Patient-Reported Outcome Measures for Severe Recurrent Bilateral Nasal Polyps: Psychometric Evaluation and Content Validity.

Objective: To date, no patient-reported outcome measures have been specifically developed to assess pharmacological treatment effect in participants with severe chronic rhinosinusitis (CRS) with recurrent bilateral nasal polyps (NP). These studies aimed to assess (1) the psychometric properties and (2) content validity of Visual Analogue Scales (VAS) assessing NP symptom severity. Study Design: (1) Retrospective psychometric validation study using clinical trial data and (2) cross-sectional qualitative patient interview study. Setting: (1) Multicentre trial; (2) real-world. Methods: (1) Psychometric validation was performed using data from a randomized, double-blind, placebo-controlled, Phase II study (NCT01362244) investigating the effect of mepolizumab in 105 participants with severe, recurrent bilateral NP currently needing polypectomy surgery. (2) Content validity was explored through cognitive debriefing interviews in 27 adults with severe CRS with recurrent bilateral NP who had received NP surgery in the past 10 years (NCT03221192). Results: (1) Acceptable reliability, validity, and responsiveness were shown for individual VAS items, although the loss of smell VAS item performed poorly in several analyses, suggesting further evaluation of this item is needed. (2) All individual VAS items were well understood, considered relevant and were consistently interpreted by most participants, providing evidence for their content validity. Conclusion: These findings support the use of symptom VAS measures to evaluate disease experience and treatment effect in clinical trials of participants with severe CRS with recurrent bilateral NP.

Mepolizumab improves work productivity, activity limitation, symptoms, and rescue medication use in severe eosinophilic asthma.

Patients with severe eosinophilic asthma experience daily activity limitations and reduced productivity at work. Using anonymized individual patient-level data from two previously conducted randomized, double-blind, placebo-controlled studies (MENSA [GSK ID:115588/NCT01691521]; MUSCA [GSK ID:200862/NCT02281318]), we investigated the effect of mepolizumab on work productivity, activity limitation, symptoms, and rescue medication use. Patient-reported outcomes including Work Productivity and Activity Impairment-General Health (WPAI-GH) scores (impairment percentages, 0%-100%), global activity limitation (scale 1-4), and perceived change in activity limitation (Likert scale 1-7) since the start of the study were analyzed. WPAI-GH scores from MENSA were analyzed post hoc for employed patients using mixed model repeated measures; global activity limitation and perceived change in activity limitation from MUSCA were analyzed by ordinal logistic regression. Mean changes from baseline in daily asthma symptom scores (scale 0-5) and rescue medication use (occasions/day) were also assessed, via a post hoc meta-analysis of MENSA and MUSCA. At study end, WPAI-GH scores indicative of overall work impairment, impairment while working, and activity impairment consistently improved with mepolizumab versus placebo. Overall, 76% versus 54% of patients rated their activity as "much better," "better," or "slightly better" since the start of the study with mepolizumab versus placebo. Mepolizumab was associated with numerically larger improvements from baseline in asthma symptoms (treatment difference 0.21-0.29 points) and rescue medication use (treatment difference -0.08 to -0.22 occasions/day) versus placebo. Our results indicate that patients with severe eosinophilic asthma may experience improved activity limitation, work productivity, symptoms, and rescue medication use with mepolizumab.

Response to mepolizumab treatment is sustained across 4-weekly dosing periods.

BACKGROUND: Mepolizumab (100 mg delivered s.c. every 4 weeks) is indicated for add-on maintenance treatment for patients with severe eosinophilic asthma. Mepolizumab has been shown to reduce exacerbations and the requirement for daily oral corticosteroids, and improve asthma control and symptoms. However, data on the durability of the response to mepolizumab during dosing periods are limited. The aim of this study was to investigate the efficacy profile in patients with severe eosinophilic asthma over the 4-weekly dosing period for various fixed mepolizumab doses. METHODS: This was a post hoc analysis of data from the phase IIb/III DREAM study. Patients ≥12 years of age with severe eosinophilic asthma were randomised (1:1:1:1) to receive intravenous mepolizumab 75 mg (equivalent to 100 mg s.c.), 250 mg, 750 mg or placebo, plus standard of care, every 4 weeks for 52 weeks. The number of exacerbations and eDiary data (peak expiratory flow, rescue medication use and symptom scores) from two periods in each 4-weekly dosing interval (days 1-14 and 15-28) over the 52-week treatment period were analysed. FINDINGS: eDiary data and the proportion of patients experiencing ≥1 exacerbation were similar during the first and second 2 weeks of a dosing period across all mepolizumab doses. INTERPRETATION: These results demonstrate that the response to mepolizumab is sustained over the 4-weekly dosing period with no differences across a 10-fold dose range and supports the use of the current mepolizumab dosing regimen in patients with severe eosinophilic asthma.

Adding new experimental arms to randomised clinical trials: Impact on error rates.

BACKGROUND: Experimental treatments pass through various stages of development. If a treatment passes through early-phase experiments, the investigators may want to assess it in a late-phase randomised controlled trial. An efficient way to do this is adding it as a new research arm to an ongoing trial while the existing research arms continue, a so-called multi-arm platform trial. The familywise type I error rate is often a key quantity of interest in any multi-arm platform trial. We set out to clarify how it should be calculated when new arms are added to a trial some time after it has started. METHODS: We show how the familywise type I error rate, any-pair and all-pairs powers can be calculated when a new arm is added to a platform trial. We extend the Dunnett probability and derive analytical formulae for the correlation between the test statistics of the existing pairwise comparison and that of the newly added arm. We also verify our analytical derivation via simulations. RESULTS: Our results indicate that the familywise type I error rate depends on the shared control arm information (i.e. individuals in continuous and binary outcomes and primary outcome events in time-to-event outcomes) from the common control arm patients and the allocation ratio. The familywise type I error rate is driven more by the number of pairwise comparisons and the corresponding (pairwise) type I error rates than by the timing of the addition of the new arms. The familywise type I error rate can be estimated using Sidák's correction if the correlation between the test statistics of pairwise comparisons is less than 0.30. CONCLUSIONS: The findings we present in this article can be used to design trials with pre-planned deferred arms or to add new pairwise comparisons within an ongoing platform trial where control of the pairwise error rate or familywise type I error rate (for a subset of pairwise comparisons) is required.

Baseline blood eosinophil count as a predictor of treatment response to the licensed dose of mepolizumab in severe eosinophilic asthma.

BACKGROUND: Previous analyses examining the relationship between blood eosinophil count and mepolizumab treatment effects in severe eosinophilic asthma have used a range of doses and administration routes. METHODS: This post hoc meta-analysis included data from the MENSA (MEA115588/NCT01691521) and MUSCA (200862/NCT02281318) trials. Patients (≥12 years) with severe eosinophilic asthma who experienced ≥2 exacerbations in the prior year received either mepolizumab 100 mg subcutaneously (SC) or 75 mg intravenously, or placebo plus standard of care every 4 weeks. This meta-analysis reports data from patients receiving the licensed dose of mepolizumab (100 mg SC) or placebo only. The primary endpoint was the annual rate of clinically significant exacerbations; secondary endpoints included rate of exacerbations requiring hospitalization/emergency room (ER) visit, proportion of patients with no clinically significant exacerbations, and changes from baseline in forced expiratory volume in 1 s, Asthma Control Questionnaire-5 and St George's Respiratory Questionnaire scores. Analyses were stratified by baseline blood eosinophil count (<150, ≥150, ≥300, ≥400, ≥500, ≥750, ≥1000, ≥150-<300, or ≥300-<500 cells/µL). RESULTS: Mepolizumab reduced annual clinically significant exacerbation rates by 45%-85%, exacerbations requiring hospitalization/ER visit by 60%-70%, and increased the odds of no clinically significant exacerbations across all eosinophil threshold subgroups versus placebo, and improved all other secondary endpoints in subgroups ≥150 cells/µL. Greater treatment effects with increasing blood eosinophil count were observed. CONCLUSIONS: Mepolizumab demonstrated consistent clinical benefits in patients with baseline blood eosinophil counts ≥150 cells/µL, confirming the suitability of this cut-off for identifying patients responsive to the licensed mepolizumab dose.

Mepolizumab reduces exacerbations in patients with severe eosinophilic asthma, irrespective of body weight/body mass index: meta-analysis of MENSA and MUSCA.

BACKGROUND: We assessed the efficacy of the licensed mepolizumab dose (100 mg subcutaneously [SC]) in patients with severe eosinophilic asthma according to body weight/body mass index (BMI). METHODS: This was a post hoc individual patient-level meta-analysis of data from the Phase 3 studies MENSA (MEA115588/NCT01691521) and MUSCA (200862/NCT02281318). Patients aged ≥12 years with severe eosinophilic asthma and a history of exacerbations were randomised to 4-weekly placebo, mepolizumab 75 mg intravenously (IV) or 100 mg SC (MENSA) or placebo or mepolizumab 100 mg SC (MUSCA) for 32 (MENSA) or 24 (MUSCA) weeks. The primary endpoint was the annual rate of clinically significant exacerbations; other outcomes included the proportion of patients with no exacerbations, lung function, St George's Respiratory Questionnaire (SGRQ) and Asthma Control Questionnaire-5 (ACQ-5) scores and blood eosinophil counts. Analyses were performed by baseline body weight and BMI (≤60, > 60-75, > 75-90, > 90, < 100, ≥100 kg; ≤25, > 25-30, > 30, < 36, ≥36 kg/m2). RESULTS: Overall, 936 patients received placebo or mepolizumab 100 mg SC. Across all body weight/BMI categories, mepolizumab reduced the rate of clinically significant exacerbations by 49-70% versus placebo. Improvements with mepolizumab versus placebo were also seen in lung function in all body weight/BMI categories except > 90 kg; improvements in SGRQ and ACQ-5 scores were seen across all categories. CONCLUSIONS: Mepolizumab 100 mg SC has consistent clinical benefits in patients with severe eosinophilic asthma across a range of body weights and BMIs. Data show that the fixed-dose regimen of mepolizumab is suitable, without the need for weight-based dosing. TRIAL REGISTRATION: This manuscript is a post hoc meta-analysis of data from the Phase 3 studies MENSA and MUSCA. ClinicalTrials.gov, NCT01691521 (MEA115588; MENSA). Registered September 24, 2012. ClinicalTrials.gov, NCT02281318 (200862; MUSCA). Registered November 3, 2014.

Effect of mepolizumab in severe eosinophilic asthma according to omalizumab eligibility.

BACKGROUND: Patients with severe asthma can present with overlapping eosinophilic and allergic phenotypes, which makes it challenging when deciding which biologic therapy is most appropriate to reduce exacerbations and help achieve asthma control. OBJECTIVE: This post hoc meta-analysis evaluated the efficacy of the licensed dose of mepolizumab (100 mg administered subcutaneously [SC]) versus placebo in patients with severe eosinophilic asthma (SEA), according to omalizumab eligibility and associated allergic characteristics. METHODS: Data from two Phase 3 studies (MENSA [MEA115588/NCT01691521]; MUSCA [200862/NCT02281318]) were analyzed. Patients ≥12 years of age with SEA who experienced ≥2 exacerbations in the previous year received placebo, mepolizumab 100 mg SC or 75 mg intravenously, plus standard of care (high-dose inhaled corticosteroids and other controllers), every 4 weeks. Data from patients who received ≥1 dose placebo or mepolizumab 100 mg SC were used for this analysis. The primary endpoint was the rate of clinically significant exacerbations; other outcomes included forced expiratory volume in 1 s (FEV1), Asthma Control Questionnaire (ACQ-5) score and quality of life measured using St George's Respiratory Questionnaire (SGRQ). RESULTS: Rate reductions in clinically significant exacerbations with mepolizumab versus placebo were similar in omalizumab eligible and ineligible patients (57% vs 55%). FEV1, ACQ-5 and SGRQ scores improved with mepolizumab versus placebo regardless of omalizumab eligibility, Immunoglobulin E levels, or atopic status. CONCLUSION: This analysis indicated that mepolizumab 100 mg SC has clinical benefit in patients with blood eosinophil counts ≥150 cells/µL (or history of ≥300 cells/µL), regardless of allergic characteristics or omalizumab eligibility.

Treatment policy estimands for recurrent event data using data collected after cessation of randomised treatment.

In the past, many clinical trials have withdrawn subjects from the study when they prematurely stopped their randomised treatment and have therefore only collected 'on-treatment' data. Thus, analyses addressing a treatment policy estimand have been restricted to imputing missing data under assumptions drawn from these data only. Many confirmatory trials are now continuing to collect data from subjects in a study even after they have prematurely discontinued study treatment as this event is irrelevant for the purposes of a treatment policy estimand. However, despite efforts to keep subjects in a trial, some will still choose to withdraw. Recent publications for sensitivity analyses of recurrent event data have focused on the reference-based imputation methods commonly applied to continuous outcomes, where imputation for the missing data for one treatment arm is based on the observed outcomes in another arm. However, the existence of data from subjects who have prematurely discontinued treatment but remained in the study has now raised the opportunity to use this 'off-treatment' data to impute the missing data for subjects who withdraw, potentially allowing more plausible assumptions for the missing post-study-withdrawal data than reference-based approaches. In this paper, we introduce a new imputation method for recurrent event data in which the missing post-study-withdrawal event rate for a particular subject is assumed to reflect that observed from subjects during the off-treatment period. The method is illustrated in a trial in chronic obstructive pulmonary disease (COPD) where the primary endpoint was the rate of exacerbations, analysed using a negative binomial model.

Anti-IL-5 treatments in patients with severe asthma by blood eosinophil thresholds: Indirect treatment comparison.

BACKGROUND: Three anti-IL-5 pathway-directed therapies are approved for use in patients with severe eosinophilic asthma (SEA); however, no head-to-head comparison data are available. OBJECTIVE: We sought to compare the efficacy of licensed doses of mepolizumab, benralizumab, and reslizumab in patients with SEA, according to baseline blood eosinophil counts. METHODS: This indirect treatment comparison (ITC) used data from a Cochrane review and independent searches. Eligible studies were randomized controlled trials in patients aged 12 years or greater with SEA. End points included annualized rate of clinically significant exacerbations and change from baseline in Asthma Control Questionnaire score and FEV1. An ITC was performed in patients with Asthma Control Questionnaire scores of 1.5 or greater and stratified by baseline blood eosinophil count. RESULTS: Eleven studies were included. All treatments significantly reduced the rate of clinically significant exacerbations and improved asthma control versus placebo in all blood eosinophil count subgroups. Mepolizumab reduced clinically significant exacerbations by 34% to 45% versus benralizumab across subgroups (rate ratio ≥400 cells/µL: 0.55 [95% CI, 0.35-0.87]; ≥300 cells/µL: 0.61 [95% CI, 0.37-0.99]; and ≥150 cells/µL: 0.66 [95% CI, 0.49-0.89]; all P < .05) and by 45% versus reslizumab in the 400 cells/µL or greater subgroup (rate ratio, 0.55 [95% CI, 0.36-0.85]; P = .007). Asthma control was significantly improved with mepolizumab versus benralizumab (all subgroups: P < .05) and versus reslizumab in the 400 cells/µL or greater subgroup (P = .004). Benralizumab significantly improved lung function versus reslizumab in the 400 cells/µL or greater subgroup (P = .025). CONCLUSIONS: This ITC of the licensed doses suggests that mepolizumab was associated with significantly greater improvements in clinically significant exacerbations and asthma control compared with reslizumab or benralizumab in patients with similar blood eosinophil counts.

Effect of continuous positive airway pressure therapy on circadian patterns of cardiac repolarization in patients with obstructive sleep apnoea: data from a randomized trial.

BACKGROUND: Obstructive sleep apnoea (OSA) has been proposed as an independent risk factor for sudden cardiac death (SCD). This study takes advantage of a previous randomized trial and seeks to evaluate circadian patterns of the QTc-interval, a marker of cardiac repolarization and biomarker for SCD, in patients with OSA. We hypothesized that patients with OSA would exhibit longest QTc during the night-time and that continuous positive airway pressure (CPAP) therapy would reverse this. METHODS: One hundred eighteen patients diagnosed with moderate-to-severe OSA were randomized to receive therapeutic or subtherapeutic CPAP for 4 weeks. Of these, 84 had full 24 h-Holter monitoring data at baseline and follow-up. Weighted means of all QTc-intervals were analysed over 24 h, during four time-periods (12 pm-6 am, 6 am-12 am, 12 am-6 pm, 6 pm-12 pm) as well as during each individual hour. A two-sided P value <0.05 was considered to be of statistical significance. RESULTS: QTc-intervals at baseline [mean (SD) over 24 h: 407.8 ms (36.6)] were highest from 6 pm-12 pm [411.7 ms (42.0)] and shortest from 6 am-12 am [405.4 ms (39.5)]. Overall 24 h CPAP treatment effect on QTc was -11.3 ms [95% confidence interval (CI), -22.1 to -0.6; P=0.039] and was estimated to be greater from 6 pm-12 pm than from 12 pm-6 am (P=0.068). The CPAP treatment effect on QTc was driven by those patients in the highest QTc decile at baseline (all >430 ms). In these patients, CPAP led to reductions in QTc, allowing reclassification into lower risk-associated values of QTc (<430 ms). CONCLUSIONS: In this exploratory study, CPAP treatment led to an overall reduction in the QTc-interval compared with subtherapeutic CPAP. This reduction seems more pronounced during evening hours and in patients with a QTc above 430 ms.

Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial.

BACKGROUND: Mepolizumab, an anti-interleukin-5 monoclonal antibody approved as add-on therapy to standard of care for patients with severe eosinophilic asthma, has been shown in previous studies to reduce exacerbations and dependency on oral corticosteroids compared with placebo. We aimed to further assess mepolizumab in patients with severe eosinophilic asthma by examining its effect on health-related quality of life (HRQOL). METHODS: We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial (MUSCA) in 146 hospitals or research centres in 19 countries worldwide. Eligible participants were patients aged 12 years or older with severe eosinophilic asthma and a history of at least two exacerbations requiring treatment in the previous 12 months before screening despite regular use of high-dose inhaled corticosteroids plus other controller medicines. Exclusion criteria included current smokers or former smokers with a history of at least ten pack-years. We randomly assigned participants (1:1) by country to receive a subcutaneous injection of either mepolizumab 100 mg or placebo, plus standard of care, every 4 weeks for 24 weeks (the final dose was given at week 20). We did the randomisation using an interactive voice response system and a centralised, computer-generated, permuted-block design of block size six. The two treatments were identical in appearance and administered in a masked manner; patients, investigators, other site staff and the entire study team including those assessing outcomes data were also masked to group assignment. The primary endpoint was the mean change from baseline in the St George's Respiratory Questionnaire (SGRQ) total score at week 24 in the modified intention-to-treat (modified ITT) population (analysed according to their randomly assigned treatment). Safety was assessed in all patients who received at least one dose of trial medication (analysed according to the actual treatment received). This trial is registered with ClinicalTrials.gov, number NCT02281318. FINDINGS: We recruited patients between Dec 11, 2014, and Nov 20, 2015, and the study was undertaken between Dec 11, 2014, and June 10, 2016. The modified ITT population comprised 274 patients assigned to mepolizumab 100 mg and 277 assigned to placebo. Mepolizumab versus placebo showed significant improvements at week 24 from baseline in SGRQ total score (least squares mean [SE] change from baseline -15·6 (1·0) vs -7·9 (1·0), a treatment difference of -7·7 (95% CI -10·5 to -4·9; p<0·0001). No deaths occurred during the study. 192 (70%) of 273 patients who received mepolizumab and 207 (74%) of 278 who received placebo reported at least one on-treatment adverse event, the most common of which were headache (in 45 [16%] given mepolizumab vs 59 [21%] given placebo) and nasopharyngitis (in 31 [11%] given mepolizumab vs 46 [17%] given placebo). 15 (5%) and 22 (8%) patients had an on-treatment serious adverse event in the mepolizumab and placebo groups, respectively; the most common was asthma in both groups (in three [1%] given mepolizumab vs nine [3%] given placebo). INTERPRETATION: Mepolizumab was associated with significant improvements in HRQOL in patients with severe eosinophilic asthma, and had a safety profile similar to that of placebo. These results add to and support the use of mepolizumab as a favourable add-on treatment option to standard of care in patients with severe eosinophilic asthma. FUNDING: GlaxoSmithKline.

Effects of CPAP and Mandibular Advancement Devices on Health-Related Quality of Life in OSA: A Systematic Review and Meta-analysis.

BACKGROUND: Untreated OSA is associated with impaired health-related quality of life (QoL) and excessive daytime sleepiness, which have been shown to improve with treatment. The aim was to compare the effects of CPAP and a mandibular advancement device (MAD) on health-related QoL in OSA. METHODS: MEDLINE and the Cochrane Library were searched up to November 2015 for randomized controlled trials (RCTs) comparing the effect of CPAP, MADs, or an inactive control treatment on health-related QoL assessed by the 36-Item Short Form Health Survey (SF-36) in OSA. Extraction of study characteristics, quality, and bias assessment were independently performed by three authors. A network meta-analysis using multivariate random-effects meta-regression was performed to assess treatment effects on the mental component score (MCS) and the physical component score (PCS) of the SF-36. RESULTS: Of 1,491 identified studies, 23 RCTs were included in the meta-analysis (2,342 patients). Compared with an inactive control, CPAP was associated with a 1.7 point (95% CI, 0.1-3.2; P = .036) improvement in the MCS and a 1.7 point (95% CI, 0.5-2.9; P = .005) improvement in the PCS. MADs were associated with a 2.4 point (95% CI, 0.0-4.9; P = .053) and a 1.5 point (95% CI, -0.2 to 3.2; P = .076) improvement in the MCS and PCS, respectively, compared with inactive control treatments. There were no statistically significant differences between treatment effects of CPAP and MAD on the SF-36 scores. CONCLUSIONS: CPAP is effective in improving health-related QoL in OSA, and MADs may be just as effective, but further RCTs comparing the two treatments are required.

Obstructive sleep apnoea and quality of life in Ehlers-Danlos syndrome: a parallel cohort study.

BACKGROUND: Patients with the connective tissue disorder Ehlers-Danlos syndrome (EDS) often suffer from fatigue, excessive daytime sleepiness and impaired quality of life. Obstructive sleep apnoea (OSA) may be an underlying cause for these symptoms but its prevalence in this population is unclear. METHODS: In this prospective parallel-cohort study, we included 100 adult patients with EDS (46% hypermobile-type, 35% classical-type and 19% other), which were one-to-one matched to 100 healthy adult controls according to sex, age, weight and height. Participants underwent structured interviews (including short-form 36) and level-3 respiratory polygraphy. OSA was defined as apnoea-hypopnea index ≥5/hour. Photographic craniofacial phenotyping was conducted in a subgroup. Conditional logistic regression was used to compare the prevalence of OSA. RESULTS: In patients with EDS, OSA prevalence was 32% versus 6% in the matched control group (OR 5.3 (95% CI 2.5 to 11.2); p<0.001). The EDS group reported impaired quality of life in all dimensions (p<0.05) and significantly higher excessive daytime sleepiness measured by the Epworth Sleepiness Scale (median (quartiles) 11 (7-14) vs 7 (5-10); p<0.001). OSA severity was positively associated with daytime sleepiness and lower quality of life in the EDS group. There was no evidence of a difference between the two study groups in terms of craniofacial phenotypes. CONCLUSIONS: The prevalence of OSA is higher in patients with EDS than in a matched control group. This is of clinical relevance as it is associated with fatigue, excessive daytime sleepiness and impaired quality of life. Further studies are needed to assess the clinical benefit of OSA treatment in patients with EDS. TRIAL REGISTRATION NUMBER: NCT02435745.