Abstract
The study aimed to determine the efficacy of a safe and well-tolerated dose and regimen of tobramycin inhalation powder (TIP) on Pseudomonas aeruginosa sputum density in patients with bronchiectasis.
This is a phase II, double-blind, randomised study in bronchiectasis patients aged ≥18 years with chronic P. aeruginosa infection. Patients were randomised 1:1:1 to either cohort A: three capsules of TIP once daily (84 mg); cohort B: five capsules once daily (140 mg) or cohort C: four capsules twice daily (224 mg). Within each cohort, patients were further randomised 2:2:1 either to TIP continuously, TIP cyclically (alternating 28 days of TIP and placebo) or placebo for 16 weeks, respectively and were followed up for 8 weeks.
Overall, 107 patients were randomised to cohorts A (n=34), B (n=36) and C (n=37). All three TIP doses significantly reduced the P. aeruginosa sputum density from baseline to day 29 versus placebo in a dose-dependent manner (p≤0.0001, each). A smaller proportion of patients in the continuous-TIP (34.1%) and cyclical-TIP (35.7%) groups experienced pulmonary exacerbations versus placebo (47.6%) and also required fewer anti-pseudomonal antibiotics (38.6% on continuous TIP and 42.9% on cyclical TIP) versus placebo (57.1%) although not statistically significant. Pulmonary exacerbation of bronchiectasis was the most frequent (37.4%) adverse event. Overall, TIP was well tolerated, however, 23.4% of the patients discontinued the study drug due to adverse events.
Continuous- and cyclical-TIP regimens with all three doses were safe and effective in reducing the P. aeruginosa sputum density in patients with bronchiectasis and chronic P. aeruginosa infection.
Abstract
Inhaled dry powder tobramycin (TOBI Podhaler) significantly reduced Pseudomonas aeruginosa sputum density and was well tolerated in patients with bronchiectasis https://bit.ly/3hsRQw9
Introduction
Bronchiectasis (BE) is characterised by the presence of chronic and progressive inflammatory airway destruction that leads to repeated exacerbations [1]. In 2013, the prevalence of bronchiectasis in the USA and the UK was estimated to be 139 cases and 486–566 cases per 100,000 inhabitants, respectively [2, 3]. A higher prevalence of bronchiectasis is seen with increasing age and in women [4, 5]. Globally, bronchiectasis is thought to be the third most common chronic respiratory disease, after asthma and chronic obstructive pulmonary disease (COPD) [5].
Global mortality rates associated with bronchiectasis have been reported to be 10–30% at 5 years and up to 35% at 15 years [6]. Recently, a study in Germany has shown that bronchiectasis is associated with substantial mortality and financial burden [7]. Pseudomonas aeruginosa in the sputum of patients with bronchiectasis is a key driver of inflammation [8, 9]. Chronic P. aeruginosa infection is associated with frequent exacerbations, worsening of forced expiratory volume in 1 s (FEV1), a three-fold increase in mortality, a seven-fold increase in risk of hospitalisation and worsening quality of life (QoL) [6, 10, 11].
In the recent European Respiratory Society (ERS) and British Thoracic Society (BTS) guidelines, long-term use of inhaled antibiotics, having localised airway delivery with minimal systemic exposure, are recommended for patients with bronchiectasis, chronic P. aeruginosa infection and frequent pulmonary exacerbations [4, 12]. A recent systematic review and meta-analysis involving 16 randomised clinical trials with over 2500 patients, demonstrated that inhaled antibiotics consistently reduce bacterial sputum density and achieve a small but statistically significant reduction (RR 0.81, 0.67 to 0.97; p=0.020) in the exacerbation frequency in patients with bronchiectasis [13].
Despite recommendations from ERS and BTS for use of oral/inhaled antibiotics, there is currently no inhaled antibiotic approved for the treatment of bronchiectasis. Most inhaled antibiotic trials have been conducted using an on/off strategy designed to minimise the emergence of antimicrobial resistance. There is lack of evidence comparing continuous versus intermittent inhaled antibiotic administration for bronchiectasis, and the European guidelines make no recommendation regarding the therapeutic regimen [14].
Tobramycin inhalation powder (TIP), TOBI Podhaler, has a proven efficacy and safety profile, and has been approved for the management of chronic P. aeruginosa pulmonary infection in patients with cystic fibrosis (CF). A potential benefit of the dry powder formulation is the reduced time burden compared with nebulised delivery, which may enhance treatment adherence [15, 16]. Several prospective studies with tobramycin solution for inhalation document its role in improving clinical bronchiectasis symptoms, reducing P. aeruginosa sputum density and improving QoL for bronchiectasis patients. However, data on adverse events (AEs) from these studies are not consistent and in the absence of more contemporary safety data, use of inhaled tobramycin in patients with bronchiectasis is limited [17–19].
This study aimed to determine the efficacy of a safe and well-tolerated dose and regimen of TIP on P. aeruginosa sputum density in patients with bronchiectasis. We tested the hypothesis that there is a dose-dependent effect of TIP on bacterial density and tolerability in patients with bronchiectasis.
Patients and methods
Study design
This was a multicentre, phase II, randomised, double-blind, parallel-group, dose- and regimen-finding study that evaluated the efficacy, safety and tolerability of three different doses of TIP in patients with radiological evidence of bronchiectasis and chronic P. aeruginosa infection.
Participants were randomised in 1:1:1 ratio to one of three treatment cohorts in addition to the local standard of care: cohort A received three capsules of TIP once daily (84 mg); cohort B, five capsules once daily (140 mg); and cohort C, four capsules twice daily (224 mg). Each capsule was of 28 mg dosage strength and inhaled via the T-326 Inhaler. Within each cohort, patients were randomised in 2:2:1 ratio to receive either continuous TIP, or cyclical TIP/placebo (cycles of TIP for 28 days, alternating with placebo for 28 days) or placebo. Treatment duration of 16 weeks (112 days) was followed by an 8-week (56-day) follow-up. The study design has been previously published and presented in figure 1 [20]. Recruitment was closed after the acquisition of the product by another company when 107 out of 180 patients were recruited. This did not lead to any changes to the study protocol. However, the following previously planned analysis were not performed due to reduced sample size: a) subgroup analysis using age group, sex, bronchiectasis severity index (BSI) in patients with pulmonary exacerbations at screening; b) primary efficacy analysis after excluding patients who were not confirmed P. aeruginosa positive at baseline; c) primary efficacy analysis using multiple imputations where the respective treatment effect replaced missing values; and d) primary efficacy analysis using multiple imputations to account for patients who required treatment with anti-pseudomonal antibiotics for exacerbation post-baseline and up to and including day 29, by assuming the placebo treatment effect for those subjects requiring anti-pseudomonal treatment.
Due to the early recruitment halt and reduced sample size, the inferential analysis should be considered as exploratory and the results obtained should be interpreted with the caution.
Patients
Included in the study were patients (aged ≥18 years) with a proven diagnosis (confirmed via chest computed tomography scan) of bronchiectasis and a history of ≥2 exacerbations treated with oral antibiotics or ≥1 exacerbation requiring parenteral antibiotic treatment as well as P. aeruginosa documented in a respiratory sample (expectorated sputum, deep-throat cough swab, oropharyngeal swab or bronchoalveolar lavage) at least once within the 12 months prior to screening. Patients with FEV1 ≥30% predicted and a positive P. aeruginosa sputum culture at screening were considered eligible. Patients with a history of cystic fibrosis, a primary diagnosis of smoking-associated COPD, a primary diagnosis of bronchial asthma and local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics were not eligible. Pregnant and/or lactating women were also excluded. Other inclusion and exclusion criteria are detailed in the study design manuscript [20].
Ethical consideration
The study was conducted in accordance with the International Council for Harmonization Good Clinical Practice (GCP) regulations/guidelines and the ethical principles set forth in the Declaration of Helsinki. Either independent ethics committee or institutional review board approved the protocol. Written informed consent was obtained from all participants before the start of the study. An independent data monitoring committee regularly reviewed the safety data.
Outcomes
Efficacy endpoints
Primary endpoint
Change from baseline to Day 29 in P. aeruginosa density in sputum (log10 colony forming units (CFUs)) was evaluated to demonstrate the effect of different doses of TIP.
Selected secondary endpoints
Antimicrobial efficacy of TIP over the entire study duration; effect of different doses of TIP and different regimens on pulmonary exacerbation at the end of the treatment epoch (day 113) and over the study period; efficacy profile of different doses of TIP and different regimens as measured by anti-pseudomonal antibiotic usage during the treatment epoch (through day 113) and study period were evaluated.
Safety endpoints
Incidence rate and severity of adverse events and serious adverse events (SAEs) were assessed to evaluate the safety and tolerability profile of different TIP doses and treatment regimens over the treatment period and study duration. Evaluation of clinical and laboratory parameters, post-inhalation events, measurement of bronchial hyperactivity and audiology testing were performed.
Selected exploratory endpoints
Treatment effect of TIP on the Respiratory Symptom Scale Quality of Life Questionnaire for Bronchiectasis (QoL-B RSS) was evaluated along with other scales of the QoL-B (e.g. physical functioning, vitality and health perceptions).
Statistical methods
Data were summarised and analysed by cohort/dose, treatment groups (including combined treatments) and/or pooled by continuous, cyclical and placebo, as appropriate. For the efficacy analyses, the placebo patients were pooled from the three cohorts.
Descriptive statistics (n, mean, sd, median, minimum and maximum) for patient demographics including age, weight, height, sex and other baseline characteristics were calculated for continuous data. Categorical data were summarised using “n” and percentages based on the number of non-missing values.
The primary efficacy endpoint was analysed using the analysis of covariance (ANCOVA) model using treatment and baseline macrolide use as fixed-effect factors, and baseline CFU (in log10 unit), as covariate. Step-wise Dunnett's procedure was used to control the family-wise type-I error rate at 5%.
Hazard ratios and 95% confidence intervals were provided for time to event variables using a Cox regression model. Relative risks and 95% confidence intervals were provided for count data using a generalised linear model. An ad hoc analysis of area under curve (AUC) for change from baseline in CFU (in log10 unit) were performed using an ANCOVA model using the same set of factors/covariates as included in primary analysis.
Data analysis was performed by ICON. Statistical analyses were performed using SAS Version 9.4. Further details of the statistical methods are provided in Supplementary methods.
Results
In total, 186 patients were screened from six countries (Belgium, France, Germany, Italy, Spain and the UK), 107 of whom were randomised (of 180 planned) to the three different treatment cohorts. 79 (42.5%) patients failed screening. Table 1 presents the patient demographics, disease characteristics and other baseline parameters.
The majority of patients were female (61.7%) except in the placebo group of Cohort A (42.9%). The mean±sd age across all treatment subgroups was 63.4±13.6 years except for cyclical TIP in cohort A (57.5±11.8 years) and placebo group in cohort C (71.3±10.4 years); 57.9% were aged ≥65 years. The majority of patients were Caucasian (89.7%); in cohort C, all patients were Caucasians. These variations within the demographics between the treatment cohorts was expected for the given patient population size and also due to the enrollment from six different European countries (UK: 24.3%; Spain: 24.3%; Italy: 15.9%; Germany: 15.0%; France: 15.0%; and Belgium: 5.6%).
From the ANCOVA model, it was shown that treatment effect (p≤0.0001) and baseline log10 CFU was statistically significant (p=0.0003), whereas macrolide use was not statically significant (p=0.7742). All three doses of TIP reduced the P. aeruginosa sputum density from baseline to day 29 significantly (p≤0.0001) when compared with placebo (figure 2). Antimicrobial efficacy of TIP versus placebo over the entire study duration showed the highest least square mean difference in cohort C. In addition, higher doses achieved higher reductions in P. aeruginosa sputum density (figure S1). These results were consistent with the changes in CFUs measured as AUC: a higher decrease (negative AUC) was observed in pooled continuous regimen (−242.8 log10 CFUs) than in the cyclical regimen (−194.7 log10 CFUs), indicating that continuous regimen has advantage over the cyclic regimen (table 2). Both results were statistically significant when compared with pooled placebo (p<0.0001 for both). Similarly, when comparing the three different daily doses, a higher decrease (negative AUC) was observed in cohort C (−185.8 log10 CFU) compared with cohort A (−122.9 log10 CFUs) or B (−145.8 log10 CFUs), indicating that twice daily dosing has advantages over once daily dosing (table 3). Statistical significance as compared to placebo was reported for all the cohorts (cohort A: p=0.0004; cohort B; and cohort C: p<0.0001).
During the treatment period, several patients had no P. aeruginosa detected in their sputum or deep throat cough samples. The proportion of patients with no P. aeruginosa detected at two consecutive post-baseline visits was similar in the continuous- and cyclical-TIP groups (23 (52.3%) patients and 21 (50.0%) patients, respectively). Of note, in the placebo group, only one (4.8%) patient had no P. aeruginosa detected during the course of the study. Moreover, at study completion about one-third of the patients in the active arms remained P. aeruginosa-free: continuous TIP 12 (38.7%) out of 31 and cyclical TIP 12 (36.4%) out of 33.
The majority of patients had a baseline isolate with a TIP minimum inhibitory concentration (MIC) of ≤8 μg·mL−1 (119 (96.7%) patients), indicating that this is a susceptible population. At the end of study, isolates from 11 patients showed four-fold or greater increase in the TIP MIC post-baseline with 10 of them in the active groups (table S1). Changes in susceptibility to the tested antibiotics were not relevant, with no particular trends in the emergence of resistance. No particular pattern was noted in the emergence of new bacterial and fungal pathogens observed in the pooled continuous- or cyclical-TIP groups, as they were irregularly found in different active groups.
There was a slightly smaller percentage of patients experiencing pulmonary exacerbation episodes (as defined per protocol) in the pooled continuous TIP group (15 (34.1%); RR: 0.81, 95% CI 0.39–1.68) and pooled cyclical TIP group (15 (35.7%), RR: 0.96, 95% CI 0.49–1.91) when compared with placebo (10 (47.6%)). However, the results were not statistically significant (figure 3a).
Similarly, only 38.6% (n=17) and 42.9% (n=18) patients in the pooled continuous and cyclical groups, respectively, used anti-pseudomonal antibiotics during the study, compared with 57.1% (n=12) patients in the placebo group (figure 3b). The reduction in use of anti-pseudomonal antibiotics appears to be significant in the cohort C continuous TIP group (RR: 0.25, 95% CI 0.07–0.98). Of note, anti-pseudomonal antibiotics were used to treat either pulmonary exacerbations or certain respiratory events, which did not reach the protocol-defined criteria for pulmonary exacerbation.
Mean (95% CI) score for QoL-B by Respiratory domain is provided in (figure S2). No definite trend was noted across the entire study period in the scores of different QoL-B domains within the active treatment groups, except for the Respiratory Symptoms domain. In the TIP group in cohort B, least square mean difference versus placebo was noted to be 9.6 (95% CI: −3.81–22.94, repeated measure analysis), numerically exceeding the published minimum clinically important difference of 8 points [21]; however, with a large variability (as indicated by the large 95% confidence intervals). In the same cohort, mean change in scores from baseline until the end of study had similar trends, with improvements for role, emotional and social functioning along with health perceptions, without reaching significance.
Safety
Overall, the study drug was well tolerated with the majority of patients in each cohort achieving >90% compliance at each visit.
The most commonly reported adverse events by preferred term were infective exacerbation of bronchiectasis (37.4%), cough (18.7%) and dyspnoea (17.8%). The majority of infective exacerbations of bronchiectasis were mild or moderate in nature and only five (4.7%) patients experienced severe infective exacerbations of bronchiectasis. SAEs were observed in 20.6% (n=22) of the patients, with infective exacerbation of bronchiectasis being the most common (n=9; 8.4%) followed by haemoptysis and respiratory failure (n=3; 2.8% for each) (table S2). No death was reported in this study.
Overall, 92 (86.0%) patients experienced at least one treatment emergent adverse events (TEAE) regardless of study drug relationship, and the incidence was similar in both the active treatment (pooled continuous- and cyclical-TIP groups) and placebo groups. In total, 45 (42.1%) patients experienced TEAEs suspected to be study-drug related and the most frequent of these were cough (nine (8.4%) patients) and dyspnoea (nine (8.4%) patients). These adverse events were variable amongst cohorts. In 25 (23.4%) patients, TEAEs led to study-drug discontinuation and the numbers were higher in the active treatment groups compared with the placebo group. Highest discontinuations were observed in cohort C (14 (37.8%)) when compared with cohort A (five (14.7%) and cohort B (six (16.7%)). The most frequently reported TEAE, leading to study-drug discontinuation across all cohorts by preferred term, was infective exacerbation of bronchiectasis (five (4.7%)) (table 4).
With regard to specific adverse events of interest, based on the known aminoglycoside safety profile, five (4.7%) patients experienced ototoxicity (adverse events of special interest (AESI) and 12 (11.2%) patients experienced haemoptysis (one was during the screening epoch). Post-inhalation clinical events were higher in the five capsules once daily dosing cohort (cohort B; nine (25.0%)) followed by the three-capsules once daily dosing cohort (cohort A; seven (20.6%)) and subsequently the four capsules twice daily dosing cohort (cohort C; five (13.5%)). In addition, no signal of clinically significant bronchial hyperreactivity was observed.
In 12 patients, renal parameter changes were found to be clinically relevant, i.e. ≥50% increase in serum creatinine and/or estimated glomerular filtration rate (eGFR) levels ≤50 mL·min−1·1.73 m−2. Seven of the 12 patients had a plausible association between the renal event and study drug. Of these, six patients were treated with pooled continuous TIP (two were in cohort B and four were in cohort C), and one with cyclical TIP (cohort B).
Discussion
This is the first study to evaluate the safety and efficacy of different doses and dosing regimens of TIP in patients with bronchiectasis and pulmonary P. aeruginosa infection. The results demonstrated that all three doses of TIP (84 mg (three capsules) once daily, 140 mg (five capsules) once daily and 224 mg (four capsules) twice daily) significantly reduced the P. aeruginosa sputum density from baseline to day 29 compared with placebo. In addition, higher dose achieved higher reduction in P. aeruginosa sputum density. From the ad hoc AUC-based analysis, it was also seen that continuous regimens have advantage over cyclic regimens in reducing P. aeruginosa density.
This study demonstrated better reduction in P. aeruginosa sputum density compared with cystic fibrosis studies using TIP [22, 23]. In addition, the microbiology results are consistent with previous studies in patients with bronchiectasis, either with inhaled tobramycin solution [17] or inhaled dual-release ciprofloxacin [24]. Several earlier studies have documented the efficacy of inhaled tobramycin solution in reducing the P. aeruginosa sputum density and improving the clinical symptoms of bronchiectasis [17–19, 25, 26]. However, data from long-term studies are limited in numbers. This study provides valuable insights into the effectiveness of TIP in patients with bronchiectasis. Patients in the pooled TIP group maintained a high (≥2.0) least square mean difference compared with the pooled placebo group at all visits, except for the follow-up visits: a pattern that is similar to previous studies with inhaled antibiotics [27–29]. Further, about half of the patients in the active groups had no P. aeruginosa detected at two consecutive post-baseline visits, with similar frequencies between the continuous- and cyclical-TIP groups (52.3% and 50%, respectively); while only one patient in the placebo group (4.8%) had no P. aeruginosa during the study. Moreover, at study completion, about one-third of the patients in the active arms was P. aeruginosa-free. Numerical differences were noted for frequency of pulmonary exacerbation episodes and use of anti-pseudomonal antibiotics favouring the TIP treatment groups. However, this study was not powered to demonstrate statistically meaningful differences for clinical outcomes. To do so, larger trials are warranted.
In this study, both continuous- and cyclical-TIP regimens showed effectiveness in reducing the P. aeruginosa sputum density (the LS mean difference was higher in the pooled continuous group compared with the cyclical group), the frequency of exacerbations and the use of anti-pseudomonal antibiotics. There was a higher decrease (negative AUC) in the pooled continuous regimen rather than the cyclical regimen. These results are consistent with previous observations suggesting that continuous antibiotic treatment controls the chronic bacterial infection and maintains treatment benefit [30]. A cyclical regimen was historically developed in CF patients with the aim to reduce the risk of the emergence of antibiotic resistance and to lower the cumulative exposure to antibiotics [31, 32]. It can be noted that in this study there was no particular trend towards an increase in TIP resistance in either treatment arm. Further, no clear trend was noted in general in the scores of different QoL-B domains with the active treatment groups.
A phase 2 study showed that BE patients experiencing improvement in their medical condition with inhaled tobramycin had a mean baseline bacterial load of 7.1 (1.4) log10 CFU·g−1 [17]. Treatment benefits in terms of QoL was observed in a 2-month study in bronchiectasis patients receiving nebulised gentamicin where the median baseline bacterial load was 8.0 (7.6–8.2) log10 CFU·g−1 [30]. Similar results were also noted with inhaled aztreonam where QoL was improved only in patients with high baseline bacterial load [33]. These results are in line with the present study where the mean±sd sputum density of P. aeruginosa was 6.4±1.8 log10 CFU.
The most frequently observed adverse events were infective exacerbation of bronchiectasis, cough and dyspnoea. SAEs observed were consistent with symptoms associated with pulmonary exacerbation and the population studied. While the efficacy outcomes tended to be better with higher TIP doses, there was a trend towards an increase in renal laboratory parameters (eGFR and blood creatinine) in this study. Of the 12 patients with plausible association between renal events and study drug, six had confounding factors. It was noted that most patients were poly-medicated and had pre-existing conditions (such as diabetes and hypertension). In addition, the exact timings of the renal events were difficult to ascertain as most of these were noted at the time of scheduled monthly clinic visits. Additionally, the advanced age of the study patients could be a predisposing factor. Previous trials with inhaled antibiotics in bronchiectasis patients did not report renal toxicity; however, they did not use the same stringent renal monitoring criteria as the iABC Bronchiectasis Efficacy Study with TIP (iBEST) study [17–25] and the events noted in this study are in line with the known safety profile of tobramycin. Cases of ototoxicity (mild tinnitus and deafness, moderate labyrinthitis,) noted in this study are consistent with a previous study [28]. Cases of tinnitus and deafness were mild, transient and did not lead to changes in the study medication administration. Also, one case of tinnitus and the case of deafness were reported in patients receiving placebo. As per protocol, audiometry was to be performed for patients with hearing complaints, however this was not performed in these specific patients, therefore the results must be interpreted with caution. Post-inhalation clinical events were short in duration (≤30 s) and did not demonstrate any dose-response pattern. TEAEs leading to study drug discontinuation were higher in active treatment cohorts with the most number of cases being in the highest dosage group (cohort C; four capsules twice daily.). Overall, TIP doses were well tolerated across all treatment groups and a compliance of ˃90% was noted. The observed type and rate of adverse respiratory effects with inhaled tobramycin is consistent with previously published studies [17, 19].
Limitations
The study was designed to demonstrate an antibacterial effect of different doses of inhaled tobramycin powder in comparison to placebo and hence was limited in terms of treatment duration and sample size. Enrolment in the trial was stopped before achieving the planned sample size after the acquisition of the product by another company. The study was not powered to demonstrate clinical outcomes such as reduction in exacerbations, use of antibiotics or hospitalisations; these endpoints would require much larger samples sizes and a longer treatment duration of at least 1 year [13, 34, 35]. The effect on P. aeruginosa density in all treated groups suggests that the study was over-powered for the primary outcome measure. Patients in this study had a high bacterial load at baseline, rendering them more likely to respond to TIP. The consistency of the effect on the reduction in P. aeruginosa CFUs across the treated groups increases confidence that this effect is a real effect of tobramycin dry powder inhalation.
Conclusion
Continuous and cyclical treatment with TIP was shown to be efficacious in reducing P. aeruginosa sputum density in patients with BE and chronic P. aeruginosa infection. All three doses of TIP reduced the P. aeruginosa sputum density significantly in a dose-dependent manner. Numerical differences favouring TIP were noted in terms of frequency of pulmonary exacerbation episodes and required use of anti-pseudomonal antibiotics. Overall, TIP was well tolerated with no new safety findings.
Supplementary material
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Acknowledgements
The authors thank Ritika Paul and Nihal Maremanda (Novartis Healthcare Pvt. Ltd, India) for providing medical writing and editorial support to draft the manuscript.
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.03390-2020
This article has supplementary material available from erj.ersjournals.com
This study is registered at www.ClinicalTrials.gov with identifier number NCT02712983.
Data sharing provision has not been made for this study.
Elements of the information presented in this publication were presented at the 2020 American Thoracic Society Conference.
Conflict of interest: E. Polverino reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and personal fees from Bayer, Menarini, Grifols, Zambon, Pfizer, Chiesi, Teva, Shire, Insmed and Polyphor, and grants from Chiesi and Grifols, outside the submitted work.
Conflict of interest: J.D. Chalmers reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and grants and personal fees from GSK, Boehringer-Ingelheim, AstraZeneca, Pfizer, Bayer Healthcare, Grifols, Napp, Aradigm corporation, and Insmed, outside the submitted work.
Conflict of interest: H.A.W.M. Tiddens reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and personal fees from Vertex and Gilead, grants and personal fees from Novartis, and grants from Roche, Vertex, Chiesi and Vectura, outside the submitted work.
Conflict of interest: H. Goossens reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study.
Conflict of interest: M. Tunney reports grants from European Union IMI grant in collaboration with Novartis, during the conduct of the study; and grants from European Union, Novartis and Alaxia SAS, outside the submitted work.
Conflict of interest: F.C. Ringhausen reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and grants, personal fees and non-financial support from Aposan, AstraZeneca, Bayer, Boehringer Ingelheim, Celtaxsys, Chiesi, Corbus, Grifols, InfectoPharm, Insmed, MSD, Novartis, PARI, Parion, Polyphor, Vertex and Zambon, outside the submitted work.
Conflict of interest: A.T. Hill reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study.
Conflict of interest: R. Pathan reports other from Novartis, outside the submitted work.
Conflict of interest: G. Angyalosi reports other from Novartis, outside the submitted work.
Conflict of interest: F. Blasi reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and grants and personal fees from AstraZeneca, Bayer, Grifols, Pfizer, Chiesi, GSK, Guidotti, Menarini, Novartis, Teva, Zambon and Insmed, outside the submitted work.
Conflict of interest: S.J. Elborn reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and grants from Novartis, and personal fees from Vertex, Galapagos and Ionis, outside the submitted work.
Conflict of interest: C.S. Haworth reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and grants and personal fees from Aradigm, Chiesi, Gilead, Grifols, GSK, Insmed, International Biophysics, Janssen, Mylan, Novartis, Teva, Vertex and Zambon, outside the submitted work.
Conflict of interest: M.R. Loebinger reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and personal fees from Bayer, Grifols, Astra Zeneca, Insmed and Polyphor, outside the submitted work.
Support statement: This work has received support from the European Union/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative Joint Undertaking iABC grant agreement n°115721. The protocol was designed and conducted by Novartis in collaboration with the authors. Novartis was responsible for data collection, data analysis, data interpretation, and writing the article. All authors had full access to the entire study data and the corresponding author had the final responsibility for the decision to submit for publication. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received April 28, 2020.
- Accepted July 18, 2020.
- Copyright ©ERS 2021