Publications by authors named "Maggie Tabberer"

45 Publications

Nemiralisib in Patients with an Acute Exacerbation of COPD: Placebo-Controlled, Dose-Ranging Study.

Int J Chron Obstruct Pulmon Dis 2021 3;16:1637-1646. Epub 2021 Jun 3.

Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.

Background: Management of acute exacerbations of chronic obstructive pulmonary disease (COPD) is sometimes inadequate leading to either prolonged duration and/or an increased risk of recurrent exacerbations in the period following the initial event.

Objective: To evaluate the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ inhibitor, in patients experiencing an acute exacerbation of COPD.

Patients And Methods: In this double-blind, placebo-controlled study, COPD patients (40-80 years, ≥10 pack-year smoking history, current moderate/severe acute exacerbation of COPD requiring standard-of-care treatment) were randomized to placebo or nemiralisib 12.5 µg, 50 µg, 100 µg, 250 µg, 500 µg, or 750 µg (ratio of 3:1:1:1:1:1:3; N=938) for 12 weeks with an exploratory 12-week follow-up period. The primary endpoint was change from baseline in post-bronchodilator FEV at week 12. Key secondary endpoints were rate of re-exacerbations, patient-reported outcomes (Exacerbations of Chronic Pulmonary Disease Tool, COPD Assessment Test, St George's Respiratory Questionnaire-COPD), plasma pharmacokinetics (PK) and safety/tolerability.

Results: There was no difference in change from baseline FEV at week 12 between the nemiralisib and placebo treatment groups (posterior adjusted median difference, nemiralisib 750 µg and placebo: -0.004L (95% CrI: -0.051L to 0.042L)). Overall, there were also no differences between nemiralisib and placebo in secondary endpoints, including re-exacerbations. Plasma PK increased in a dose proportional manner. The most common adverse event for nemiralisib was post-inhalation cough which appeared to be dose-related.

Conclusion: The addition of nemiralisib to standard-of-care treatment for 12 weeks did not improve lung function or re-exacerbations in patients with, and following an acute exacerbation of COPD. However, this study demonstrated that large clinical trials recruiting acutely exacerbating patients can successfully be conducted.
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http://dx.doi.org/10.2147/COPD.S309320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184152PMC
August 2021

INTREPID: single- multiple-inhaler triple therapy for COPD in usual clinical practice.

ERJ Open Res 2021 Apr 7;7(2). Epub 2021 Jun 7.

Global Respiratory Franchise, GSK, Brentford, UK.

Introduction: Real-world trial data comparing single- with multiple-inhaler triple therapy (MITT) in COPD patients are currently lacking. The effectiveness of once-daily single-inhaler fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) and MITT were compared in usual clinical care.

Methods: INTREPID was a multicentre, randomised, open-label, phase IV effectiveness study comparing FF/UMEC/VI 100/62.5/25 µg the ELLIPTA inhaler with a clinician's choice of any approved non-ELLIPTA MITT in usual COPD clinical practice in five European countries. Primary end-point was proportion of COPD Assessment Test (CAT) responders (≥2-unit decrease in CAT score from baseline) at week 24. Secondary end-points in a subpopulation included change from baseline in forced expiratory volume in 1 s (FEV) and percentage of patients making at least one critical error in inhalation technique at week 24. Safety was also assessed.

Results: 3092 patients were included (FF/UMEC/VI n=1545; MITT n=1547). The proportion of CAT responders at week 24 was significantly greater with FF/UMEC/VI non-ELLIPTA MITT (OR 1.31, 95% CI 1.13-1.51; p<0.001) and mean change from baseline in FEV was significantly greater with FF/UMEC/VI (77 mL 28 mL; treatment difference 50 mL, 95% CI 26-73 mL; p<0.001). The percentage of patients with at least one critical error in inhalation technique was low in both groups (FF/UMEC/VI 6%; non-ELLIPTA MITT 3%). Safety profiles, including incidence of pneumonia serious adverse events, were similar between treatments.

Conclusions: In a usual clinical care setting, treatment with once-daily single-inhaler FF/UMEC/VI resulted in significantly more patients gaining health status improvement and greater lung function improvement non-ELLIPTA MITT.
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http://dx.doi.org/10.1183/23120541.00950-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181617PMC
April 2021

Improved Decision-Making Confidence Using Item-Based Pharmacometric Model: Illustration with a Phase II Placebo-Controlled Trial.

AAPS J 2021 06 2;23(4):79. Epub 2021 Jun 2.

Department of Pharmacy, Uppsala University, Box 580, 751 23, Uppsala, Sweden.

This study aimed to illustrate how a new methodology to assess clinical trial outcome measures using a longitudinal item response theory-based model (IRM) could serve as an alternative to mixed model repeated measures (MMRM). Data from the EXACT (Exacerbation of chronic pulmonary disease tool) which is used to capture frequency, severity, and duration of exacerbations in COPD were analyzed using an IRM. The IRM included a graded response model characterizing item parameters and functions describing symptom-time course. Total scores were simulated (month 12) using uncertainty in parameter estimates. The 50th (2.5th, 97.5th) percentiles of the resulting simulated differences in average total score (drug minus placebo) represented the estimated drug effect (95%CI), which was compared with published MMRM results. Furthermore, differences in sample size, sensitivity, specificity, and type I and II errors between approaches were explored. Patients received either oral danirixin 75 mg twice daily (n = 45) or placebo (n = 48) on top of standard of care over 52 weeks. A step function best described the COPD symptoms-time course in both trial arms. The IRM improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of 2.5 times larger for the MMRM analysis to achieve the IRM precision. The IRM showed a higher probability of a positive predictive value (34%) than MMRM (22%). An item model-based analysis data gave more precise estimates of drug effect than MMRM analysis for the same endpoint in this one case study.
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http://dx.doi.org/10.1208/s12248-021-00600-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172506PMC
June 2021

Validity and responsiveness of the Daily- and Clinical visit-PROactive Physical Activity in COPD (D-PPAC and C-PPAC) instruments.

Thorax 2021 03 21;76(3):228-238. Epub 2021 Jan 21.

Department of Respiratory Diseases, University Hospital Leuven, Leuven, Belgium.

Background: The Daily-PROactive and Clinical visit-PROactive Physical Activity (D-PPAC and C-PPAC) instruments in chronic obstructive pulmonary disease (COPD) combines questionnaire with activity monitor data to measure patients' experience of physical activity. Their amount, difficulty and total scores range from 0 (worst) to 100 (best) but require further psychometric evaluation.

Objective: To test reliability, validity and responsiveness, and to define minimal important difference (MID), of the D-PPAC and C-PPAC instruments, in a large population of patients with stable COPD from diverse severities, settings and countries.

Methods: We used data from seven randomised controlled trials to evaluate D-PPAC and C-PPAC internal consistency and construct validity by sex, age groups, COPD severity, country and language as well as responsiveness to interventions, ability to detect change and MID.

Results: We included 1324 patients (mean (SD) age 66 (8) years, forced expiratory volume in 1 s 55 (17)% predicted). Scores covered almost the full range from 0 to 100, showed strong internal consistency after stratification and correlated as a priori hypothesised with dyspnoea, health-related quality of life and exercise capacity. Difficulty scores improved after pharmacological treatment and pulmonary rehabilitation, while amount scores improved after behavioural physical activity interventions. All scores were responsive to changes in self-reported physical activity experience (both worsening and improvement) and to the occurrence of COPD exacerbations during follow-up. The MID was estimated to 6 for amount and difficulty scores and 4 for total score.

Conclusions: The D-PPAC and C-PPAC instruments are reliable and valid across diverse COPD populations and responsive to pharmacological and non-pharmacological interventions and changes in clinically relevant variables.
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http://dx.doi.org/10.1136/thoraxjnl-2020-214554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892393PMC
March 2021

Defining Chronic Mucus Hypersecretion Using the CAT in the SPIROMICS Cohort.

Int J Chron Obstruct Pulmon Dis 2020 13;15:2467-2476. Epub 2020 Oct 13.

GSK R&D, Discovery Medicine, Collegeville, PA, USA.

Background: Chronic cough and phlegm are frequently reported chronic obstructive pulmonary disease (COPD) symptoms. Prior research classified chronic mucus hypersecretion (CMH) based on the presence of these symptoms for ≥3 months, called chronic bronchitis (CB) if respiratory infection symptoms were present for 1-2 years (Medical Research Council [MRC] definition). We explored whether the COPD Assessment Test (CAT), a simple measure developed for routine clinical use, captures CMH populations and outcomes similarly to MRC and St. George's Respiratory Questionnaire (SGRQ) definitions.

Methods: We identified CMH in the SPIROMICS COPD cohort using (a) MRC definitions, (b) SGRQ questions for cough and phlegm (both as most/several days a week), and (c) CAT cough and phlegm questions. We determined optimal cut-points for CAT items and described exacerbation frequencies for different CMH definitions. Moderate exacerbations required a new prescription for antibiotics/oral corticosteroids or emergency department visit; severe exacerbations required hospitalization. Results were stratified by smoking status.

Results: In a population of 1431 participants (57% male; mean FEV% predicted 61%), 47% and 49% of evaluable participants had SGRQ- or CAT-defined CMH, respectively. A cut-point of ≥2 for cough and phlegm items defined CMH in CAT. Among SGRQ-CMH+ participants, 80% were also defined as CMH+ by the CAT. CMH+ participants were more likely to be current smokers. A higher exacerbation frequency was observed for presence of CMH+ versus CMH- in the year prior to baseline for all CMH definitions; this trend continued across 3 years of follow-up, regardless of smoking status.

Conclusion: Items from the CAT identified SGRQ-defined CMH, a frequent COPD trait that correlated with exacerbation frequency. The CAT is a short, simple questionnaire and a potentially valuable tool for telemedicine or real-world trials. CAT-based CMH is a novel approach for identifying clinically important characteristics in COPD that can be ascertained in these settings.
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http://dx.doi.org/10.2147/COPD.S267002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568676PMC
June 2021

Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial.

Lancet Respir Med 2021 01 9;9(1):69-84. Epub 2020 Sep 9.

Nuffield Department of Medicine and Oxford Respiratory NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. Electronic address:

Background: Despite inhaled corticosteroid plus long-acting β-agonist (ICS/LABA) therapy, 30-50% of patients with moderate or severe asthma remain inadequately controlled. We investigated the safety and efficacy of single-inhaler fluticasone furoate plus umeclidinium plus vilanterol (FF/UMEC/VI) compared with FF/VI.

Methods: In this double-blind, randomised, parallel-group, phase 3A study (Clinical Study in Asthma Patients Receiving Triple Therapy in a Single Inhaler [CAPTAIN]), participants were recruited from 416 hospitals and primary care centres across 15 countries. Participants were eligible if they were aged 18 years or older, with inadequately controlled asthma (Asthma Control Questionnaire [ACQ]-6 score of ≥1·5) despite ICS/LABA, a documented health-care contact or a documented temporary change in asthma therapy for treatment of acute asthma symptoms in the year before screening, pre-bronchodilator FEV between 30% and less than 85% of predicted normal value, and reversibility (defined as an increase in FEV of ≥12% and ≥200 mL in the 20-60 min after four inhalations of albuterol or salbutamol) at screening. Participants were randomly assigned (1:1:1:1:1:1), via central based randomisation stratified by pre-study ICS dose at study entry, to once-daily FF/VI (100/25 μg or 200/25 μg) or FF/UMEC/VI (100/31·25/25 μg, 100/62·5/25 μg, 200/31·25/25 μg, or 200/62·5/25 μg) administered via Ellipta dry powder inhaler (Glaxo Operations UK, Hertfordshire, UK). Patients, investigators, and the funder were masked to treatment allocation. Endpoints assessed in the intention-to-treat population were change from baseline in clinic trough FEV at week 24 (primary) and annualised moderate and/or severe asthma exacerbation rate (key secondary). Other secondary endpoints were change from baseline in clinic FEV at 3 h post-dose, St George's Respiratory Questionnaire (SGRQ) total score, and ACQ-7 total score, all at week 24. Change from baseline in Evaluating Respiratory Symptoms in Asthma total score at weeks 21-24 was also a secondary endpoint but is not reported here. Exploratory analyses of biomarkers of type 2 airway inflammation on treatment response were also done. This study is registered with ClinicalTrials.gov, NCT02924688, and is now complete.

Findings: Between Dec 16, 2016, and Aug 31, 2018, 5185 patients were screened and 2439 were recruited and randomly assigned to FF/VI (100/25 μg n=407; 200/25 μg n=406) or FF/UMEC/VI (100/31·25/25 μg n=405; 100/62·5/25 μg n=406; 200/31·25/25 μg n=404; 200/62·5/25 μg n=408), with three patients randomly assigned in error and not included in analyses. In the intention-to-treat population, 922 (38%) patients were men, the mean age was 53·2 years (SD 13·1) and body-mass index was 29·4 (6·6). Baseline demographics were generally similar across all treatment groups. The least squares mean improvement in FEV change from baseline for FF/UMEC/VI 100/62·5/25 μg versus FF/VI 100/25 μg was 110 mL (95% CI 66-153; p<0·0001) and for 200/62·5/25 μg versus 200/25 μg was 92 mL (49-135; p<0·0001). Adding UMEC 31·25 μg to FF/VI produced similar improvements (FF/UMEC/VI 100/31·25/25 μg vs FF/VI 100/25 μg: 96 mL [52-139; p<0·0001]; and 200/31·25/25 μg vs 200/25 μg: 82 mL [39-125; p=0·0002]). These results were supported by the analysis of clinic FEV at 3 h post-dose. Non-significant reductions in moderate and/or severe exacerbation rates were observed for FF/UMEC 62·5 μg/VI versus FF/VI (pooled analysis), with rates lower in FF 200 μg-containing versus FF 100 μg-containing treatment groups. All pooled treatment groups demonstrated mean improvements (decreases) in SGRQ total score at week 24 compared with baseline in excess of the minimal clinically important difference of 4 points; however, there were no differences between treatment groups. For mean change from baseline to week 24 in asthma control questionnaire-7 score, improvements (decreases) exceeding the minimal clinically important difference of 0·5 points were observed in all pooled treatment groups. Adding UMEC to FF/VI resulted in small, dose-related improvements compared with FF/VI (pooled analysis: FF/UMEC 31·25 μg/VI versus FF/VI, -0·06 (95% CI -0·12 to 0·01; p=0·094) FF/UMEC 62·5 μg/VI versus FF/VI, -0·09 (-0·16 to -0·02, p=0·0084). By contrast with adding UMEC, the effects of higher dose FF on clinic trough FEV and annualised moderate and/or severe exacerbation rate were increased in patients with higher baseline blood eosinophil count and exhaled nitric oxide. Occurrence of adverse events was similar across treatment groups (patients with at least one event ranged from 210 [52%] to 258 [63%]), with the most commonly reported adverse events being nasopharyngitis (51 [13%]-63 [15%]), headache (19 [5%]-36 [9%]), and upper respiratory tract infection (13 [3%]-24 [6%]). The incidence of serious adverse events was similar across all groups (range 18 [4%]-25 [6%)). Three deaths occurred, of which one was considered to be related to study drug (pulmonary embolism in a patient in the FF/UMEC/VI 100/31·25/25 μg group).

Interpretation: In patients with uncontrolled moderate or severe asthma on ICS/LABA, adding UMEC improved lung function but did not lead to a significant reduction in moderate and/or severe exacerbations. For such patients, single-inhaler FF/UMEC/VI is an effective treatment option with a favourable risk-benefit profile. Higher dose FF primarily reduced the rate of exacerbations, particularly in patients with raised biomarkers of type 2 airway inflammation. Further confirmatory studies into the differentiating effect of type 2 inflammatory biomarkers on treatment outcomes in asthma are required to build on these exploratory findings and further guide clinical practice.

Funding: GSK.
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http://dx.doi.org/10.1016/S2213-2600(20)30389-1DOI Listing
January 2021

Single-Inhaler Triple Therapy and Health-Related Quality of Life in COPD: The IMPACT Study.

Adv Ther 2020 09 9;37(9):3775-3790. Epub 2020 Jul 9.

GlaxoSmithKline plc, Collegeville, PA, USA.

Introduction: The phase 3 InforMing the PAthway of COPD (chronic obstructive pulmonary disease) Treatment (IMPACT) trial, single-inhaler therapy with fluticasone furoate (FF) 100 μg, umeclidinium (UMEC) 62.5 μg, and vilanterol (VI) 25 μg demonstrated a reduction in the rate of moderate or severe exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic COPD at risk of exacerbations. This article reports additional evidence of improvements in symptoms and health-related quality of life (HRQoL) with FF/UMEC/VI compared with either FF/VI or UMEC/VI from the IMPACT study.

Methods: Patient-reported HRQoL assessments and symptom measures included as pre-specified IMPACT end points were the St George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), and Baseline Dyspnea Index (BDI) as the anchor for the Transitional Dyspnea Index (TDI) focal score (BDI/TDI) in a subset of patients enrolled at study sites in North America and Europe. Change from baseline was assessed at weeks 4, 28, and 52.

Results: The intent-to-treat population included 10,355 patients (TDI population: 5058 patients). Clinically meaningful improvements in SGRQ total score between baseline and week 52 favored FF/UMEC/VI over FF/VI (- 1.8 units, p < 0.001) and UMEC/VI (- 1.8 units, p < 0.001). Similar improvements in the CAT and TDI focal score were also observed with FF/UMEC/VI versus FF/VI or UMEC/VI.

Conclusions: This study demonstrates that in patients with symptomatic COPD at risk of exacerbations, once-daily FF/UMEC/VI, compared with FF/VI or UMEC/VI, improves patient-perceived HRQoL and symptoms.

Trial Registration Number: NCT02164513.
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http://dx.doi.org/10.1007/s12325-020-01409-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444357PMC
September 2020

Assessment of the COPD Assessment Test Within U.S. Primary Care.

Chronic Obstr Pulm Dis 2020 Jan;7(1):26-37

U.S. Value Evidence and Outcomes, GlaxoSmithKline plc., Research Triangle Park, North Carolina.

Rationale: Uptake of the COPD Assessment Test (CAT) is not yet widespread in patients with chronic obstructive pulmonary disease (COPD) within U.S. primary care and its alignment with other assessments has not been evaluated in U.S. clinical practice.

Objectives: To assess the alignment of the CAT with other standard measures of COPD severity and its usability in a U.S. primary care population.

Methods: This was a multicenter, prospective, observational, longitudinal study of patients with COPD and their primary care physicians. Patients with spirometry-confirmed airflow restriction completed a daily electronic diary (eDiary) over 12 weeks; surveys were also administered at baseline and at 6- and 12-week follow-up.

Measurements And Main Results: In the study population (=178), statistically significant differences (<0.05) were found across 4 CAT impact score groups where at all time points patients in the Low Impact CAT score group had superior lung function and physical/mental health status than patients in the Medium, High, and Very High Impact groups. Numerical, though lesser, differences were also found across these latter 3 groups. Furthermore, the average total EXAcerbations of COPD Tool (EXACT®) score was significantly worse in patients in the highest CAT score group over the first 7 days.

Conclusions: COPD severity; respiratory symptoms; frequency, severity, and duration of pulmonary exacerbations; and overall physical and mental health status are linked concurrently and prospectively to CAT impact score categories. The stratification of patients according to CAT impact scores, and application of clinical and functional health status information to these categories, enhances the usability of the CAT in practice settings for COPD management.
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http://dx.doi.org/10.15326/jcopdf.7.1.2019.0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182383PMC
January 2020

Clinical effectiveness of once-daily fluticasone furoate/umeclidinium/vilanterol in usual practice: the COPD INTREPID study design.

ERJ Open Res 2019 Oct 4;5(4). Epub 2019 Nov 4.

Global Respiratory Franchise, GlaxoSmithKline plc., Brentford, UK.

Effectiveness studies complement conventional randomised controlled trials by providing a holistic view of treatments in the setting of usual clinical practice. We present the protocol for the ongoing INTREPID (INvestigation of TRelegy Effectiveness: usual PractIce Design; ClinicalTrials.gov identifier: NCT03467425) study, a randomised, open-label, 24-week effectiveness study of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI; Trelegy) delivered by the ELLIPTA inhaler non-ELLIPTA multiple-inhaler triple therapy in patients with chronic obstructive pulmonary disease (COPD) in usual practice settings. INTREPID was designed to provide evidence of FF/UMEC/VI effectiveness in patients with COPD managed in routine healthcare systems across multiple European countries. Between study initiation and end-of-study visits, patients will receive their medication and care as they would ordinarily receive it, from their usual healthcare provider at their usual healthcare centre. Study-specific intervention will be minimal. The primary end-point will be the proportion of COPD assessment test (CAT) responders, defined as a clinically meaningful improvement from baseline of ≥2 units, at week 24. The CAT was chosen as it provides health status information relevant to patients, physicians, health technology agencies and payers. Lung function (forced expiratory volume in 1 s) and critical inhaler errors will also be assessed in a subgroup of patients. The strengths and weaknesses of the protocol and some of the challenges associated with conducting this multicountry study, such as differences in healthcare systems and treatment practices across sites, will also be discussed.
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http://dx.doi.org/10.1183/23120541.00061-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826246PMC
October 2019

Preventing clinically important deterioration with single-inhaler triple therapy in COPD.

ERJ Open Res 2018 Oct 3;4(4). Epub 2018 Oct 3.

Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.

Clinically important deterioration (CID) is a novel composite end-point (lung function, health status, exacerbations) for assessing disease stability in patients with chronic obstructive pulmonary disease (COPD). We prospectively analysed CID in the FULFIL study. FULFIL (ClinicalTrials.gov NCT02345161; randomised, double-blind, double-dummy, multicentre study) compared 24 weeks of once daily, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg with twice daily budesonide/formoterol (BUD/FOR) 400/12 μg in patients aged ≥40 years with symptomatic advanced COPD (Global Initiative for Chronic Obstructive Lung Disease group D). A subset of patients received study treatment for up to 52 weeks. Time to first CID event was assessed over 24 and 52 weeks using two approaches for the health status component: St George's Respiratory Questionnaire and COPD assessment test. FF/UMEC/VI significantly reduced the risk of a first CID event by 47-52% BUD/FOR in the 24- and 52-week populations using both CID definitions (p<0.001). The median time to first CID event was ≥169 days and ≤31 days with FF/UMEC/VI and BUD/FOR, respectively. Only stable patients with no CID at 24 weeks demonstrated sustained clinically important improvements in lung function and health status at 52 weeks those who had experienced CID. Once daily, single-inhaler FF/UMEC/VI significantly reduced the risk of CID twice daily BUD/FOR with a five-fold longer period without deterioration.
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http://dx.doi.org/10.1183/23120541.00047-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168763PMC
October 2018

Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD.

N Engl J Med 2018 May 18;378(18):1671-1680. Epub 2018 Apr 18.

From GlaxoSmithKline, Collegeville (D.A. Lipson, J.B., S.J.P.), and the Perelman School of Medicine, University of Pennsylvania (D.A. Lipson), and Lewis Katz School of Medicine at Temple University (G.J.C.), Philadelphia - all in Pennsylvania; GlaxoSmithKline, Research Triangle Park, NC (F.B., C.E.J.); GlaxoSmithKline, Stockley Park West, Uxbridge (N.B., N.C.D., S.K., M.T.), the Department of Respiratory Medicine, Royal Devon and Exeter Hospital, Exeter (D.M.G.H.), UCL Respiratory, University College London, London (D.A. Lomas), and the Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester University NHS Foundation Trust, Manchester (D.S.) - all in the United Kingdom; the Division of Pulmonary, Allergy, and Critical Care Medicine, Lung Health Center, University of Alabama at Birmingham, Birmingham (M.T.D.); the Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor (M.K.H.); the Department of Public Health, University of Copenhagen, Copenhagen (P.L.), and the Medical Department, Pulmonary Section, Herlev-Gentofte Hospital, Herlev (P.L.) - both in Denmark; New York-Presbyterian Hospital/Weill Cornell Medical Center, New York (F.J.M.); and the Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore (R.A.W.).

Background: The benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β-agonist (LABA), as compared with dual therapy (either inhaled glucocorticoid-LABA or LAMA-LABA), are uncertain.

Methods: In this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once-daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 μg, umeclidinium (a LAMA) at a dose of 62.5 μg, and vilanterol (a LABA) at a dose of 25 μg (triple therapy) with fluticasone furoate-vilanterol (at doses of 100 μg and 25 μg, respectively) and umeclidinium-vilanterol (at doses of 62.5 μg and 25 μg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment.

Results: The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate-vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P<0.001) and 1.21 per year in the umeclidinium-vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001). The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium-vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P<0.001). There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium-vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium-vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001).

Conclusions: Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate-vilanterol or umeclidinium-vilanterol in this population. Triple therapy also resulted in a lower rate of hospitalization due to COPD than umeclidinium-vilanterol. (Funded by GlaxoSmithKline; IMPACT ClinicalTrials.gov number, NCT02164513 .).
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http://dx.doi.org/10.1056/NEJMoa1713901DOI Listing
May 2018

Once-Daily Triple Therapy in Patients with COPD: Patient-Reported Symptoms and Quality of Life.

Adv Ther 2018 01 8;35(1):56-71. Epub 2018 Jan 8.

Respiratory Research and Development, GSK, King of Prussia, PA, USA.

Introduction: Directly recorded patient experience of symptoms and health-related quality of life (HRQoL) can complement lung function and exacerbation rate data in chronic obstructive pulmonary disease (COPD) clinical studies. The FULFIL study recorded daily symptoms and activity limitation together with additional patient-reported outcomes of dyspnea and HRQoL, as part of the prespecified analyses. FULFIL co-primary endpoint data have been previously reported.

Methods: FULFIL was a phase III, 24-week, randomized, double-blind, double-dummy, multicenter study comparing once-daily single inhaler triple therapy [fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI)] 100 µg/62.5 µg/25 µg with twice-daily inhaled corticosteroid/long-acting β-agonist therapy [budesonide/formoterol (BUD/FOR)] 400 µg/12 µg in patients with symptomatic COPD at risk of exacerbations. A subset participated for 52 weeks. Patient-reported assessments were: Evaluating Respiratory Symptoms in COPD™ (E-RS: COPD), St George's Respiratory Questionnaire (SGRQ) for COPD, COPD Assessment Test (CAT), baseline and transitional dyspnea indices (TDI) and daily and global anchor questions for activity limitation.

Results: FF/UMEC/VI showed greater reductions from baseline in 4-weekly mean E-RS: COPD total and all subscale scores compared with BUD/FOR; differences were statistically significant (P < 0.05) at each time period. FF/UMEC/VI also demonstrated greater improvements from baseline at weeks 4 and 24 in SGRQ domain scores and TDI focal score compared with BUD/FOR. At weeks 4 and 24, improvements greater than the minimal clinically important difference from baseline were observed in CAT score with FF/UMEC/VI, but not BUD/FOR; differences were statistically significant (P ≤ 0.003).

Conclusion: These findings demonstrate sustained daily symptom and HRQoL benefits of FF/UMEC/VI versus BUD/FOR. The inclusion of the CAT may provide data that are readily generalizable to everyday clinical practice.

Trial Registration: ClinicalTrials.gov number: NCT02345161.

Funding: GSK.
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http://dx.doi.org/10.1007/s12325-017-0650-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778187PMC
January 2018

Once-Daily Triple Therapy in Patients with Advanced COPD: Healthcare Resource Utilization Data and Associated Costs from the FULFIL Trial.

Adv Ther 2017 09 5;34(9):2163-2172. Epub 2017 Sep 5.

Respiratory Research and Development, GSK, King of Prussia, PA, USA.

Introduction: Chronic obstructive pulmonary disease is associated with a high healthcare resource and cost burden. Healthcare resource utilization was analyzed in patients with symptomatic chronic obstructive pulmonary disease at risk of exacerbations in the FULFIL study. Patients received either once-daily, single inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol) 100 µg/62.5 µg/25 µg or twice-daily dual inhaled corticosteroid/long-acting beta agonist therapy (budesonide/formoterol) 400 µg/12 µg.

Methods: FULFIL was a phase III, randomized, double-blind, double-dummy, multicenter study. Unscheduled contacts with healthcare providers were recorded by patients in a daily electronic diary; the costs of healthcare resource utilization were calculated post hoc using UK reference costs.

Results: Over 24 weeks, slightly fewer patients who received fluticasone furoate/umeclidinium/vilanterol (169/911; 18.6%) required contacts with healthcare providers compared with budesonide/formoterol (180/899; 20.0%). Over 52 weeks in an extension population, fewer patients who received fluticasone furoate/umeclidinium/vilanterol required unscheduled contacts with healthcare providers compared with budesonide/formoterol (25.2% vs. 32.7%). Non-drug costs per treated patient per year were lower in the fluticasone furoate/umeclidinium/vilanterol group than the budesonide/formoterol group over 24 and 52 weeks (£653.80 vs. £763.32 and £749.22 vs. £988.03, respectively), with the total annualized cost over 24 weeks being slightly greater for fluticasone furoate/umeclidinium/vilanterol than budesonide/formoterol (£1,289.35 vs. £1,267.45).

Conclusions: This healthcare resource utilization evidence suggests that, in a clinical trial setting over a 24- or 52-week timeframe, non-drug costs associated with management of a single inhaler fluticasone furoate/umeclidinium/vilanterol are lower compared with twice-daily budesonide/formoterol.

Trial Registration: ClinicalTrials.gov number: NCT02345161.

Funding: GSK.
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http://dx.doi.org/10.1007/s12325-017-0604-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599456PMC
September 2017

Socioeconomic Status as a Determinant of Health Status Treatment Response in COPD Trials.

Chronic Obstr Pulm Dis 2017 Apr 1;4(2):150-158. Epub 2017 Apr 1.

Research and Development, GlaxoSmithKline, Uxbridge, United Kingdom.

: Randomized controlled trials (RCTs) often recruit patients from low and high socioeconomic status (SES) countries, but little is known about the effect of SES on clinical outcomes, particularly patient-centered measures of symptomatic benefit. : Combined individual chronic obstructive pulmonary disease (COPD) patient data from the placebo and long-acting bronchodilator arms of 17 RCTs (from the COPD Biomarkers Qualification Consortium database) were analyzed. Health status was measured using the St George's Respiratory Questionnaire (SGRQ) (minimum clinically important difference [MCID]: 4 units). Trials were grouped into short-term (≤12 months) and medium-term (>12 months to 48 months). A participant's country of residence was categorized into Low/Medium or High SES using World Health Organization criteria. : Data from 19765 individuals (6109 Low/Medium SES) were available. Patients in Low/Medium SES countries had more severe disease at baseline. Improvement in SGRQ score with placebo was ≈2 units greater in Low/Medium than in High SES countries; at its greatest, the improvement from baseline exceeded the MCID in Low/Medium countries. This difference was maintained for at least 1 year. Improvement with bronchodilator was also greater in Low/Medium versus High SES countries; overall there was no evidence that the treatment effect versus placebo was different between countries of different SES status. : Participants in Low/Medium SES countries experienced significantly larger treatment effects, irrespective of treatment group (placebo and bronchodilator). Despite this, COPD patients in Low/Medium SES countries experienced a health status gain from long-acting bronchodilator treatment that is similar to that seen in High SES countries.
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http://dx.doi.org/10.15326/jcopdf.4.2.2017.0132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559114PMC
April 2017

St George's Respiratory Questionnaire Score Predicts Outcomes in Patients with COPD: Analysis of Individual Patient Data in the COPD Biomarkers Qualification Consortium Database.

Chronic Obstr Pulm Dis 2017 Mar 28;4(2):141-149. Epub 2017 Mar 28.

Research and Development, GlaxoSmithKline, Uxbridge, United Kingdom.

We aimed to estimate the usefulness of a disease specific health status measure, the St George's Respiratory Questionnaire (SGRQ), to predict outcomes in patients with chronic obstructive pulmonary disease (COPD). Individual patient-data of 12043 patients from long-term randomized clinical trials (2-4 years' duration) in the COPD Biomarkers Qualification Consortium database were analyzed. The adverse COPD outcomes were: exacerbations of COPD, hospital admissions due to exacerbation and all-cause mortality. Cox proportional hazards regression was used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for quartiles of SGRQ scores at baseline and time to first event, and time from first to second event, where appropriate. The risk of adverse COPD outcomes increased with each increasing quartile of SGRQ score for all time to first event analyses. When comparing the lowest versus the highest quartile, the event risk (HRs [95% CIs]) increased by 40% for exacerbations (1.40 [1.29, 1.51]); 2-fold for hospital admissions (2.01 [1.78, 2.28]) and more than 2-fold for all-cause mortality (2.30 [1.91, 2.78]). For second event analyses in a subset of eligible patients, these trends persisted albeit with reduced risk estimates for exacerbations. Among patients with COPD, health status measured by a SGRQ score predicted exacerbations of COPD, hospital admissions due to exacerbations and their recurrence and death after adjustment. These data support the rationale for a health status measure use as a drug development tool and suggest that a health status measure may also have a role in risk assessment for COPD patients in routine medical care.
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http://dx.doi.org/10.15326/jcopdf.4.2.2017.0131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559113PMC
March 2017

Baseline Severity as Predictor of Change in St George's Respiratory Questionnaire Scores in Trials of Long-acting Bronchodilators with COPD Patients.

Chronic Obstr Pulm Dis 2017 Mar 21;4(2):132-140. Epub 2017 Mar 21.

Research and Development, GlaxoSmithKline, Uxbridge, United Kingdom.

In trials oflong-acting bronchodilators, health status is an important trial outcome, however the influence of baseline severity on response measured by St George's Respiratory Questionnaire (SGRQ) is not known. We have compared SGRQ changes between patients with chronic obstructive pulmonary disease (COPD) of mild-moderate severity or dyspnea (Global initiative for chronic Obstructive Lung disease [GOLD] grades 1 and 2; modified Medical Research Council [mMRC] grades 1 and 2) to those with severe-very severe severity or dyspnea (GOLD grades 3 and 4; mMRC grades 3 and 4). Combined individual patient data from the COPD Biomarkers Qualification Consortium database (trials of long-acting bronchodilators) were used comprising of patients from short-term (≤1-year duration; n=10802) and medium-term (2-4 years' duration; n=8963) studies. A repeated measures analysis of variance (ANOVA) was used to determine the effects of baseline severity (GOLD/mMRC) on SGRQ response to treatment. All treatment arms were combined. In short-term studies, milder patients showed a greater response than those with more severe disease in terms of GOLD grade (partial Eta = 0.03, < 0.0001) and mMRC grade (partial Eta = 0.05, < 0.0001). Similar results were seen in the medium-term studies (partial Eta = 0.02, < 0.0001; mMRC: partial Eta = 0.05, < 0.0001,). Patients with less severe airflow limitation and less severe dyspnea showed larger improvements in SGRQ score than more severely obstructed or dyspneic patients. Although these severity influences are small (2%-5% of the variance in SGRQ score), they do suggest that pre-specified separate analyses are warranted to test for differences in response, based on baseline severity.
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http://dx.doi.org/10.15326/jcopdf.4.2.2017.0129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559112PMC
March 2017

Responder Analyses for Treatment Effects in COPD Using the St George's Respiratory Questionnaire.

Chronic Obstr Pulm Dis 2017 Mar 2;4(2):124-131. Epub 2017 Mar 2.

Research and Development, GlaxoSmithKline, Uxbridge, United Kingdom.

: Patient-reported outcomes data in clinical trials are usually reported as mean values, interpreted in comparison to a minimum clinically important difference (MCID) and ignoring the possibility of a sizable proportion of patients experiencing a worthwhile benefit when the majority did not. This analysis tested the reliability of calculated responder rates (from chronic obstructive pulmonary disease [COPD] patients) with the St George's Respiratory Questionnaire (SGRQ) using a range of responder cut-points above and below the MCID (4 units). : Individual patient data (i.e., data from long-acting bronchodilator [LAB] and inhaled corticosteroids [ICS]/long-acting beta2-agonist [LABA] randomized clinical studies) in the COPD Biomarker Qualification Consortium database were used: short-term (≤1-year duration; 14,814 patients,) and medium-term (2-4 years; 12,043 patients). Responder rates versus placebo across SGRQ score change thresholds ranging from -1.5 to -8.0 were tested; differences were expressed as the odds ratio (OR) of a patient exceeding the threshold versus no change or deterioration. : The ORs measuring benefit of active treatment were similar across thresholds in short-term studies (LAB, ORs 1.40-1.42; LABA/ICS, 1.50-1.56) and medium-term LAB studies (ORs 1.34-1.43), whereas ORs in medium-term studies with LABA/ICS intervention showed a trend for higher response rates at higher values of threshold cut-points (1.64-1.79). In short-term studies, different thresholds had little effect on the OR between active drugs versus a trend for lower ORs with lower thresholds in medium-term studies. : The OR for a treatment effect compared with placebo appears consistent across a range of responder cut-points. In medium-term trials, the treatment difference between active drugs suggests that use of a lower threshold would not increase the odds of observing a measured treatment difference.
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http://dx.doi.org/10.15326/jcopdf.4.2.2017.0130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559111PMC
March 2017

The COPD Biomarkers Qualification Consortium Database: Baseline Characteristics of the St George's Respiratory Questionnaire Dataset.

Chronic Obstr Pulm Dis 2017 Mar 13;4(2):112-123. Epub 2017 Mar 13.

Research and Development, GlaxoSmithKline, Uxbridge, United Kingdom.

The COPD Biomarkers Qualification Consortium (CBQC) is a public-private partnership formed in 2010 with a goal of qualifying biomarkers and clinical assessment tools for use in clinical or nonclinical decision-making and particularly within the regulatory context. The St George's Respiratory Questionnaire (SGRQ) is a measure of health-related quality of life widely used in clinical research. The aim of the CBQC working group on SGRQ was to construct an individual patient level database of clinical trial data that included the SGRQ, to use this to confirm the reliability and validity of the SGRQ as an outcome measure of health status, and investigate its use as a predictor of future events (exacerbations and mortality). This manuscript describes the formulation of the CBQC database and presents the baseline demographic and clinical characteristics of the integrated SGRQ database overall, and by study type (short-term [≤1 year], medium-term [2-4 years] and observational studies). Distribution of baseline SGRQ scores varied little by demographic determinants except for income region in the observational data set (low-middle income countries +10 units compared with high income, <0.0001) and this observation held across studies. SGRQ scores increased with increasing modified Medical Research Council dyspnea scores (mean differences ranged 6.9-17.9 units) and with increasing airflow limitations (Global initiative for chronic Obstructive Lung Disease grades 1 to 4; differences ranged 4.5-16.1 units), consistent across study types. As a method of cross-sectional comparison, the SGRQ appears to be relatively free of bias from demographic factors although care should be taken when making cross sectional comparisons of scores between patients in countries at different levels of socio-economic development/.
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http://dx.doi.org/10.15326/jcopdf.4.2.2017.0128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559110PMC
March 2017

The COPD Biomarkers Qualification Consortium St George's Respiratory Questionnaire Manuscripts: Output of a Consortium to Advance Drug Development.

Chronic Obstr Pulm Dis 2017 Feb 28;4(2):109-111. Epub 2017 Feb 28.

Research and Development, GlaxoSmithKline, Uxbridge, United Kingdom.

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http://dx.doi.org/10.15326/jcopdf.4.2.2017.0127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559109PMC
February 2017

FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med 2017 08;196(4):438-446

1 GlaxoSmithKline, King of Prussia, Pennsylvania.

Rationale: Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) are limited.

Objectives: We compared the effects of once-daily triple therapy on lung function and health-related quality of life with twice-daily ICS/LABA therapy in patients with COPD.

Methods: The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 μg/62.5 μg/25 μg; ELLIPTA inhaler) with twice-daily ICS/LABA therapy (budesonide/formoterol 400 μg/12 μg; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co-primary endpoints were change from baseline in trough FEV and in St. George's Respiratory Questionnaire (SGRQ) total score at Week 24.

Measurements And Main Results: In the intent-to-treat population (n = 1,810) at Week 24 for triple therapy (n = 911) and ICS/LABA therapy (n = 899), mean changes from baseline in FEV were 142 ml (95% confidence interval [CI], 126 to 158) and -29 ml (95% CI, -46 to -13), respectively, and mean changes from baseline in SGRQ scores were -6.6 units (95% CI, -7.4 to -5.7) and -4.3 units (95% CI, -5.2 to -3.4), respectively. For both endpoints, the between-group differences were statistically significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% reduction; 95% CI, 14-51; P = 0.002). The safety profile of triple therapy reflected the known profiles of the components.

Conclusions: These results support the benefits of single-inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02345161).
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http://dx.doi.org/10.1164/rccm.201703-0449OCDOI Listing
August 2017

Assessment of the efficacy and safety of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler versus a multi-dose inhaler in patients with chronic obstructive pulmonary disease.

Pulm Pharmacol Ther 2017 04 21;43:12-19. Epub 2017 Jan 21.

GlaxoSmithKline, Stockley Park, Uxbridge, UK.

Background: This study tested the clinical non-inferiority of the fluticasone propionate/salmeterol combination 50/250 μg (FSC) Rotacaps/Rotahaler system, a single unit dose inhaler, with the multi-dose FSC Diskus inhaler in adults with chronic obstructive pulmonary disease (COPD).

Methods: This multi-centre, randomised, double-blind, double-dummy, two-way cross-over study compared 12 weeks' treatment of FSC administered twice daily using Rotacaps/Rotahaler or Diskus. The primary endpoint was change from baseline in trough morning forced expiratory volume in 1 s (FEV) at Day 85, and the pre-defined non-inferiority criteria was: the lower limit of the confidence interval (CI) for the treatment difference (Rotacaps/Rotahaler-Diskus) in least squares (LS) mean change from baseline, being greater than -45 mL. Secondary endpoints included change in breathlessness (as measured by transition dyspnoea index (TDI)) and COPD-specific health status measures.

Results: The LS mean increase from baseline in trough FEV at Day 85 was 116 mL in the Rotacaps/Rotahaler group and 91 mL in the Diskus group (difference in model-adjusted LS mean change: 25 mL (95% CI 2 mL, 47 mL)), the lower limit of the CI for the treatment difference being greater than the protocol-defined criterion for non-inferiority i.e. -45 mL. Data for breathlessness, COPD-specific health status and safety parameters were similar following FSC treatment via either inhaler.

Conclusions: This study demonstrated the clinical non-inferiority of FSC 50/250 μg when administered using Rotacaps/Rotahaler compared with Diskus in patients with COPD. The risk:benefit profile for the two inhalers was comparable.
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http://dx.doi.org/10.1016/j.pupt.2017.01.009DOI Listing
April 2017

Interpreting patient-reported outcomes from clinical trials in COPD: a discussion.

Int J Chron Obstruct Pulmon Dis 2016 7;11:3069-3078. Epub 2016 Dec 7.

Global Respiratory Franchise, GlaxoSmithKline, Uxbridge, UK; William Harvey Institute, Bart's and the London School of Medicine and Dentistry, London, UK.

One of the challenges faced by the practising physician is the interpretation of patient-reported outcomes (PROs) in clinical trials and the relevance of such data to their patients. This is especially true when caring for patients with progressive diseases such as COPD. In an attempt to incorporate the patient perspective, many clinical trials now include assessments of PROs. These are formalized methods of capturing patient-centered information. Given the importance of PROs in evaluating the potential utility of an intervention for a patient with COPD, it is important that physicians are able to critically interpret (and critique) the results derived from them. Therefore, in this paper, a series of questions is posed for the practising physician to consider when reviewing the treatment effectiveness as assessed by PROs. The focus is on the St George's Respiratory Questionnaire for worked examples, but the principles apply equally to other symptom-based questionnaires. A number of different ways of presenting PRO data are discussed, including the concept of the minimum clinically important difference, whether there is a ceiling effect to PRO results, and the strengths and weaknesses of responder analyses. Using a worked example, the value of including a placebo arm in a study is illustrated, and the influence of the study on PRO results is considered, in terms of the design, patient withdrawal, and the selection of the study population. For the practising clinician, the most important consideration is the importance of individualization of treatment (and of treatment goals). To inform such treatment, clinicians need to critically review PRO data. The hope is that the questions posed here will help to build a framework for this critical review.
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http://dx.doi.org/10.2147/COPD.S117378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153282PMC
August 2017

Assessment of the efficacy and safety of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler in patients with asthma.

Pulm Pharmacol Ther 2016 12 4;41:19-24. Epub 2016 Sep 4.

Clinical Pharmacology Modeling Simulation, GlaxoSmithKline, Research Triangle Park, NC, USA.

Background: In developing countries, there is a need for access to affordable inhaled respiratory medicines. This study tested the clinical non-inferiority of fluticasone propionate/salmeterol combination (FSC) 50/250 μg Rotacaps/Rotahaler compared with FSC 50/250 μg Diskus.

Methods: A multi-centre, randomised, double-blind, double-dummy study evaluated 12 weeks, twice daily treatment of FSC 50/250 μg administered using Rotacaps/Rotahaler or Diskus inhaler in a crossover design in patients with asthma (pre-bronchodilator forced expiratory volume in 1 s (FEV) 40%-85% of predicted, FEV reversibility ≥12%, prior stable dose with inhaled corticosteroid (ICS) or ICS/long acting beta-agonist). The primary efficacy endpoint, change from baseline in trough morning FEV at Day 85, was analysed using a model for repeated measures analysis. The pre-defined criterion for non-inferiority was the lower limit of the CI (0.025, one-sided significance level) for the treatment difference (Rotacaps/Rotahaler-Diskus) in least squares (LS) mean change from baseline, being greater than -125 mL. Secondary endpoints included serial FEV measurements, morning peak expiratory flow (PEF), rescue medication use, day- and night-time asthma symptoms, Asthma Control Test (ACT) scores, and serial cortisol measured over 12 h (area under the curve (AUC)).

Results: Treatment with FSC 50/250 μg via Rotacaps/Rotahaler or Diskus resulted in a similar LS mean increase from baseline in trough FEV at Day 85 (231 mL and 203 mL respectively). The difference in the model-adjusted LS mean change was 28 mL (95% CI -24 mL, 80 mL), fulfilling the criterion for non-inferiority. Data for all secondary endpoints were similar for the two treatments, supporting the primary endpoint findings. Both treatments were well tolerated and demonstrated similar safety profiles.

Conclusion: This study demonstrated the clinical non-inferiority of FSC 50/250 μg when administered using Rotacaps/Rotahaler compared with administration using Diskus in patients with asthma, and suggests there is no difference in the risk:benefit profile between the two FSC inhalers.
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http://dx.doi.org/10.1016/j.pupt.2016.09.002DOI Listing
December 2016

Correct usage, ease of use, and preference of two dry powder inhalers in patients with COPD: analysis of five phase III, randomized trials.

Int J Chron Obstruct Pulmon Dis 2016 16;11:1873-80. Epub 2016 Aug 16.

Respiratory Medicines Development Center, GlaxoSmithKline, Durham, NC, USA.

Background: Handheld inhalers are used to deliver treatment for COPD. Incorrect usage leads to suboptimal disease control. Complex treatment regimens and use of multiple inhalers may reduce patient compliance. The Anoro Ellipta™ dry powder inhaler (DPI) simultaneously delivers umeclidinium bromide (UMEC) and vilanterol (VI) without coformulation being required.

Aim: To assess the correct usage and ease of use of the Ellipta™ DPI administering UMEC/VI and to compare patient preference for Ellipta™ with the HandiHaler(®) through exploratory analyses of patient and observer questionnaires in five Phase III studies.

Methods: Two Phase III, 3-month double-blind, placebo-controlled studies assessed the correct usage of the Ellipta™ DPI at Day 1 and after 6 weeks, and ease of use of the Ellipta™ DPI using a nonvalidated patient questionnaire after 6 weeks or early withdrawal. In three 6-month, blinded double-dummy, active comparator studies (two Phase IIIa and one Phase IIIb), patients completed a COPD device preference questionnaire between the Ellipta™ DPI and the Handi-Haler(®) at Day 168 (Week 24) or early withdrawal.

Results: In the 3-month placebo-controlled studies, ≥98% of patients used the Ellipta™ DPI correctly and 99% of patients found the inhaler easy/very easy-to-use and the dose counter easy/very easy to read. Across the two Phase IIIa active comparator studies, patients consistently stated a preference for the Ellipta™ DPI over HandiHaler(®) regarding the number of steps to use (59% vs 17%), time taken to use (62% vs 14%), and ease of use (63% vs 15%) regardless of which inhaler contained active drug. Results were consistent in the Phase IIIb active comparator study.

Conclusion: Delivery of UMEC/VI via the Ellipta™ DPI was considered easy-to-use, and patients with COPD demonstrated clear preference for this inhaler compared with HandiHaler(®).
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http://dx.doi.org/10.2147/COPD.S109121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996255PMC
August 2017
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