The TRIFLOW study: a randomised, cross-over study evaluating the effects of extrafine beclometasone/formoterol/glycopyrr
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RESEARCH
The TRIFLOW study: a randomised, cross‑over study evaluating the effects of extrafine beclometasone/formoterol/ glycopyrronium on gas trapping in COPD James Dean1* , Catalina Panainte1, Naimat Khan1 and Dave Singh1,2
Abstract Background: The effects of triple therapy on gas trapping in COPD are not fully understood. We evaluated the effects of the long acting bronchodilator components of the extrafine single inhaler triple therapy beclometasone dipropionate/formoterol/glycopyrronium (BDP/F/G) pMDI on gas trapping. Methods: This open-label, randomised, single centre, 2-way cross-over study recruited 23 COPD patients taking inhaled corticosteroid combination treatments and with residual volume (RV) > 120% predicted at screening. Inhaled BDP was taken during run-in and washout periods. Baseline lung function (spirometry, lung volumes, oscillometry) was measured over 12 h prior to randomisation to BDP/F/G or BDP/F for 5 days followed by washout and crossover. Lung function was measured prior to dosing on day 1 and for 12 h post-dose on day 5. Results: Co-primary endpoint analysis: BDP/F/G had a greater effect than BDP/F on F EV1 area under the curve over 12 h (AUC0–12) (mean difference 104 mls, p = 0.0071) and RV AUC0–12 (mean difference − 163 mls, p = 0.0028). Oscillometry measurements showed a greater effect of BDP/F/G on the difference between resistance at 5 and 20 Hz (R5–R20) AUC0–12, which measures small airway resistance (mean difference − 0.045 kPa/L/s, p = 0.0002). Comparison of BDP/F with the baseline measurements (BDP alone) showed that F increased F EV1 AUC0–12 (mean difference 227 mls) and improved RV AUC0–12 (mean difference − 558 mls) and R5–R20 AUC0–12 (mean difference − 0.117 kPa/L/s), all p 0.23 L (FEV1 AUC0–12) between treatments. This corresponds to a 2-sided t-test with 80% power conducted at the 5% significance level, assuming a standard deviation of 0.17 L for the paired differences between treatment groups. The primary analysis was conducted using a mixed model. The model included fixed effects for treatment and period and a random effect for patient within treatment sequence. For the primary endpoint, the AUC0–12 from the baseline visit was included as a covariate. The AUC0–12 (normalised by time), peak and trough (defined as the 12 h measurement post-dose on day 5) values were analysed as change from within-period day 1 pre-dose measurement. All were analysed without any procedures to account for multiple comparisons.
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Results Participants
Sixty-six patients were screened, with 23 randomised, as shown in Fig. 2. One patient was withdrawn due to lack of treatment compliance, leaving 22 patients analysed. Patient characteristics are shown in Table 1. The mean FEV1% predicted (post-bronchodilator) was 49%, and RV was 152% predicted. Primary endpoints
Both BDP/F/G and BDP/F caused improvements in F EV1 and RV on day 5 compared to day 1 pre-dose (Figs. 3, 4). The FEV1 AUC 0–12 change with BDP/F/G was greater compared to BDP/F; mean differ
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