Article Text
Abstract
Introduction Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression.
Methods This phase 1b, randomised, open-label, dose–response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%–90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks.
Results We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were −2.5 (95% CI −5.3 to 0.4, −88 mL) and −4.9 (−7.5 to −2.3,–188 mL) in the 50 mg once per day and 0.6 (−2.2 to 3.4, 10 mL) and −0.4 (−3.2 to 2.3, −34 mL) in the 100 mg two times per day group.
Discussion Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted.
Trial registration number ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.
- idiopathic pulmonary fibrosis
- cough/mechanisms/pharmacology
Data availability statement
Data are available on reasonable request. Data are available from Avalyn Pharma on reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Though oral pirfenidone reduces lung function decline and mortality from idiopathic pulmonary fibrosis (IPF), systemic exposure runs the risk of substantial adverse effects.
WHAT THIS STUDY ADDS
ATLAS phase 1b trial finds inhaled pirfenidone (AP01) has fewer adverse effects than antifibrotics currently used to treat IPF.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The potential for efficacy in slowing progression of fibrosis and ameliorating decline in forced vital capacity warrants further study.
Introduction
Idiopathic pulmonary fibrosis (IPF) is a severe progressive lung disorder, leading to increasing breathlessness and cough with a profound impact on health-related quality of life. Many patients die of respiratory failure or comorbidities within 3–5 years of diagnosis.1 2 IPF affects up to 200 000 Americans and 135 000 Europeans.3 4 Worldwide, two oral antifibrotic medications are approved to treat IPF: nintedanib and pirfenidone.5 6 At the recommended dosing, both can be associated with liver enzyme elevation and gastrointestinal side effects; oral pirfenidone is also associated with photosensitivity and rash.7 8 In pooled oral pirfenidone trials (pirfenidone: n=1299; placebo: n=624), nausea (38% vs 16%), rash (25% vs 10%), dyspepsia (18% vs 7%), weight loss (16% vs 5%), vomiting (16% vs 6%) and liver enzyme elevation (3% vs 0.9%) were more common with oral pirfenidone than with placebo.8 In pooled nintedanib trials (nintedanib: n=723; placebo: n=508), diarrhoea (62% v 18%), nausea (24% v 7%), abdominal pain (15% v 6%), liver enzyme elevation (14% v 3%), and vomiting (12% v 3%) were more common with nintedanib than with placebo.7 These adverse events (AEs) may lead to dose reductions or discontinuations. In US and French studies of patients newly prescribed antifibrotics, more than 20% discontinued oral pirfenidone and 30% nintedanib after 6 months; 12-month discontinuation rates exceeded 40% for both antifibrotics.9 10 Efficacy of both medications is suboptimal, slowing disease progression by ~50% but not halting lung function decline.5 6
Aerosol administration improves efficacy and safety of many drugs by increasing delivery to lung tissue and decreasing systemic exposure.11 AP01 is an inhaled formulation of pirfenidone optimised for lung delivery. In a phase 1, single ascending dose study evaluating safety, tolerability and pharmacokinetics, the PARI investigational eFlow nebuliser delivered >40% of the dose to the lung and enabled alveolar delivery. AP01 was well tolerated by healthy volunteers and patients with IPF. Compared with the approved thrice-daily, 801 mg dose of oral pirfenidone, the highest dose of AP01 tested (100 mg) achieved 35-fold higher peak epithelial lining fluid concentrations with ~1/15 systemic exposure.12
The ATLAS study assessed the safety, tolerability and efficacy of two AP01 doses in patients with IPF. We present results for week 24, the primary endpoint and week 48 for comparability to published trials of antifibrotics. The Data and Safety Monitoring Board (DSMB) recommended transitioning all patients to the higher dose midstudy following review of week 24 data in all patients. Only five patients transitioned to the higher dose by the week 48 visit. An additional 16 patients on 50 mg once per day transitioned to 100 mg two times per day by week 72. Therefore, week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study.
Methods
Study design
ATLAS is a 24-week (optional extension to 72 weeks) randomised, parallel-group, open-label trial conducted from May 2019 to October 2021 at 25 sites in Australia, New Zealand, Czech Republic, Poland, Netherlands and the UK. The trial was conducted in compliance with the Declaration of Helsinki and the Harmonised Tripartite Guideline for Good Clinical Practice of the International Conference on Harmonisation and approved by local ethics committees. All patients provided written informed consent.
Eligibility
Principal eligibility criteria included being ≥40 years of age, with a confident diagnosis of IPF according to European Respiratory Society/American Thoracic Society (ERS/ATS) criteria within 5 years, forced vital capacity (FVC) ≥40% and ≤90% predicted and forced expiratory volume in 1 s (FEV1)/FVC ratio ≥0.7, not currently taking oral pirfenidone or nintedanib. Exclusion criteria included acute IPF exacerbation requiring hospitalisation in the previous 3 months, any alternative diagnoses that could lead to pulmonary fibrosis or connective tissue disease, asthma, chronic obstructive pulmonary disease or active infection. Full eligibility criteria are provided in online supplemental table 1.
Supplemental material
Randomisation and stratification
Patients were randomly assigned using interactive response technology 1:1 to AP01 50 mg once per day or 100 mg two times per day administered with a PARI investigational eFlow nebuliser. Randomisation was stratified by region (Asia-Pacific/Europe) and disease severity (FVC % predicted <50/≥50).
Sample size
The target sample size of 100 patients (50 per dose group) was selected to provide adequate data to assess the safety and tolerability of AP01 given once or two times per day and estimates of changes in outcomes over time. With the target sample size, there was a 92% chance of detecting an AE with a true population rate of 5%.
Study treatment
The first dose was administered at the study site. Patients experiencing cough limiting their ability to complete the first dose were pretreated with one to two puffs of salbutamol for remaining doses, as were patients with a history of asthma, smoking history ≥20 pack-years or ≥15% decrease in FEV1 % predicted (post–pre dose) unless already receiving a long-acting beta-2 agonist.
Safety assessments
An independent DSMB reviewed safety data after the first 20 patients completed 4 weeks and when all patients completed 24 and 48 weeks. Safety outcome measures included treatment-emergent AEs, change in FEV1 (post–pre dose) for the initial dose and changes in vital signs and clinical laboratory findings.
Efficacy assessments
Laboratory, in-clinic spirometry and patient-reported outcome (PRO) measures were collected every 4 weeks for 24 weeks, then every 12 weeks through week 72. Spirometry was performed according to ATS/ERS guidelines.13 PROs included the Leicester Cough Questionnaire (LCQ) and the King’s Brief Interstitial Lung Disease (KBILD) questionnaire.14 15 Laboratory testing was performed using a central laboratory. Leicester Cough Monitor (LCM) 24-hour measurements were collected at baseline and weeks 12 and 24 and centrally scored.16 High-resolution CT (HRCT) scans were performed at baseline and week 24 and centrally interpreted and quantified, including total lung capacity volume (litres) and quantitative lung fibrosis computer-aided diagnosis (QLFCAD) score (millilitres) for the whole lung.17
The primary efficacy endpoint was absolute change from baseline to week 24 in FVC % predicted. Prespecified secondary endpoints included change from baseline in diffusion capacity to carbon monoxide (DLCO), PROs, cough frequency and intensity, and extent of fibrosis and lung volumes measured by quantitative scoring of HRCT.
Analysis
All analyses were consistent with our prespecified Statistical Analysis Plan (provided in online supplemental materials). Safety, disposition and baseline analyses were conducted in patients who received ≥1 dose of AP01, and analyses for all other outcomes were performed on the per-protocol sample specified in the Statistical Analysis Plan. Inferential analyses implicitly handled missing data assuming missingness was explained by observed variables (missing at random). Change in FVC % predicted was analysed using a random coefficients model, with random slopes and intercepts for patients. Baseline FVC % predicted,18 region, age at screening, sex, baseline DLCO % predicted19 and baseline progression-related biomarkers (CXCL13, CCL18, MMP3, each categorised as >or ≤ median level) were included as covariates. The model required all covariates and three follow-up measurements of FVC % predicted for the intercept and slope to be identifiable. The average slope, representing FVC decline, was estimated for each dose group using the random coefficients model and compared between groups. Significance tests comparing dose groups were based on these fixed slope effects and summarised using p values and two-sided 95% CIs for the difference between dose groups. A similar analysis was conducted for FVC in litres. For patients who transitioned to 100 mg two times per day, spirometry data collected after transition were not included when estimating slopes. For visit-based analyses comparing means, a linear mixed-effects model was used with change from baseline in FVC as the dependent variable, patient as a random effect, fixed effect of time and time-varying effects for treatment group (dose group was treated as time-varying to accommodate patients who transitioned) and treatment-by-time interaction and baseline FVC % predicted, region, sex, baseline DLCO % predicted, age at screening, baseline progression-related biomarkers (CXCL13, CCL18, MMP3), each categorised as >median level versus ≤median level as fixed effects. To account for correlated repeated measures within patients, a spatial power variance–covariance matrix was used. These comparisons were summarised using least-squares means and two-sided 95% CIs.
Supplemental material
Descriptive analyses were conducted for other endpoints. LCM data analyses include the subgroup with baseline cough frequency during awake hours ≥10 coughs/hour to assess treatment impact in patients for whom coughing is of the greatest concern.20 The absolute change from baseline in fibrosis in the whole lung obtained from the HRCT scans was calculated and correlated with change from baseline in FVC (millilitres). PROs, including KBILD and LCQ, were summarised as absolute changes from baseline at each visit.
Results
Patient information
Ninety-one patients enrolled (46 at 50 mg once per day, 45 at 100 mg two times per day); 77 (85%) of patients completed 24 weeks and 68 (75%) completed week 48 (figure 1). The target enrolment of 100 was not reached because the COVID-19 pandemic closed most sites from March to April 2020. Ongoing intermittent closures prevented some office visits and spirometry measurements.
All patients had a confident diagnosis of IPF, based on ATS guidelines (online supplemental table 1).21 Although median IPF duration was shorter in the 50 mg once per day group, the percentage of patients diagnosed within 1 year was lower, and patients had higher quantitative fibrosis on average (table 1). A greater percentage of 50 mg once per day patients had CXCL13 and MMP3 above the median compared with 100 mg two times per day patients.
Safety
Initial doses were well tolerated with no adverse effects on respiratory rate, spirometry or oxygenation during or following administration; median administration times were 5 and 8 min for the 50 mg and 100 mg doses, respectively. Eight patients (9%) had cough associated with nebulisation. Of the eight, one patient received salbutamol before the first dose, four were given salbutamol to continue dosing and three did not require salbutamol. All cough events associated with first-dose nebulisation were mild or moderate in severity and transient.
AEs reported for ≥10% of patients included cough, rash, dyspnoea, nausea, IPF (includes progression, deterioration, exacerbation and worsening), fatigue, lower respiratory tract infection and upper respiratory tract infection (table 2). AEs generally occurred within 3 months, with median time to first AE being 53 (IQR 1–153) days for rash, 32 (9–187) days for nausea and 72 (22–155) days for fatigue. Cough (n=14/91, 15.4%) was the most reported treatment-related AE, with three events related to nebulisation (two in the 50 mg once per day group, one in the 100 mg two times per day group). Except for throat irritation, the incidences of the most common treatment-related AEs were lower for the 50 mg once per day group. One grade 3 event of parainfluenza virus infection was considered serious; all other treatment-related events were mild or moderate.
Thirteen serious AEs were reported in nine patients assigned 50 mg once per day, with 11 serious AEs in 7 patients assigned 100 mg two times per day (table 2). AEs leading to study termination were cough (n=2), progression of IPF (n=2), pneumonia (n=1), rash (as defined in table 2) (n=1) and abnormal CT chest scan (n=1), the latter in a patient suspected of having lung carcinoma who also had abnormal tumour markers at the time.
All liver AEs were mild or moderate and resolved. One patient in the 100 mg two times per day group had elevated hepatic enzymes considered related to treatment, which resolved after dose interruption. The patient was restarted on 50 mg once per day, rechallenged with 100 mg two times per day and hepatic enzyme levels remained within normal limits. All other events were judged unrelated to treatment and included two 50 mg once per day patients with elevated liver function tests, one 50 mg once per day patient with two increased blood bilirubin events, one 100 mg two times per day patient with increased blood potassium and one 100 mg two times per day patient with elevated serum creatinine.
There were four deaths among patients on study. There were two deaths (one in the 50 mg once per day group from embolic stroke/septic embolus and one in the 100 mg two times per day dose from IPF) among patients on study through 24 weeks and two additional deaths (one in the 50 mg once per day group from IPF, one in the 100 mg two times per day group from pulmonary embolism) between 24 and 48 weeks.
Efficacy
Baseline and changes from baseline in pulmonary function testing and sample sizes at landmark timepoints are shown in table 3 and figure 2. Mean changes from baseline in DLCO were comparable between dose groups.
The differences in slopes (100 mg two times a day − 50 mg once per day) were 3.0 (95% CI −0.9 to 7.0; p=0.133) at 24 weeks and 4.5 (95% CI 0.7 to 8.2; p=0.022) at 48 weeks.
The one-sided lower 95% CI limit for the difference with 50 mg once per day and 100 mg two times a day was −0.84 (n=35) and 2.0 (n=35) at 24 weeks and 0.19 (n=39) and 4.2 (n=35) at 48 weeks, respectively.
Change in the QLFCAD score correlated moderately well with change in FVC for 100 mg two times a day but did not correlate for 50 mg once per day (online supplemental figure 1). Three patients assigned 100 mg two times a day had markedly increased FVC at 24 weeks (380, 500 and 850 mL) and 48 weeks (600, 450 and 830 mL) and a corresponding reduction in QLFCAD score in the whole lung at 24 weeks (−237,–151 and −644 mL, respectively).
Supplemental material
At baseline, 48% of patients (46% assigned to 50 mg once per day and 50% assigned to 100 mg two times a day) had cough frequency at baseline ≥10/hour while awake (figure 3). Among patients with baseline cough ≥10 /hour, median cough frequency decreased in both dose groups; a more detailed analysis is presented in the online supplemental findings.
Supplemental material
Regardless of baseline objective cough frequency, on average, patients reported modest changes in cough-related quality of life (online supplemental table 2). Similarly, small changes were observed in health-related quality of life within dose groups; however, differences in the breathlessness and activities, chest symptoms, psychological and total scores of the KBILD questionnaire were on average higher in the 100 mg two times a day group (online supplemental table 2; figure 4).
Supplemental material
Transition to single dosing regimen
Based on a review of safety and efficacy performed after all patients reached the week 24 visit, the DSMB recommended transitioning all patients to 100 mg two times a day for the remainder of the trial because FVC data showed that most patients who received 100 mg two times a day were stabilised. Three patients transitioned to 100 mg two times a day before the week 48 visit and two patients at the week 48 visit. At 72 weeks, all patients had the option of continuing to receive 100 mg two times a day AP01 in an open-label extension trial; 47/54 patients (87%) chose to continue.
Discussion
The ATLAS study shows the potential of aerosolised pirfenidone for improved safety and efficacy compared with oral pirfenidone in treating IPF. Both AP01 doses were well tolerated, and the most common dose-limiting AEs associated with oral pirfenidone22 were reduced or absent. As with oral pirfenidone,23 AEs generally occurred within 3 months. AEs deemed related to AP01 suggested a possible dose response for cough, rash, nausea, taste disorder, fatigue, dizziness and dyspnoea, with higher incidence in the 100 mg two times a day group than in the 50 mg once per day group.
The incidence of rash for 100 mg two times a day was 17.8%, and all events were mild or moderate. Rash events generally were managed by AP01 dose reduction, topical therapies or sun protection. Because patients intolerant to oral pirfenidone could be enrolled, these rash rates may over-represent expected incidence in the IPF and interstitial lung disease populations. Although patients with prior intolerance may be predisposed to sensitivity, not all patients with a history of rash on oral pirfenidone experienced rash with AP01. Patients with a history of intolerance to oral pirfenidone should not be assumed intolerant to AP01.
Taste disorder was reported in three patients assigned 100 mg two times a day, and dysgeusia was reported in one patient assigned 100 mg two times a day. Although the bitter taste of pirfenidone is masked by adding trace saccharin, sensitivity varied.
The low incidence of systemic AEs observed with AP01 is not surprising because the 100 mg two times a day nebulised dose leads to 1/15 systemic exposure of the approved oral pirfenidone daily dose and, regarding liver toxicity, has no first-pass effect. The elevated hepatic enzymes related to treatment in a single patient returned to normal limits after interruption and rechallenge. Early studies in small populations can miss rare AEs; however, the well-characterised safety profile of oral pirfenidone combined with decreased systemic exposure makes the detection of novel AEs outside the respiratory tract in larger studies unlikely.
Cough is a common IPF symptom. Through 48 weeks, 25 patients were reported to have cough AE with cough AEs in 14 patients judged related to treatment. Most related events (n=12) were considered related to nebulisation and self-resolving or controllable by salbutamol or similar drugs or caused by another trigger such as upper respiratory tract infection and self-resolving. Two related cough events in the 100 mg two times a day group were considered long term. Two patients (one from each dose group) discontinued therapy due to cough. As with oral pirfenidone,24 both doses of AP01 decreased frequency of cough in IPF patients with high baseline cough frequency, encouraging further study.
The 100 mg two times a day dose group showed significantly less loss of FVC % predicted compared with the 50 mg once per day group at 48 weeks. Changes in quantitative lung fibrosis scores from HRCT correlated well with changes in FVC for the 100 mg two times a day group. PRO results remained stable over 48 weeks in both dose groups with average changes from baseline in LCQ and KBILD domain and total scores less than the minimal clinically important difference.20 25
Three patients randomised to 100 mg two times a day had large increases in FVC at 24 and 48 weeks and steady improvement over the course of the study. At screening, their HRCT pattern was typical or probable UIP; time since diagnosis and disease severity varied, and these patients had no ongoing bronchodilator use, no signs of mucus plugging on screening HRCT and no productive cough. Structural changes seen with HRCT are eventually manifested as changes in FVC. FVC increases were consistent with improvements in quantitative fibrosis assessed by HRCT and similar improvements in other secondary efficacy endpoints, including KBILD scores.
The median administration time for the 100 mg two times a day dose was 8 min using the PARI investigational eFlow nebuliser. Duration is important because the pirfenidone half-life in epithelial lining fluid is ~10 min; efficacy due to a peak drug concentration would be decreased with extended nebulisation.26 Nebulisers with lower delivery efficiency, slower administration or larger particle sizes favouring airway delivery would likely not deliver AP01 with optimal efficacy and safety. Our study design does not lend itself to clearly determining whether the difference seen in efficacy between the 50 and 100 mg doses at 48 weeks resulted from the dose amount or dose frequency.
Findings of this phase 1b study, designed to establish multidose safety and tolerability and to obtain variability and effect size estimates, should be interpreted cautiously. Blinding dose groups was not feasible because it would require a diluted formulation to produce equal volumes, leading to reduced Cmax levels with the 50 mg dose. A placebo-control group without the allowance of background therapies was not included because approved antifibrotic therapies are available for the target IPF population. Spirometry data were missing from some postbaseline visits because of site restrictions due to the COVID-19 pandemic and early terminations. A slope-based analysis was used to leverage all observed data in estimating change over time in FVC % predicted, and a visit-based analysis showed consistent findings at weeks 24 and 48.
In summary, inhaled pirfenidone (AP01) is a promising treatment for IPF. Future studies exploring the potential for fewer adverse effects and improved efficacy compared with current antifibrotics in reducing or slowing progression of fibrosis, ameliorating decline in FVC and meaningfully improving quality of life are warranted.
Supplemental material
Data availability statement
Data are available on reasonable request. Data are available from Avalyn Pharma on reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
There were over 30 sites involved in this study, in six countries. A table presenting the Ethics Committee/Institutional Board information as well as the approval IDs has been submitted as a separate document titled 'EC:IRB, approval numbers', as supplementary material for editors only. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
Mark Surber and Stephan Pham developed and supervised the manufacture of the AP01 combination product used in the study. Paul Guttry of Acumen Medical Communications, LLC, assisted in the preparation and submission of the manuscript.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @ILDIPFDoc_NI
Contributors All authors had the ability to access the data. The authors assume responsibility for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The initial draft of this manuscript was written by the authors without outside assistance. MLS and ABM have both verified the underlying data, and ABM is acting as guarantor. AW, NC, AB, MLW, TJC, MŠ, AV, EJ, MSW, WP and GR contributed to study conduct, data interpretation and manuscript writing. PH, IG and CG contributed to study design, study conduct, data interpretation,and manuscript writing. DN contributed to data collection, data interpretation and manuscript writing. KO contributed to study design, data analysis, data interpretation and manuscript writing. MLS contributed to data analysis, data interpretation and manuscript writing. LF and ABM contributed to study design, data interpretation and manuscript writing.
Funding Avalyn Pharma sponsored the study and was involved in the study design, the analysis and interpretation of data, the writing of this report and in the decision to submit the paper for publication.
Competing interests NC received a grant from Boehringer Ingelheim and consulting fees from Boehringer Ingelheim, Carrick, Redex, UCB, and Novartis; speaker fees and travel sponsorship from Boehringer Ingelheim and Roche; and payment for participation on data monitoring/advisory board from Boehringer Ingelheim. IG reports consulting fees from Amplia, Ad Alta and Accendatech; speaking fees from Boehringer Ingelheim; and payment for participation in a safety review committee from Accendatech. TJC reports receiving grants/contracts from Boehringer Ingelheim, Roche, Bristol Myers Squibb, Biogen, Galapagos and Avalyn Pharma; speaker’s honoraria from Boehringer Ingelheim and Roche; and payment for participation on data safety monitoring/advisory board from Boehringer Ingelheim, Roche, Bristol Myers Squibb and Promedior. EJ received honoraria for lectures from Boehringer Ingelheim, Roche, AstraZeneca, MDS and Chiesi; sponsored travel to meetings from Boehringer Ingelheim and Roche; and payment for participation in advisory boards from Boehringer Ingelheim, Roche, AstraZeneca, Novartis, MDS, Berlin-Chemie and Chiesi. MW reports payments to her institution from Boehringer Ingelheim, Roche, the Netherlands Organisation for Health Research and Development, the Dutch Lung Foundation, the Dutch Pulmonary Fibrosis Patient Association, the Thorax Foundation, ErasmusMC and Sarcoidoisis.nl. Consulting fees were paid to her institution by Boehringer Ingelheim, Roche, Galapagos, Bristol Myers Squibb, Galecto and Respivant; honoraria were paid to her institution by Boehringer Ingelheim, Roche and Novartis. MW received sponsored travel from Boehringer Ingelheim and Roche, and her institution received payment for her participation in data safety monitoring/advisory board from Savara and Galapagos. CG received consulting fees from Avalyn Pharma. GR reports receiving support from Avalyn Pharma for consulting and for chairing the Data Safety Monitoring Board during the conduct of the study; personal and consulting fees from Boehringer Ingelheim, Respivant and Roche; grants from the NIH; and consulting fees from Bellerophon Therapeutics, Biogen, Bristol Myers Squibb, Fibrogen, Nitto, Promedior, Respivant and Veracyte.
Provenance and peer review Not commissioned; externally peer reviewed.
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