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Background The safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines have not yet been reported. We therefore aimed to report the results of a substudy within a phase 3 UK trial, by evaluating the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with licensed seasonal influenza vaccines. Methods We did a planned exploratory substudy as part of the randomised, observer-blinded, placebo-controlled, phase 3 trial of the safety and efficacy of the COVID-19 vaccine (NVX-CoV2373) by co-administrating the influenza vaccine at four study hospitals in the UK. Approximately, the first 400 participants meeting the main study entry criteria—with no contraindications to influenza vaccination—were invited to join the substudy. Participants of the main study were randomly assigned (1:1) to receive two intramuscular injections of either NVX-CoV2373 (5 μg) or placebo (normal saline) 21 days apart; participants enrolled into the substudy were co-vaccinated with a single (0·5 mL) intramuscular, age-appropriate (quadrivalent influenza cell-based vaccine [Flucelvax Quadrivalent; Seqirus UK, Maidenhead] for those aged 18–64 years and adjuvanted trivalent influenza vaccine [Fluad; Seqirus UK, Maidenhead] for those ≥65 years), licensed, influenza vaccine on the opposite deltoid to that of the first study vaccine dose or placebo. The influenza vaccine was administered in an open-label manner and at the same time as the first study injection. Reactogenicity was evaluated via an electronic diary for 7 days after vaccination in addition to monitoring for unsolicited adverse events, medically attended adverse events, and serious adverse events. Immunogenicity was assessed with influenza haemagglutination inhibition and SARS-CoV-2 anti-spike protein IgG assays. Vaccine efficacy against PCR-confirmed, symptomatic COVID-19 was assessed in participants who were seronegative at baseline, received both doses of study vaccine or placebo, had no major protocol deviations affecting the primary endpoint, and had no confirmed cases of symptomatic COVID-19 from the first dose until 6 days after the second dose (per-protocol efficacy population). Immunogenicity was assessed in participants who received scheduled two doses of study vaccine, had a baseline sample and at least one post-vaccination sample, and had no major protocol violations before unmasking (per-protocol immunogenicity population). Reactogenicity was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo and had data collected for reactogenicity events. Safety was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo. Comparisons were made between participants of the substudy and the main study (who were not co-vaccinated for influenza). This study is registered with ClinicalTrials.gov, number NCT04583995. Findings Between Sept 28, 2020, and Nov 28, 2020, a total of 15 187 participants were randomised into the main phase 3 trial, of whom 15 139 received treatment (7569 received dose one of NVX-CoV2373 and 7570 received dose one of placebo). 431 participants were co-vaccinated with a seasonal influenza vaccine in the substudy (217 received NVX-CoV2373 plus the influenza vaccine and 214 received placebo plus the influenza vaccine). In general, the substudy participants were younger, more racially diverse, and had fewer comorbid conditions than those in the main study. Reactogenicity events were more common in the co-administration group than in the NVX-CoV2373 alone group: tenderness (113 [64·9%] of 174 vs 592 [53·3%] of 1111) or pain (69 [39·7%] vs 325 [29·3%]) at injection site, fatigue (48 [27·7%] vs 215 [19·4%]), and muscle pain (49 [28·3%] vs 237 [21·4%]). Incidences of unsolicited adverse events, treatment-related medically attended adverse events, and serious adverse events were low and balanced between the co-administration group and the NVX-CoV2373 alone group. No episodes of anaphylaxis or deaths were reported within the substudy. Co-administration resulted in no change to influenza vaccine immune response although a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. NVX-CoV2373 vaccine efficacy in the substudy (ie, participants aged 18 to

Introduction Recurrent pulmonary exacerbations lead to progressive lung damage in cystic fibrosis (CF). Inhaled medications (mucoactive agents and antibiotics) help prevent exacerbations, but objectively measured adherence is low. We investigated whether a multi-component (complex) self-management intervention to support adherence would reduce exacerbation rates over 12 months.Methods Between October 2017 and May 2018, adults with CF (aged ≥16 years; 19 UK centres) were randomised to the intervention (data-logging nebulisers, a digital platform and behavioural change sessions with trained clinical interventionists) or usual care (data-logging nebulisers). Outcomes included pulmonary exacerbations (primary outcome), objectively measured adherence, body mass index (BMI), lung function (FEV1) and Cystic Fibrosis Questionnaire-Revised (CFQ-R). Analyses were by intent to treat over 12 months.Results Among intervention (n=304) and usual care (n=303) participants (51% female, median age 31 years), 88% completed 12-month follow-up. Mean exacerbation rate was 1.63/year with intervention and 1.77/year with usual care (adjusted ratio 0.96; 95% CI 0.83 to 1.12; p=0.64). Adjusted mean differences (95% CI) were in favour of the intervention versus usual care for objectively measured adherence (9.5% (8.6% to 10.4%)) and BMI (0.3 (0.1 to 0.6) kg/m2), with no difference for %FEV1 (1.4 (−0.2 to 3.0)). Seven CFQ-R subscales showed no between-group difference, but treatment burden reduced for the intervention (3.9 (1.2 to 6.7) points). No intervention-related serious adverse events occurred.Conclusions While pulmonary exacerbations and FEV1 did not show statistically significant differences, the intervention achieved higher objectively measured adherence versus usual care. The adherence difference might be inadequate to influence exacerbations, though higher BMI and lower perceived CF treatment burden were observed.Data availability statementData are available on reasonable request. Requests for patient level data and statistical code should be made to the corresponding author and will be considered by members of the original trial management group, including the chief investigators and members of clinical trials research unit, who will release data on a case-by-case basis. Data will be shared following the principles for sharing patient level data as described by Tudur Smith C, et al BMC Medicine 2015;13:298 (https://doi.org/10.1186/s12916-015-0532-z). The data will not contain any direct identifiers, and we will minimise indirect identifiers and remove free-text data to minimise the risk of identification.

Background: Although solid evidence has indicated that respiratory symptoms are common amongst patients with chronic heart failure (CHF), state-of-the-art cardiac rehabilitation (CR) programs do not typically include management strategies to address respiratory symptoms. This study investigated the effect of the addition of breathing exercises (BE) to the CR programs in CHF. Methods: In a two parallel-arm randomized controlled study (RCT), 40 middle-aged patients with CHF and respiratory symptoms were recruited and randomized into two equal groups (n = 20); group (A): standard CR with BE and group (B): standard CR alone. Primary outcomes were respiratory parameters and secondary outcomes included cardiovascular and cardiopulmonary outcomes. All the participants attended a program of aerobic exercise (three sessions/week, 60–75% MHR, 45–55 min) for 12 weeks, plus educational, nutritional, and psychological counseling. Group (A) patients attended the same program together with BE using inspiratory muscle training (IMT) and breathing calisthenics (BC) (six sessions/week, 15–25 min) for the same duration. Results: There was a significant improvement in the respiratory outcomes, and most of the cardiovascular and cardiopulmonary outcomes in both groups with a greater change percentage in group A (p < 0.05). Conclusions: These results indicate that the addition of BE to the CR programs in CHF is effective and is a “patient-centered” approach.

PurposeAcute respiratory failure (ARF) is a common cause of admission to intensive care units (ICUs). Mucoactive agents are medications that promote mucus clearance and are frequently administered in patients with ARF, despite a lack of evidence to underpin clinical decision making. The aim of this systematic review was to determine if the use of mucoactive agents in patients with ARF improves clinical outcomes.MethodsWe searched electronic and grey literature (January 2020). Two reviewers independently screened, selected, extracted data and quality assessed studies. We included trials of adults receiving ventilatory support for ARF and involving at least one mucoactive agent compared with placebo or standard care. Outcomes included duration of mechanical ventilation. Meta-analysis was undertaken using random-effects modelling and certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation.ResultsThirteen randomised controlled trials were included (1712 patients), investigating four different mucoactive agents. Mucoactive agents showed no effect on duration of mechanical ventilation (seven trials, mean difference (MD) −1.34, 95% CI −2.97 to 0.29, I2=82%, very low certainty) or mortality, hospital stay and ventilator-free days. There was an effect on reducing ICU length of stay in the mucoactive agent groups (10 trials, MD −3.22, 95% CI −5.49 to −0.96, I2=89%, very low certainty).ConclusionOur findings do not support the use of mucoactive agents in critically ill patients with ARF. The existing evidence is of low quality. High-quality randomised controlled trials are needed to determine the role of specific mucoactive agents in critically ill patients with ARF.PROSPERO registration numberCRD42018095408.

Background People with cystic fibrosis frequently have low levels of adherence to inhaled medications. Objectives The objectives were to develop and evaluate an intervention for adults with cystic fibrosis to improve adherence to their inhaled medication. Design We used agile software methods to develop an online platform. We used mixed methods to develop a behaviour change intervention for delivery by an interventionist. These were integrated to become the CFHealthHub intervention. We undertook a feasibility study consisting of a pilot randomised controlled trial and process evaluation in two cystic fibrosis centres. We evaluated the intervention using an open-label, parallel-group randomised controlled trial with usual care as the control. Participants were randomised in a 1 : 1 ratio to intervention or usual care. Usual care consisted of clinic visits every 3 months. We undertook a process evaluation alongside the randomised controlled trial, including a fidelity study, a qualitative interview study and a mediation analysis. We undertook a health economic analysis using both a within-trial and model-based analysis. Setting The randomised controlled trial took place in 19 UK cystic fibrosis centres. Participants Participants were people aged ≥ 16 years with cystic fibrosis, on the cystic fibrosis registry, not post lung transplant or on the active transplant list, who were able to consent and not using dry-powder inhalers. Intervention People with cystic fibrosis used a nebuliser with electronic monitoring capabilities. This transferred data automatically to a digital platform. People with cystic fibrosis and clinicians could monitor adherence using these data, including through a mobile application (app). CFHealthHub displayed graphs of adherence data as well as educational and problem-solving information. A trained interventionist helped people with cystic fibrosis to address their adherence. Main outcome measures Randomised controlled trial – adjusted incidence rate ratio of pulmonary exacerbations meeting the modified Fuchs criteria over a 12-month follow-up period (primary outcome); change in percentage adherence; and per cent predicted forced expiratory volume in 1 second (key secondary outcomes). Process evaluation – percentage fidelity to intervention delivery, and participant and interventionist perceptions of the intervention. Economic modelling – incremental cost per quality-adjusted life-year gained. Results Randomised controlled trial – 608 participants were randomised to the intervention (n = 305) or usual care (n = 303). To our knowledge, this was the largest randomised controlled trial in cystic fibrosis undertaken in the UK. The adjusted rate of exacerbations per year (primary outcome) was 1.63 in the intervention and 1.77 in the usual-care arm (incidence rate ratio 0.96, 95% confidence interval 0.83 to 1.12; p = 0.638) after adjustment for covariates. The adjusted difference in mean weekly normative adherence was 9.5% (95% confidence interval 8.6% to 10.4%) across 1 year, favouring the intervention. Adjusted mean difference in forced expiratory volume in 1 second (per cent) predicted at 12 months was 1.4% (95% confidence interval –0.2% to 3.0%). No adverse events were related to the intervention. Process evaluation – fidelity of intervention delivery was high, the intervention was acceptable to people with cystic fibrosis, participants engaged with the intervention [287/305 (94%) attended the first intervention visit], expected mechanisms of action were identified and contextual factors varied between randomised controlled trial sites. Qualitative interviews with 22 people with cystic fibrosis and 26 interventionists identified that people with cystic fibrosis welcomed the objective adherence data as proof of actions to self and others, and valued the relationship that they built with the interventionists. Economic modelling – the within-trial analysis suggests that the intervention generated 0.01 additional quality-adjusted life-years at an additional cost of £865.91 per patient, leading to an incremental cost-effectiveness ratio of £71,136 per quality-adjusted life-year gained. This should be interpreted with caution owing to the short time horizon. The health economic model suggests that the intervention is expected to generate 0.17 additional quality-adjusted life-years and cost savings of £1790 over a lifetime (70-year) horizon; hence, the intervention is expected to dominate usual care. Assuming a willingness-to-pay threshold of £20,000 per quality-adjusted life-year gained, the probability that the intervention generates more net benefit than usual care is 0.89. The model results are dependent on assumptions regarding the duration over which costs and effects of the intervention apply, the impact of the intervention on forced expiratory volume in 1 second (per cent) predicted and the relationship between increased adherence and drug-prescribing levels. Limitations Number of exacerbations is a sensitive and valid measure of clinical change used in many trials. However, data collection of this outcome in this context was challenging and could have been subject to bias. It was not possible to measure baseline adherence accurately. It was not possible to quantify the impact of the intervention on the number of packs of medicines prescribed. Conclusions We developed a feasible and acceptable intervention that was delivered to fidelity in the randomised controlled trial. We observed no statistically significant difference in the primary outcome of exacerbation rates over 12 months. We observed an increase in normative adherence levels in a disease where adherence levels are low. The magnitude of the increase in adherence may not have been large enough to affect exacerbations. Future work Given the non-significant difference in the primary outcome, further research is required to explore why an increase in objective normative adherence did not reduce exacerbations and to develop interventions that reduce exacerbations. Trial registration Work package 3.1: Current Controlled Trials ISRCTN13076797. Work packages 3.2 and 3.3: Current Controlled Trials ISRCTN55504164. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 11. See the NIHR Journals Library website for further project information.

Background: Both continuous positive airway pressure (CPAP) and high-flow nasal oxygenation (HFNO) have been recommended for acute respiratory failure in COVID-19. However, uncertainty exists regarding effectiveness and safety. Methods: In the Recovery-Respiratory Support multi-center, three-arm, open-label, adaptive, randomized controlled trial, adult hospitalized patients with acute respiratory failure due to COVID-19, deemed suitable for treatment escalation, were randomly assigned to receive CPAP, HFNO, or conventional oxygen therapy. Comparisons were made between each intervention and conventional oxygen therapy. The primary outcome was a composite of tracheal intubation or mortality within 30-days. Results: Over 13-months, 1272 participants were randomized and analysed (380 (29.9%) CPAP; 417 (32.8%) HFNO; 475 (37.3%) conventional oxygen therapy). The need for tracheal intubation or mortality within 30-days was lower in the CPAP group (CPAP 137 of 377 participants (36.3%) vs conventional oxygen therapy 158 of 356 participants (44.4%); unadjusted odds ratio 0.72; 95% CI 0.53 to 0.96, P=0.03). There was no difference between HFNO and conventional oxygen therapy (HFNO 184 of 414 participants (44.4%) vs conventional oxygen therapy 166 of 368 participants (45.1%); unadjusted odds ratio 0.97; 95% CI 0.73 to 1.29, P=0.85). Conclusions: CPAP, compared with conventional oxygen therapy, reduced the composite outcome of intubation or death within 30 days of randomisation in hospitalized adults with acute respiratory failure due to COVID-19. No effect was observed with the use of HFNO. (Funded by the UK National Institute for Health Research; ISRCTN 16912075).

BackgroundBoth continuous positive airway pressure (CPAP) and high-flow nasal oxygenation (HFNO) have been recommended for acute respiratory failure in COVID-19. However, uncertainty exists regarding effectiveness and safety.MethodsIn the Recovery-Respiratory Support multi-center, three-arm, open-label, adaptive, randomized controlled trial, adult hospitalized patients with acute respiratory failure due to COVID-19, deemed suitable for treatment escalation, were randomly assigned to receive CPAP, HFNO, or conventional oxygen therapy. Comparisons were made between each intervention and conventional oxygen therapy. The primary outcome was a composite of tracheal intubation or mortality within 30-days.ResultsOver 13-months, 1272 participants were randomized and included in the analysis (380 (29.9%) CPAP; 417 (32.8%) HFNO; 475 (37.3%) conventional oxygen therapy). The need for tracheal intubation or mortality within 30-days was lower in the CPAP group (CPAP 137 of 377 participants (36.3%) vs conventional oxygen therapy 158 of 356 participants (44.4%); unadjusted odds ratio 0.72; 95% CI 0.53 to 0.96, P=0.03). There was no difference between HFNO and conventional oxygen therapy (HFNO 184 of 414 participants (44.4%) vs conventional oxygen therapy 166 of 368 participants (45.1%); unadjusted odds ratio 0.97; 95% CI 0.73 to 1.29, P=0.85).ConclusionsCPAP, compared with conventional oxygen therapy, reduced the composite outcome of intubation or death within 30 days of randomisation in hospitalized adults with acute respiratory failure due to COVID-19. There was no effect observed, compared with conventional oxygen therapy, with the use of HFNO.(Funded by the UK National Institute for Health Research; ISRCTN 16912075).

The COVID-19 pandemic has provided an opportunity for reform and rejuvenation to cardiac rehabilitation services, which have problems with recruitment and retention of patients.

Introduction Understanding the psychometric properties of health-related quality of life (HRQoL) questionnaires can help inform selection in clinical trials. Our objective was to assess the psychometric properties of HRQoL questionnaires in bronchiectasis using a systematic review and meta-analysis of the literature. Methods A literature search was conducted. HRQoL questionnaires were assessed for psychometric properties (reliability, validity, minimal clinically important difference (MCID) and floor/ceiling effects). Meta-analyses assessed the associations of HRQoL with clinical measures and responsiveness of HRQoL in clinical trials. Results 166 studies and 12 HRQoL questionnaires were included. The Bronchiectasis Health Questionnaire (BHQ), Leicester Cough Questionnaire (LCQ), Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) had good internal consistency in all domains reported (Cronbach's α≥0.7) across all studies, and the Quality of Life-Bronchiectasis (QOL-B), St George's Respiratory Questionnaire (SGRQ), Chronic Respiratory Disease Questionnaire (CRDQ) and Seattle Obstructive Lung Disease Questionnaire (SOLQ) had good internal consistency in all domains in the majority of (but not all) studies. BHQ, SGRQ, LCQ and CAT had good test–retest reliability in all domains reported (intraclass correlation coefficient ≥0.7) across all studies, and QOL-B, CRDQ and SOLQ had good test–retest reliability in all domains in the majority of (but not all) studies. HRQoL questionnaires were able to discriminate between demographics, important markers of clinical status, disease severity, exacerbations and bacteriology. For HRQoL responsiveness, there was a difference between the treatment and placebo effect. Conclusions SGRQ was the most widely used HRQoL questionnaire in bronchiectasis studies and it had good psychometric properties; however, good psychometric data are emerging on the bronchiectasis-specific HRQoL questionnaires QOL-B and BHQ. Future studies should focus on the medium- to long-term test–retest reliability, responsiveness and MCID in these HRQoL questionnaires which show potential in bronchiectasis., The psychometric properties of health-related quality of life questionnaires should inform the selection of patient-reported outcomes in bronchiectasis clinical trials https://bit.ly/3wQuSrm

Background Evaluation of multiple breath washout (MBW) set-up including staff training, certification and central “over-reading” for data quality control is essential to determine the feasibility of MBW in future bronchiectasis studies. Aims To assess the outcomes of a MBW training, certification and central over-reading programme. Methods MBW training and certification was conducted in European sites collecting lung clearance index (LCI) data in the BronchUK Clinimetrics and/or i-BEST-1 studies. The blended training programme included the use of an eLearning tool and a 1-day face-to-face session. Sites submitted MBW data to trained central over-readers who determined validity and quality. Results Thirteen training days were delivered to 56 participants from 22 sites. Of 22 sites, 18 (82%) were MBW naïve. Participant knowledge and confidence increased significantly (p, LCI is feasible in a bronchiectasis multicentre clinical trial setting; however, consideration of site experience in terms of training as well as assessment of skill drift and the need for re-training may be important to optimise data quality https://bit.ly/2WZ4L1e

Introduction: Airways Clearance Treatments (ACT) in respiratory physiotherapy are highlighted as a key research priority by both experts and people with bronchiectasis (1). Current practice is unclear. We are conducting a survey to determine current practice in Northern Ireland (NI). Patient and public involvement (PPI) is key to ensure survey content, format and delivery are optimised. Methods: Two focus groups (5 patients, 3 physiotherapists treating people with bronchiectasis) and 5 semi-structured interviews (2 patients, 5 physiotherapists) were conducted using a schedule of questions pre-prepared by the project team and a patient advisory group member. Audio recordings were transcribed and grouped into themes using template analysis (2). Themes were used to generate a list of updates to the draft patient and physiotherapist surveys. Results: The following themes emerged: Patient survey: access to and outcomes for physiotherapy, ACT dose, ACT choice, barriers to ACT, support for ACT and feasibility of an online survey. Physiotherapy survey: factors influencing choice of ACT, initial ACT prescription, follow-up for ACT, barriers to ACT delivery, current ACT service delivery, concomitant therapies, outcomes from ACT, ACT dose, technology and survey engagement. Substantial updates were made to the patient (n=24 updates) and physiotherapy survey (n=52 updates), including amendments to current questions, addition of new questions and changes to survey delivery plan. Conclusion: PPI Patient and public involvement and engagement is essential to ensure survey content, format and delivery are optimised. 1. Aliberti et al Eur Respir J. 2016;48(3):632-647. 2. King et al Sage; 2012.

Objective The trial objective is to determine if Continuous Positive Airway Pressure (CPAP) or High-Flow Nasal Oxygen (HFNO) is clinically effective compared to standard oxygen therapy in patients with confirmed or suspected COVID-19. Trial design Adaptive (group-sequential), parallel group, pragmatic, superiority randomised controlled, open-label, multi-centre, effectiveness trial. Participants The trial is being conducted across approximately 60 hospitals across England, Wales, Scotland, and Northern Ireland. Inpatients at participating hospitals are eligible to participate if they have respiratory failure with suspected or proven COVID-19, and meet all of the inclusion criteria and none of the exclusion criteria. Inclusion criteria: 1) Adults ≥ 18 years; 2) Admitted to hospital with suspected or proven COVID-19; 3) Receiving oxygen with fraction of inspired oxygen (FiO2) ≥0.4 and peripheral oxygen saturation (SpO2) ≤94%; and 4) Plan for escalation to tracheal intubation if needed. Exclusion criteria: 1) Planned tracheal intubation and mechanical ventilation imminent within 1 hour; 2) Known or clinically apparent pregnancy; 3) Any absolute contraindication to CPAP or HFNO; 4) Decision not to intubate due to ceiling of treatment or withdrawal of treatment anticipated; and 5) Equipment for both CPAP and HFNO not available. Intervention and comparator Intervention one: Continuous positive airway pressure delivered by any device. Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Intervention two: High-flow nasal oxygen delivered by any device. Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Comparator group: Standard care- oxygen delivered by face mask or nasal cannula (excluding the use of continuous positive airway pressure or high-flow nasal oxygen). Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Intervention delivery continues up to the point of death, tracheal intubation, or clinical determination that there is no ongoing need (palliation or improvement). Main outcomes The primary outcome is a composite outcome comprising tracheal intubation or mortality within 30 days following randomisation. Secondary outcomes include tracheal intubation rate, time to tracheal intubation, duration of invasive ventilation, mortality rate, time to mortality, length of hospital stay, and length of critical care stay. Randomisation Participants are randomised in a 1:1:1 ratio to receive either continuous positive airway pressure, high-flow nasal oxygen or standard care. Due to the challenging environment of study delivery, a specific intervention may not always be available at the hospital site. The study uses two integrated randomisation systems to allow, where required, the site to randomise between all three interventions, between CPAP and standard care, and between HFNO and standard care. System integration ensures maintenance of balance between interventions. Randomisation is performed using a telephone-based interactive voice response system to maintain allocation concealment. The randomisation sequence was computer-generated using the minimisation method. Participant randomisation is stratified by site, gender (M/F), and age (=50 years). Blinding (masking) The nature of the trial interventions precludes blinding of the researcher, patient and clinical team. Primary and secondary outcomes are all objective outcomes, thereby minimising the risk of detection bias. Numbers to be randomised (sample size) 4002 participants (1334 to be randomized to each of the three study arms) Trial Status Current protocol: Version 4.0, 29th May 2020. Recruitment began on April 6, 2020 and is anticipated to be complete by April 5, 2021. The trial has been awarded Urgent Public Health status by the National Institute of Health Research on 13th April 2020. Trial registration ISRCTN, ISRCTN16912075. Registered 6th April 2020, http://www.isrctn.com/ISRCTN16912075 Full protocol The full protocol (version 4.0, 29th May 2020) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Background Mechanical ventilation for acute respiratory failure is one of the most common indications for admission to intensive care units (ICUs). Airway mucus clearance is impaired in these patients medication, impaired mucociliary motility, increased mucus production etc. and mucoactive agents have the potential to improve outcomes. However, studies to date have provided inconclusive results. Despite this uncertainty, mucoactives are used in adult ICUs, although the extent of use and perceptions about place in therapy are not known. Aims and Objectives We aim to describe the use of mucoactive agents in mechanically ventilated patients in UK adult critical care units. Specifically, our objectives are to describe clinicians perceptions about the use of mucoactive agents, understand the indications and anticipated benefits, and describe the prevalence and type of mucoactive agents in use. Methods We conducted three surveys. Firstly, a practitioner-level survey aimed at nurses, physiotherapists and doctors to elucidate individual practitioners perceptions about the use of mucoactive agents. Secondly, a critical care unit-level survey aimed at pharmacists to understand how these perceptions translate into practice. Thirdly, a point prevalence survey to describe the extent of prescribing and range of products in use. The practitioner-level survey was disseminated through the UK Intensive Care Society for completion by a multi-professional membership. The unit-level and point prevalence surveys were disseminated cthrough the UK Clinical Pharmacy Association for completion by pharmacists. Results The individual practitioners survey ranked ‘thick secretions’ as the main reason for commencing mucoactive agents determined using clinical assessment. The highest ranked perceived benefit for patient centred outcomes was the duration of ventilation. Of these respondents, 79% stated that further research was important and 87% expressed support for a clinical trial. The unit-level survey found that mucoactive agents were used in 83% of units. The most highly ranked indication was again ‘thick secretions’ and the most highly ranked expected patient centred clinical benefit being improved gas exchange and reduced ventilation time. Only five critical care units provided guidelines to direct the use of mucoactive agents (4%). In the point prevalence survey, 411/993 (41%) of mechanically ventilated patients received at least one mucoactive agent. The most commonly administered mucoactives were inhaled sodium chloride 0.9% (235/993, 24%), systemic carbocisteine (161/993, 16%) and inhaled hypertonic sodium cloride (127/993, 13%). Conclusions Mucoactive agents are used extensively in mechanically ventilated adult patients in UK ICUs to manage ‘thick secretions’, with a key aim to reduce the duration of ventilation. There is widespread support for clinical trials to determine the optimal use of mucoactive agent therapy in this patient population.

Background Cystic fibrosis (CF) is a life-limiting genetic condition in which daily therapies to maintain lung health are critical, yet treatment adherence is low. Previous interventions to increase adherence have been largely unsuccessful and this is likely due to a lack of focus on behavioural evidence and theory alongside input from people with CF. This intervention is based on a digital platform that collects and displays objective nebuliser adherence data. The purpose of this paper is to identify the specific components of an intervention to increase and maintain adherence to nebuliser treatments in adults with CF with a focus on reducing effort and treatment burden. Methods Intervention development was informed by the Behaviour Change Wheel (BCW) and person-based approach (PBA). A multidisciplinary team conducted qualitative research to inform a needs analysis, selected, and refined intervention components and methods of delivery, mapped adherence-related barriers and facilitators, associated intervention functions and behaviour change techniques, and utilised iterative feedback to develop and refine content and processes. Results Results indicated that people with CF need to understand their treatment, be able to monitor adherence, have treatment goals and feedback and confidence in their ability to adhere, have a treatment plan to develop habits for treatment, and be able to solve problems around treatment adherence. Behaviour change techniques were selected to address each of these needs and were incorporated into the digital intervention developed iteratively, alongside a manual and training for health professionals. Feedback from people with CF and clinicians helped to refine the intervention which could be tailored to individual patient needs. Conclusions The intervention development process is underpinned by a strong theoretical framework and evidence base and was developed by a multidisciplinary team with a range of skills and expertise integrated with substantial input from patients and clinicians. This multifaceted development strategy has ensured that the intervention is usable and acceptable to people with CF and clinicians, providing the best chance of success in supporting people with CF with different needs to increase and maintain their adherence. The intervention is being tested in a randomised controlled trial across 19 UK sites.

Background and objective In bronchiectasis (BE) not caused by cystic fibrosis, chronic, polymicrobial airway infection contributes to the underlying pathogenesis of disease. There is little information on whether bacterial community composition relates to clinical status. We determined the relationship between bacterial community composition, chest high‐resolution computed tomography (HRCT) scores and clinical markers in BE. Methods A subgroup of BE patients from a previous cross‐sectional study were analysed. Spontaneously expectorated sputum was analysed using culture‐independent sequencing on the Roche 454‐FLX platform covering the V1–V3 region of the 16S rRNA marker gene. Chest HRCT scans, multiple breath washout, spirometry and blood inflammatory markers were collected. Spearman's rank (r) correlation coefficient was used to assess relationships. Results Data from 21 patients were analysed (mean (SD) age: 64.0 (7.7); female : male 14:7; mean (SD) forced expiratory volume in 1 s (FEV1): 76.5 (17.2)). All bacterial community composition metrics (bacterial richness, diversity, evenness and dominance) correlated with percentage BE score, with more severe HRCT abnormality relating to lower bacterial richness, evenness and diversity (range r = −0.47 to −0.66; P

IntroductionThe development of multiple breath washout (MBW) testing in respiratory disease highlights the need for increased awareness amongst respiratory physiotherapists and a potential opportunity for professional development in the use of an important outcome measure for clinical trials.Objectives To rationalise how MBW may be a useful assessment tool for respiratory physiotherapists and to describe a local MBW training and certification programme for physiotherapists. ResultsThe respiratory Multi-Disciplinary Team in the Belfast Health and Social Care Trust (BHSCT) identified a need for MBW testing to be available to facilitate clinical research and assessment. A 2 day training programme consisting of pre-reading preparation, self-directed learning, theory presentations, practical demonstrations and hands-on practice was developed and delivered. All participants underwent a certification process.Conclusion: We have demonstrated the successful training and certification of clinical and research physiotherapists and encourage other respiratory physiotherapists to consider MBW test training.

Background Lung clearance index (LCI) has good clinimetric properties and an acceptable feasibility profile as a surrogate end point in cystic fibrosis (CF). Although most studies to date have been in children, increasing numbers of adults with CF also have normal spirometric findings. Further study of LCI as an end point in adults with CF is required. Therefore, the purpose of this study was to determine the clinimetric properties of LCI across the age range of people with CF. Methods Clinically stable adults and children with CF and age-matched healthy control subjects were recruited. Results LCI and spirometry data for 110 subjects with CF and 61 control subjects were collected at a stable visit. The CF Questionnaire-Revised (CFQ-R) was completed by 80 of 110 subjects with CF. Fifty-six subjects with CF completed a second stable visit. The LCI coefficient of variation percent was 4.1% in adults and 6.3% in children with CF. The coefficient of repeatability of LCI was 1.2 in adults and 1.3 in children. In both adults and children, LCI (area under the receiving operator characteristic curve [AUC ROC ] = 0.93 and 0.84, respectively) had greater combined sensitivity and specificity to discriminate between people with CF and control subjects when compared with FEV 1 (AUC ROC = 0.88 and 0.60, respectively) and forced expiratory flow at 25% to 75% of the curve (AUC ROC = 0.87 and 0.68, respectively). LCI correlated significantly with the CFQ-R treatment burden in adults ( r = –0.37; P r = –0.50; P Conclusions These data support the use of LCI as a surrogate outcome measure in CF clinical trials in adults as well as in children.

Introduction Two quality of life instruments are widely used in bronchiectasis clinical trials, the Quality of Life bronchiectasis questionnaire and the St Georges Respiratory Questionnaire with few large scale multi-centre direct comparisons. Convergent validity represents an assessment of the instrument against other measures that are considered to represent severity of disease, since a valid instrument should agree with clinical assessments of severity of disease and disease burden. We evaluated the convergent validity in the BRONCH-UK dataset. Methods Prospective registry of adults with bronchiectasis from 13 secondary care centres across the UK, embedded within the EMBARC European platform. Patients completed baseline QOL-B and SGRQ and comprehensive clinical assessment. Linear regression and Spearman correlation evaluated the relationship between QOL scores and clinical variables. Results 1403 patients were recruited. We report data on the first 813 with complete core datasets; 504 were female (62%), 309 male (38%). The mean age 65 years SD 12.6. The mean QOL-B RSS was 61 points (SD 22) and mean SGRQ was 42.2 (SD 22) indicating a population with moderate to severe impairment of quality of life There was a strong inverse relationship between the QOL-B respiratory symptom score and the SGRQ (r=-0.74, p The QOL-B RSS correlated with FEV1% predicted (r=0.31, p High risk populations e.g. chronic P. aeruginosa infection and frequent exacerbators (3 or more per year) had higher SGRQ and lower QOL-B RSS scores (p Conclusion Both the QOL-B RSS and the St Georges Respiratory Questionnaire show acceptable convergent validity in large representative population of patients with bronchiectasis in the UK. Acknowledgements MRC Funding grant MR/L011263/1, Recruiting sites and patients

Bronchiectasis is increasingly recognised but poorly described. There is variability in aetiology, management and outcomes. We have adapted the EMBARC platform and created a multisite UK based registry with affiliated biobank. The BronchUK partnership (www.bronch.ac.uk) aimed to recruit 1500 adult patients with annual follow up over 3–5 years. We report our demographic data. Methods Multicentre recruitment (13 secondary care sites) with databasing of patient demographics. Data is quality assured on a routine basis. We followed the EMBARC protocol for data collection including Quality of Life Bronchiectasis (QOL-B) and SGRQ questionnaires. Results 1403 patients have been recruited. We report data on the first 813 with complete core datasets; 504 were female (62%), 309 male (38%). The mean age 65 years SD 12.6 (median is 67 IQR 61–73). Patients were predominantly Caucasian (93%). The majority were never smokers 478 (58.8%) or ex-smokers 304 (37.4%) with only 31 (3.8%) self-reporting current smoking. Morbidity was high; Cardiovascular disease was present in 234 (28.8%). 147 (18.1%) were hospitalised in the last year due to respiratory disease, 666 (81.9%) were not. Exacerbations were common with one – 144 (17.7%), Two – 144 (17.7%) three or more- 319 (39.3%). Only 206 (25.3%) reported no exacerbations in prior 12 months. Haemophilus influenzae was the most frequent organism isolated (19.1% of all patients/29.3% of patients producing baseline sputum). Pseudomonas was cultured in most recent sputum in 98 (12.1%) rising to 223 (27.4%) isolating Pseudomonas in the last 2 years. The mean BMI was 26.5 (22.3–29.3) and median, FEV1% predicted median 76.9 (59.1–95.1). The Bronchiectasis severity index (BSI) was - mild= 233 (29%), moderate= 391 (48%), severe= 189 (23%). Common aetiologies were idiopathic (40%) and post infectious (34%). COPD and Asthma were either common comorbidities or suspected aetiologies (16–21% and 3–39%) respectively. Conclusions The BronchUK registry has a broadly representative cohort of patients in terms of simple demographics (female predominant, Haemophilus infections, idiopathic/post infectious aetiologies) but the morbidity levels and hospitalisation rates are noteworthy. Long term follow up will help us ascertain which patients are at highest risk of poor outcomes. Acknowledgements MRC Funding grant MR/L011263/1, Recruiting sites and patients.

Background Preventative medication reduces hospitalisations in people with cystic fibrosis (PWCF) but adherence is poor. We assessed the feasibility of a randomised controlled trial of a complex intervention, which combines display of real time adherence data and behaviour change techniques. Methods Design: Pilot, open-label, parallel-group RCT with concurrent semi-structured interviews. Participants: PWCF at two Cystic Fibrosis (CF) units. Eligible: aged 16 or older; on the CF registry. Ineligible: post-lung transplant or on the active list; unable to consent; using dry powder inhalers. Interventions: Central randomisation on a 1:1 allocation to: (1) intervention, linking nebuliser use with data recording and transfer capability to a software platform, and behavioural strategies to support self-management delivered by trained interventionists (n = 32); or, (2) control, typically face-to-face meetings every 3 months with CF team (n = 32). Outcomes: RCT feasibility defined as: recruitment of ≥ 48 participants (75% of target) in four months (pilot primary outcome); valid exacerbation data available for ≥ 85% of those randomised (future RCT primary outcome); change in % medication adherence; FEV1 percent predicted (key secondaries in future RCT); and perceptions of trial procedures, in semi-structured interviews with intervention (n = 14) and control (n = 5) participants, interventionists (n = 3) and CF team members (n = 5). Results The pilot trial recruited to target, randomising 33 to intervention and 31 to control in the four-month period, June–September 2016. At study completion (30th April 2017), 60 (94%; Intervention = 32, Control =28) participants contributed good quality exacerbation data (intervention: 35 exacerbations; control: 25 exacerbation). The mean change in adherence and baseline-adjusted FEV1 percent predicted were higher in the intervention arm by 10% (95% CI: -5.2 to 25.2) and 5% (95% CI -2 to 12%) respectively. Five serious adverse events occurred, none related to the intervention. The mean change in adherence was 10% (95% CI: -5.2 to 25.2), greater in the intervention arm. Interventionists delivered insufficient numbers of review sessions due to concentration on participant recruitment. This left interventionists insufficient time for key intervention procedures. A total of 10 key changes that were made to RCT procedures are summarised. Conclusions With improved research processes and lower monthly participant recruitment targets, a full-scale trial is feasible. Trial registration ISRCTN13076797. Prospectively registered on 07/06/2016. Electronic supplementary material The online version of this article (10.1186/s12890-019-0834-6) contains supplementary material, which is available to authorized users.

Background: Current guidelines for the management of bronchiectasis (BE) highlight the lack of evidence to recommend mucoactive agents, such as hypertonic saline (HTS) and carbocisteine, to aid sputum-removal as part of standard care. We hypothesise that mucoactive agents (HTS or cabocisteine, or a combination) are effective in reducing exacerbations over a 52-week period, compared to usual care. Methods: A 52-week, 2x2 factorial randomised open label trial to determine the clinical and cost-effectiveness of HTS 6% and carbocisteine for airway clearance versus usual care: CLEAR (clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care). Patients will be randomised to either (i) Standard care and twice daily nebulised HTS (6%), (ii) Standard care and carbocisteine (750mg three times per day until visit 3 reducing to 750mg twice per day), (iii) Standard care and combination of twice-daily nebulised HTS and carbocisteine, or (iv) Standard care. The primary outcome is the mean number of exacerbations over 52 weeks. Key inclusion criteria: adults with a diagnosis of BE on computed tomography scans, BE as the primary respiratory diagnosis, two or more pulmonary exacerbations in the last year requiring antibiotics and production of daily sputum. Discussion: This trial’s pragmatic research design avoids the significant costs associated with double-blind trials whilst optimising rigor in other areas of trial-delivery. CLEAR will provide evidence as to whether HTS, carbocisteine or both are effective and cost-effective for BE patients. Trial registration: EudraCT Number: 2017-000664-14. (Date on which this record was first entered in the database 20/10/2017). ISRCTN89040295. (Date assigned 06/07/2018). Funder: National Institute for Health Research, Health Technology Assessment Programme (15/100/01). Sponsor: Belfast Health and Social Care Trust. Ethics Reference Number: 17/NE/0339. Protocol version: v3.0 Final_14052018. Keywords: Clinical trial protocol, factorial design, bronchiectasis, hypertonic saline, carbocisteine, exacerbation, SWAT.

Introduction Multiple Breath Washout (MBW) to measure Lung Clearance Index (LCI) is increasingly being used as a secondary endpoint in multicentre bronchiectasis studies. LCI data quality control or “over-reading” is resource intensive and the impact is unclear. Objectives To assess the proportion of MBW tests deemed unacceptable with over-reading, and to assess the change in LCI (number of turnovers), LCI coefficient of variation (CV%) and tidal volume (VT) CV% results after over-reading. Methods Data were analysed from 250 MBW tests (from 98 adult bronchiectasis patients) collected as part of the Bronch-UK Clinimetrics study in 5 UK centres. Each MBW test was over-read centrally using pre-defined criteria. MBW tests with

Objectives: To identify the definitions used for treatment fidelity in the behaviour change literature and to explore the extent to which the assessment of fidelity has been reported according to the five domains by Bellg et al.Methods: Three databases (Scopus, Medline Ovid and CINAHL) were searched. Results were limited to studies published between 2012 and 2015. Definitions/summaries of treatment fidelity used were recorded. Methods for assessing/monitoring treatment fidelity were extracted, summarised and categorised according to the five domains.Results: Sixty-five papers were included for analysis. A definition of treatment fidelity was provided by n = 34 studies; n = 9 defined fidelity according to Bellg et al. In the context of treatment fidelity, n = 9 (13.8%) reported on study design; n = 22 (33.8%) reported on an element of training of providers; n = 59 (90.7%) papers reported on delivery of treatment; n = 13 (20%) reported on receipt of treatment; and n = 10 (15.3%) reported on enactment of treatment skills.Conclusion: The definitions of treatment fidelity in the literature and the extent to which it has been reported were limited. Delivery of treatment was the most frequently reported component of treatment fidelity but other important aspects were poorly reported. The potential consequence of this is that translation of research interventions into clinical practice may not be optimised.

The transtheoretical model has been successful in promoting health behavior change in general and clinical populations. However, there is little knowledge about the application of the transtheoretical model to explain physical activity behavior in individuals with non-cystic fibrosis bronchiectasis. The aim was to examine patterns of (1) physical activity and (2) mediators of behavior change (self-efficacy, decisional balance, and processes of change) across stages of change in individuals with non-cystic fibrosis bronchiectasis.Fifty-five subjects with non-cystic fibrosis bronchiectasis (mean age ± SD = 63 ± 10 y) had physical activity assessed over 7 d using an accelerometer. Each component of the transtheoretical model was assessed using validated questionnaires. Subjects were divided into groups depending on stage of change: Group 1 (pre-contemplation and contemplation; n = 10), Group 2 (preparation; n = 20), and Group 3 (action and maintenance; n = 25). Statistical analyses included one-way analysis of variance and Tukey-Kramer post hoc tests.Physical activity variables were significantly (P.05) higher in Group 3 (action and maintenance) compared with Group 2 (preparation) and Group 1 (pre-contemplation and contemplation). For self-efficacy, there were no significant differences between groups for mean scores (P = .14). Decisional balance cons (barriers to being physically active) were significantly lower in Group 3 versus Group 2 (P = .032). For processes of change, substituting alternatives (substituting inactive options for active options) was significantly higher in Group 3 versus Group 1 (P = .01), and enlisting social support (seeking out social support to increase and maintain physical activity) was significantly lower in Group 3 versus Group 2 (P = .038).The pattern of physical activity across stages of change is consistent with the theoretical predictions of the transtheoretical model. Constructs of the transtheoretical model that appear to be important at different stages of change include decisional balance cons, substituting alternatives, and enlisting social support. This study provides support to explore transtheoretical model-based physical activity interventions in individuals with non-cystic fibrosis bronchiectasis. (ClinicalTrials.gov registration NCT01569009.).

This paper aims to provide physiological rationale for airway clearance, mucoactive therapy and pulmonary rehabilitation (PR) (or exercise interventions) in bronchiectasis. There is increasing emphasis on the role of airway clearance techniques (ACT) in the management of bronchiectasis. No single ACT has currently shown superior effect over another. Given the large range of different techniques available, consideration of the physiological effects underpinning a technique including expiratory flow, ventilation and oscillation, is essential to effectively personalize ACT. Key clinical trials of mucoactives in bronchiectasis are underway and will provide clarity on the role of these agents in the management of patients with bronchiectasis. Prescription of mucoactive therapies should be done in conjunction with ACT and therefore the mechanism of action of mucoactive drugs and their timing with ACT should be taken into consideration. PR and/or exercise training are recommended in all current bronchiectasis guidelines. There is a clear physiological rationale that muscle weakness and physical inactivity may play a role in disease progression as well as impacting health-related quality of life, frequency of pulmonary exacerbations and ability to mobilize sputum. However, there are residual unanswered questions surrounding the delivery and accessibility to PR. This review summarizes the physiological principles and supporting evidence for airway clearance, mucoactive medication and PR, which are key components in the management of bronchiectasis.

Background The aim of this position statement was to inform the choice of physical activity tools for use within CF research and clinical settings. Methods A systematic review of physical activity tools to explore evidence for reliability, validity, and responsiveness. Narrative answers to "four key questions" on motion sensors, questionnaires and diaries were drafted by the core writing team and then discussed at the Exercise Working Group in ECFS Lisbon 2013. Results and summary Our current position is that activity monitors such as SenseWear or ActiGraph offer informed choices to facilitate a comprehensive assessment of physical activity, and should as a minimum report on dimensions of physical activity including energy expenditure, step count and time spent in different intensities and sedentary time. The DigiWalker pedometer offers an informed choice of a comparatively inexpensive method of obtaining some measurement of physical activity. The HAES represents an informed choice of questionnaire to assess physical activity. There is insufficient data to recommend the use of one diary over another. Future research should focus on providing additional evidence of clinimetric properties of these and new physical activity assessment tools, as well as further exploring the added value of physical activity assessment in CF.

The chapter describes the bronchiectasis pathophysiology that informs and influences airways clearance techniques (ACT) and provides an overview of the aims of ACT and current practices in bronchiectasis. The main physiological mechanisms underlying ACTs as well as the current evidence base are detailed. Mucoactive drugs are discussed particularly in terms of dose, delivery device/route and timing with ACT to facilitate airway clearance. Recognising that the evidence base for ACT in bronchiectasis is low with few high-quality studies, a review of the outcomes used in randomised crossover and controlled trials (RCTs) in bronchiectasis has been included. This has also focused on the utility and feasibility of the commonly used endpoints as well as the potential clinical endpoints that could be considered for use in future ACT clinical trials.

Background: The REVIVE randomized controlled trial (RCT) investigated the effectiveness of an individually tailored (personalized) exercise program for patients discharged from hospital after critical illness. By including qualitative methods, we aimed to explore patients’ perceptions of engaging in the exercise program. Methods: Patients were recruited from general intensive care units in 6 hospitals in Northern Ireland. Patients allocated to the exercise intervention group were invited to participate in this qualitative study. Independent semistructured interviews were conducted at 6 months after randomization. Interviews were audio-recorded, transcribed, and content analysis used to explore themes arising from the data. Results: Of 30 patients allocated to the exercise group, 21 completed the interviews. Patients provided insight into the physical and mental sequelae they experienced following critical illness. There was a strong sense of patients’ need for the exercise program and its importance for their recovery following discharge home. Key facilitators of the intervention included supervision, tailoring of the exercises to personal needs, and the exercise manual. Barriers included poor mental health, existing physical limitations, and lack of motivation. Patients’ views of outcome measures in the REVIVE RCT varied. Many patients were unsure about what would be the best way of measuring how the program affected their health. Conclusions: This qualitative study adds an important perspective on patients’ attitude to an exercise intervention following recovery from critical illness, and provides insight into the potential facilitators and barriers to delivery of the program and how programs should be evolved for future trials.

Background Adherence to treatment is low in bronchiectasis and is associated with poorer health outcomes. Factors affecting adherence decisions have not been explored in patients with bronchiectasis. Objective We aimed to explore patients’ perspectives on adherence, factors affecting adherence decision making and to develop a conceptual model explaining this decision-making process in adults with bronchiectasis. Methods Adults with bronchiectasis participated in one-to-one semi-structured interviews. Interviews were audio-recorded, transcribed verbatim and analysed independently by two researchers using thematic analysis. Data from core themes were extracted, categorized into factors affecting adherence decision making and used to develop the conceptual model. Results Participants’ beliefs about treatment, the practical aspects of managing treatment, their trust in health-care professionals and acceptance of disease and treatment were important aspects of treatment adherence. The conceptual model demonstrated that adherence decisions were influenced by participants’ individual balance of barriers and motivating factors (treatment-related, diseaserelated, health-care-related, personal and social factors). Conclusion Adherence decision-making in bronchiectasis is complex, but there is the potential to enhance adherence by understanding patients’ specific barriers and motivators to adherence and using this to tailor adherence strategies to individual patients and treatments.

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF. © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V.

Background Streamlining the timing of treatments in cystic fibrosis (CF) is important to optimise adherence while ensuring efficacy. The optimal timing of treatment with hypertonic saline (HTS) and airway clearance techniques (ACT) is unknown. Objectives This study hypothesised that HTS before ACT would be more effective than HTS during ACT as measured by Lung Clearance Index (LCI). Methods Adults with CF providing written informed consent were randomised to a crossover trial of HTS before ACT or HTS during ACT on consecutive days. ACT treatment consisted of Acapella Duet. Patients completed LCI and spirometry at baseline and 90 min post treatment. Mean difference (MD) and 95% CIs were reported. Results 13 subjects completed the study (mean (SD) age 33 (12) years, forced expiratory volume in 1second % (FEV 1 %) predicted 51% (22), LCI (no. turnovers) 14 (4)). Comparing the two treatments (HTS before ACT vs HTS during ACT), the change from baseline to 90 min post treatment in LCI (MD (95% CI) −0.02 (−0.63 to 0.59)) and FEV 1 % predicted (MD (95% CI) −0.25 (−2.50 to 1.99)) was not significant. There was no difference in sputum weight (MD (95% CI) −3.0 (−14.9 to 8.9)), patient perceived ease of clearance (MD (95% CI) 0.4 (−0.6 to 1.3) or satisfaction (MD (95% CI) 0.4 (−0.6 to 1.5)). The time taken for HTS during ACT was significantly shorter (MD (95% CI) 14.7 (9.8 to 19.6)). Conclusions In this pilot study, HTS before ACT was no more effective than HTS during ACT as measured by LCI. Trial registration number NCT01753869; Pre-results.