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.

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.

Sedation during bronchoscopy: data from a nationwide sedation and monitoring survey.

BACKGROUND: There is limited knowledge on practice patterns in procedural sedation and analgesia (PSA), the use of propofol, and monitoring during flexible bronchoscopy (FB). The purpose of this study was to assess the current practice patterns of FBs and to focus on the use of propofol, the education of the proceduralist, and the involvement of anaesthesiologists during FB. METHODS: An anonymous questionnaire was sent to 299 pulmonologists. Only respondents who were active physicians in adult respiratory medicine performing FB were subsequently analysed. RESULTS: The response rate was 78 % and 27,149 FB in the previous 12 months were analysed. The overall sedation-related morbidity rate was 0.02 % and mortality was 7/100'000 FB. Sedation was used in 95 % of bronchoscopies. The main drugs used for PSA were propofol (77 %) and midazolam (46 %). In 84 % of PSAs propofol was used without the attendance of an anaesthesiologist. The use of propofol was associated with high volume bronchoscopists (p < 0.010) and career-young pulmonologists (p < 0.001). While monitoring vital parameters has become standard practice, pulmonologists reported a very low rate of systematic basic education and training in the field of PSA (50 %). CONCLUSIONS: In Switzerland, PSA during FB is mostly performed with propofol without the attendance of an anaesthesiologist and the use of this drug is expected to increase in the future. While monitoring standards are very high there is need for policies to improve education, systematic training, and support for pulmonologists for PSA during FB.

Target-controlled versus fractionated propofol sedation in flexible bronchoscopy: A randomized noninferiority trial.

BACKGROUND AND OBJECTIVE: Fractionated propofol administration (FPA) in flexible bronchoscopy (FB) may lead to oversedation and an increased risk of adverse events, because a stable plasma concentration of propofol is not maintainable. The purpose of this randomized noninferiority trial was to evaluate whether target-controlled infusion (TCI) of propofol is noninferior to FPA in terms of safety in FB. METHODS: Coprimary outcomes were the mean lowest arterial oxygen saturation (SpO2 ) during FB and the number of propofol dose adjustments in relation to procedure duration. Secondary outcomes were the number of occasions with SpO2 < 90% and/or oxygen desaturations of >4% from baseline, number of occasions with systolic blood pressure < 90 mm Hg, cough frequency, cumulative propofol dose, recovery time, maximum transcutaneous CO2 , mean SpO2 and O2 delivery during FB. RESULTS: Seventy-seven patients were included. TCI was noninferior to FPA in terms of mean (standard deviation) lowest SpO2 during the procedure (88.3% (5.4%) vs 86.9% (7.3%)) and required fewer dose adjustments (0.04/min vs 0.28/min, P < 0.001) but a higher cumulative propofol dose (264 vs 194 mg, P = 0.003). All other secondary outcomes were comparable between the groups. CONCLUSION: We suggest that TCI of propofol is a favourable sedation technique for FB with equal safety issues and fewer dose adjustments compared with FPA.

Effect of rituximab on pulmonary function in patients with rheumatoid arthritis.

BACKGROUND: Rituximab (RTX), a B-cell depleting monoclonal antibody is increasingly used in several antibody-mediated diseases. It has been reported to cause pulmonary toxicity, though mainly during polychemotherapy of malignant lymphoma. Prospective data on RTX-induced pulmonary complications in patients with rheumatoid arthritis (RA) are lacking. METHODS AND METHODS: Serial spirometries and measurements of diffusion capacity of the lung for carbon monoxide (DLCO) in patients with RA before and 2, 4, 8, and 26 weeks after treatment with RTX were performed. A reduction from baseline of forced vital capacity (FVC) of ≥10%, or ≥15% of DLCO was defined as indicative for pulmonary toxicity. RESULTS: Thirty-three patients (mean (SD) age 59 (12) years, 27% males) were included. Mean (SD) FVC predicted and DLCO predicted at baseline were 108% (18%) and 88% (18%), respectively. In contrast to FVC, DLCO showed a progressive decline during follow-up with a maximum reduction of 6.1% (95%CI 2.5%, 9.7%; p = 0.001) at 26 weeks compared with baseline. After 26 weeks, 22% of the patients had a ≥15% DLCO decline. None of the patients reported increased dyspnea during follow-up. Risk factors for pulmonary function changes after treatment with RTX were cigarette smoking, repeated administration of the drug, and co-medication with Prednisone. CONCLUSION: Although no cases of symptomatic lung injury were observed, the progressive DLCO decline seems to indicate the presence of subclinical RTX-induced pulmonary toxicity.

Prevalence and Risk Factors of Sleep Disordered Breathing in Fabry disease: A Prospective Cohort Study.

Excessive daytime sleepiness (EDS) is a frequently reported and not well-understood symptom in patients with Fabry disease (FD). Sleep-disordered breathing (SDB) is a possible factor. As deposition of glycosphingolipids in the upper airway muscles is likely, we hypothesized that obstructive sleep apnoea (OSA) is highly prevalent in FD and positively associated with its severity.All patients with FD who are followed in the Fabry cohort of the University Hospital Zurich (n = 62) were asked to participate in this prospective cohort study. Eligible patients were prospectively investigated by assessing their daytime sleepiness using the Epworth Sleepiness Scale (ESS), the severity of FD using the Mainz Severity Score Index (MSSI), and by an ambulatory overnight respiratory polygraphy between November 1, 2013, and January 31, 2015. SDB was defined as an apnea/hypopnea index (AHI) of > 5/h.Fifty-two patients (mean ±â€ŠSD age 42.8 ±â€Š14.7 years, 33% men, mean ±â€ŠSD BMI 23.4 ±â€Š3.6 kg/m) with a median (IQR) MSSI of 12 (5-19) were included. Median (IQR) ESS was 6 (2-10) and 7 patients (14%) had an ESS > 10. Thirteen patients (25%) had SDB (78% obstructive sleep apnea, 22% central sleep apnea). In the multivariable analysis, the age was the only statistically significant predictor of SDB (OR 1.11, 95% CI 1.04-1.18, P = 0.001). ESS was associated with depression (P < 0.001) but not AHI nor age.This study shows that SDB, especially obstructive sleep apnea is highly prevalent in patients with Fabry disease. However, EDS in FD seems to be related with depression rather than SDB.ClinicalTrials.gov (identifier: NCT01947634).

Reducing bias in open-label trials where blinded outcome assessment is not feasible: strategies from two randomised trials.

BACKGROUND: Blinded outcome assessment is recommended in open-label trials to reduce bias, however it is not always feasible. It is therefore important to find other means of reducing bias in these scenarios. METHODS: We describe two randomised trials where blinded outcome assessment was not possible, and discuss the strategies used to reduce the possibility of bias. RESULTS: TRIGGER was an open-label cluster randomised trial whose primary outcome was further bleeding. Because of the cluster randomisation, all researchers in a hospital were aware of treatment allocation and so could not perform a blinded assessment. A blinded adjudication committee was also not feasible as it was impossible to compile relevant information to send to the committee in a blinded manner. Therefore, the definition of further bleeding was modified to exclude subjective aspects (such as whether symptoms like vomiting blood were severe enough to indicate the outcome had been met), leaving only objective aspects (the presence versus absence of active bleeding in the upper gastrointestinal tract confirmed by an internal examination).TAPPS was an open-label trial whose primary outcome was whether the patient was referred for a pleural drainage procedure. Allowing a blinded assessor to decide whether to refer the patient for a procedure was not feasible as many clinicians may be reluctant to enrol patients into the trial if they cannot be involved in their care during follow-up. Assessment by an adjudication committee was not possible, as the outcome either occurred or did not. Therefore, the decision pathway for procedure referral was modified. If a chest x-ray indicated that more than a third of the pleural space filled with fluid, the patient could be referred for a procedure; otherwise, the unblinded clinician was required to reach a consensus on referral with a blinded assessor. This process allowed the unblinded clinician to be involved in the patient's care, while reducing the potential for bias. CONCLUSIONS: When blinded outcome assessment is not possible, it may be useful to modify the outcome definition or method of assessment to reduce the risk of bias. TRIAL REGISTRATION TRIGGER: ISRCTN85757829. Registered 26 July 2012.TAPPS: ISRCTN47845793. Registered 28 May 2012.

Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial.

BACKGROUND: Continuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious. METHODS: This multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status. RESULTS: Of 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2 : 39 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS -2.0 (95% CI -2.6 to -1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components. CONCLUSIONS: In patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk.