Transition Dyspnea Index Total Score Research Articles

FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease.

Current Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommends the combination of two long-acting bronchodilators of different pharmacologic classes for the management of chronic obstructive pulmonary disease (COPD) if symptoms are not adequately controlled by a single bronchodilator. The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 (indacaterol/glycopyrrolate), a fixed-dose combination of a long-acting β2-agonist (indacaterol) and a long-acting muscarinic antagonist (glycopyrrolate), compared with its monocomponents and placebo in patients with moderate-to-severe COPD. FLIGHT1 and FLIGHT2 were 12-week, identical, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled studies. Patients were randomized (1:1:1:1) to indacaterol/glycopyrrolate (27.5/15.6 μg twice daily), indacaterol (27.5 μg twice daily), glycopyrrolate (15.6 μg twice daily), or placebo, all delivered via the Neohaler device. The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for standardized area under the curve from 0-12 hours for FEV1 at Week 12. Secondary objectives included St. George's Respiratory Questionnaire total score and transition dyspnea index total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo. In total, 2,038 patients were included in the pooled analysis. Indacaterol/glycopyrrolate was statistically superior in terms of FEV1 area under the curve from 0-12 hours compared with its monocomponents (P < 0.001). Statistically and clinically meaningful improvements in St. George's Respiratory Questionnaire total score, transition dyspnea index total score, and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo (P < 0.001). The safety profile was comparable across the treatment groups. Indacaterol/glycopyrrolate twice daily can be an alternative treatment option for the management of symptomatic patients with moderate-to-severe COPD. Clinical trial registered with www.clinicaltrials.gov (NCT 01727141 and NCT 0171251).

Glycopyrronium Improves Health Status, Lung Function in COPD

Glycopyrronium Improves Health Status, Lung Function in COPD

Efficacy and safety of once-daily QVA149 compared with the free combination of once-daily tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a randomised, non-inferiority study

BackgroundQVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY...

Minimal Clinically Important Differences in Pharmacological Trials

The concept of a minimal clinically important difference (MCID) is well established. Here, we review the evidence base and methods used to define MCIDs as well as their strengths and limitations. Most MCIDs in chronic obstructive pulmonary disease (COPD) are empirically derived estimates applying to populations of patients. Validated MCIDs are available for many commonly used outcomes in COPD, including lung function (100 ml for trough FEV1), dyspnea (improvement of ≥ 1 unit in the Transition Dyspnea Index total score or 5 units in the University of California, San Diego Shortness of Breath Questionnaire), health status (reduction of 4 units in the St George's Respiratory Questionnaire total score), and exercise capacity (47.5 m for the incremental shuttle walking test, 45-85 s for the endurance shuttle walking test, and 46-105 s for constant-load cycling endurance tests), but there is currently no validated MCID for exacerbations. In a clinical trial setting, many factors, including study duration, withdrawal rate, baseline severity, and Hawthorne effects, can influence the measured treatment effect and determine whether it reaches the MCID. We also address recent challenges presented by clinical trials that compare active treatments and suggest that MCIDs should be used to identify the additional proportion of patients who benefit, for example, when one drug is replaced by another or when a second drug is added to a first. We propose the term "minimum worthwhile incremental advantage" to describe this parameter.

P236 Superior lung function with once-daily QVA149 translates into improvements in patient-reported breathlessness compared with placebo and tiotropium in COPD patients: the BLAZE study

IntroductionQVA149, a novel once-daily inhaled dual bronchodilator combining a fixed dose of the long-acting β2 agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium, has demonstrated improvements in dyspnoea versus its...

P233 Efficacy and safety of once-daily glycopyrronium compared with blinded tiotropium in patients with COPD: the GLOW5 study

BackgroundGlycopyrronium, a once-daily long-acting muscarinic antagonist (LAMA), has demonstrated a similar efficacy and safety profile to open-label tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).1 The GLOW5 study...

Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study

We evaluated the effect of QVA149, a dual bronchodilator combining indacaterol and glycopyrronium, on direct patient-reported dyspnoea in patients with moderate-to-severe chronic obstructive pulmonary disease. In this multicentre, blinded, double-dummy, three-period crossover study, 247 patients were randomised to once-daily QVA149 110/50 μg, placebo or tiotropium 18 μg. Superiority of QVA149 versus placebo (primary objective) and tiotropium (secondary objective) was assessed for improvement in dyspnoea via the self-administered computerised (SAC) version of the Baseline and Transition Dyspnoea Index after 6 weeks. Secondary end-points included lung function, rescue medication use and safety. After 6 weeks, the SAC Transition Dyspnoea Index total score was significantly higher with QVA149 versus placebo (least squares mean (LSM) treatment difference 1.37, p<0.001) and tiotropium (LSM treatment difference 0.49, p=0.021). QVA149 provided significant improvements in lung function, with higher forced expiratory volume in 1 s area under the curve from 0-4 h post-dose versus placebo and tiotropium at day 1 and week 6 (all p<0.001). Rescue medication use was significantly lower with QVA149 versus placebo (p<0.001) and tiotropium (p=0.002). All treatments were well tolerated. Once-daily QVA149 provided superior improvements in patient-reported dyspnoea and lung function versus placebo and tiotropium. These benefits were associated with improvements in other symptoms and reduced use of rescue medication.

Efficacy and safety of indacaterol and tiotropium in COPD patients according to dyspnoea severity

BackgroundGuidelines for chronic obstructive pulmonary disease (COPD) recommend that treatment choices be based partly on symptoms. MethodsA post-hoc analysis of pooled data from clinical studies compared the efficacy and safety of once-daily inhaled bronchodilators indacaterol (150 and 300 μg) and open-label tiotropium (18 μg) according to baseline dyspnoea severity on the modified Medical Research Council (mMRC) scale in patients with COPD (mMRC scores <2 = ‘less dyspnoea’; scores ≥2 = ‘more dyspnoea’). Outcomes were assessed after 26 weeks. ResultsThe analysis included 3177 patients. In patients with less dyspnoea: indacaterol (both doses) improved 24-h post-dose (‘trough’) forced expiratory volume in 1 s (FEV1), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores at week 26 and reduced the risk of COPD exacerbations vs placebo; and open-label tiotropium improved trough FEV1 and TDI total score vs placebo at week 26. In patients with more dyspnoea: indacaterol (both doses) improved trough FEV1, TDI and SGRQ total scores at week 26; indacaterol 300 μg was the only treatment to improve the TDI total score by more than the minimum clinically important difference (≥1 point) vs placebo; and open-label tiotropium improved trough FEV1, TDI total score at week 26 and decreased the risk of COPD exacerbations vs placebo. In both subgroups, all treatments were well tolerated. ConclusionsIn patients with less dyspnoea, all treatments had similar effects. Indacaterol 300 μg may be a useful treatment option for patients with COPD who experience more severe breathlessness.

Efficacy of Indacaterol 75 μg Once-Daily on Dyspnea and Health Status: Results of Two Double-Blind, Placebo-Controlled 12-Week Studies

Indacaterol is an inhaled, once-daily, long-acting ®2-agonist for the treatment of COPD. Most previous studies were conducted with doses of 150 and/or 300 μg once-daily, and data with the 75 μg dose are limited. Two identically designed studies were, therefore, conducted to evaluate the efficacy and safety of the 75 μg once-daily dose. In two double-blind studies conducted in the USA, patients with moderate-to-severe COPD were randomized to treatment with indacaterol 75 μg once-daily (n = 163 and 159) or matching placebo (n = 160 and 159) for 12 weeks. The primary variable was forced expiratory volume in 1 s measured 24 h post-dose after 12 weeks (reported elsewhere). This report describes secondary efficacy endpoints, including transition dyspnea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores, and the percentages of patients with improvements of or above the minimal clinically important difference (MCID; ≥1 in TDI score and ≥4 in SGRQ score). Differences between indacaterol and placebo for TDI total score at week 12 were 1.23 (p < 0.001) and 0.45 (p = 0.16), with odds ratios for achieving the MCID of 2.19 (p = 0.002) and 1.58 (p = 0.065). SGRQ total score decreased (improved) from baseline by 5.8 and 4.9 units with indacaterol at week 12 (2.0 and 0.9 with placebo), with odds ratios for achieving the MCID of 1.80 (p = 0.024) and 1.71 (p = 0.031). Patients receiving indacaterol had statistically significant or numerical improvements in diary-derived symptom variables compared with placebo. Treatment with indacaterol 75 μg may provide useful improvements in patient-reported outcomes in patients with moderate-to-severe COPD.

Efficacy of Once-Daily Indacaterol Relative to Alternative Bronchodilators in COPD: A Patient-Level Mixed Treatment Comparison

ObjectiveIndacaterol was evaluated versus placebo, formoterol, and salmeterol in randomized controlled trials. No direct comparisons, however, are available for indacaterol 150 μg with formoterol or indacaterol 300 μg with salmeterol. Indacaterol trial evidence was synthesized to provide coherent estimates of indacaterol 150 μg and indacaterol 300 μg relative to formoterol, salmeterol, and tiotropium. MethodsFour randomized controlled trials were combined with Bayesian mixed treatment comparisons by using individual patient-level data. End points of interest were trough forced expiratory volume in 1 second (FEV1), St. George's Respiratory Questionnaire (SGRQ) total score and response (≥4 points), and Transition Dyspnea Index total score and response (≥1 point). ResultsIndacaterol 150 μg demonstrated a higher FEV1 than did formoterol at 12 weeks and 6 months (0.10 L difference; 95% credible interval [CrI] = 0.06–0.14), as did indacaterol 300 μg versus salmeterol (0.06 L difference at 12 weeks; CrI = 0.02–0.10; 0.06 L at 6 months; CrI = 0.02–0.11). Regarding SGRQ, indacaterol 150 μg demonstrated a comparable proportion of responders versus formoterol, as did indacaterol 300 μg versus salmeterol. In comparison to tiotropium, indacaterol 150 μg demonstrated a greater proportion of responders (odds ratio = 1.52 at 12 weeks; CrI 1.15–2.00). For Transition Dyspnea Index, indacaterol 150 μg and formoterol showed a similar response. Indacaterol 300 μg was more efficacious than salmeterol (odds ratio = 1.65 at 12 weeks; CrI 1.16–2.34). Overall, indacaterol 150 μg showed the greatest efficacy for SGRQ and indacaterol 300 μg for FEV1 and Transition Dyspnea Index. ConclusionIndacaterol is expected to be comparable to formoterol, salmeterol, and tiotropium, providing higher FEV1 than formoterol and salmeterol and greater improvement in the SGRQ total score than tiotropium. Indacaterol 150 μg provided comparable improvement in dyspnea, while indacaterol 300 μg demonstrated the greatest response overall.

Effects of beclomethasone/formoterol fixed combination on lung hyperinflation and dyspnea in COPD patients

BackgroundChronic obstructive pulmonary disease (COPD) is a common disease characterized by airflow obstruction and lung hyperinflation leading to dyspnea and exercise capacity limitation.ObjectivesThe present study was designed to evaluate whether an extra-fine combination of beclomethasone and formoterol (BDP/F) was effective in reducing air trapping in COPD patients with hyperinflation. Fluticasone salmeterol (FP/S) combination treatment was the active control.MethodsCOPD patients with forced expiratory volume in one second <65% and plethysmographic functional residual capacity ≥120% of predicted were randomized to a doubleblind, double-dummy, 12-week, parallel group, treatment with either BDP/F 400/24 μg/day or FP/S 500/100 μg/day. Lung volumes were measured with full body plethysmography, and dyspnea was measured with transition dyspnea index.ResultsEighteen patients were evaluable for intention to treat. A significant reduction in air trapping and clinically meaningful improvement in transition dyspnea index total score was detected in the BDP/F group but not in the FP/S group. Functional residual capacity, residual volume (RV) and total lung capacity significantly improved from baseline in the BDP/F group only. With regard to group comparison, a significantly greater reduction in RV was observed with BDP/F versus FP/S.ConclusionBDP/F extra-fine combination is effective in reducing air trapping and dyspnea in COPD patients with lung hyperinflation.