Summary Background Once-daily combination treatment is an attractive maintenance therapy for COPD. However, the dose of inhaled corticosteroid to use in a once-daily combination is unknown. We ...compared two strengths of fluticasone furoate (FF) plus vilanterol (VI), the same strengths of the individual components, and placebo. Methods Multicentre, randomised, 24-week, double-blind, placebo-controlled, parallel-group study in stable, moderate-to-severe COPD subjects ( N = 1224). Subjects were randomised to FF/VI (200/25 μg; 100/25 μg), FF (200 μg; 100 μg), VI 25 μg, or placebo, once daily in the morning. Co-primary efficacy endpoints; 0–4 h weighted mean (wm) FEV1 on day 168, and change from baseline in trough (23–24 h post-dose) FEV1 on day 169. The primary safety objective was adverse events (AEs). Results There was a statistically significant ( p < 0.001) increase in wm FEV1 (209 ml) and trough FEV1 (131 ml) for FF/VI 200/25 μg vs. placebo; similar changes were seen for FF/VI 100/25 μg vs. placebo. Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV1 (32 ml) was not statistically significant ( p = 0.224), the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV1 (168 ml) was significantly different ( p < 0.001). VI 25 μg significantly improved wm and trough FEV1 vs. placebo (209 ml and 131 ml, respectively). No increase was seen in on-treatment AEs or serious AEs (SAEs), with active therapy vs. placebo. Conclusions FF/VI provides rapid and significant sustained improvement in FEV1 in subjects with moderate-to-severe COPD, which was not influenced by the dose of FF. These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study. GSK study number : HZC112207. ClinicalTrials.gov : NCT01054885.
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