Nintedanib in children and adolescents with fibrosing interstitial lung diseases

Robin Deterding, Lisa R Young, Emily M DeBoer, David Warburton, Steven Cunningham, Nicolaus Schwerk, Kevin R Flaherty, Kevin K Brown, Mihaela Dumistracel, Elvira Erhardt, Julia Bertulis, Martina Gahlemann, Susanne Stowasser, Matthias Griese, for the InPedILD trial investigators
European Respiratory Journal 2022; DOI: 10.1183/13993003.01512-2022

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Abstract

Childhood interstitial lung disease comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. Patients aged 6–17 years with fibrosing ILD on HRCT and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary endpoints were the area under the plasma concentration-time curve at steady state (AUCτ,ss) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24. Twenty-six patients received nintedanib and 13 placebo. The geometric mean (gCV%) AUCτ,ss for nintedanib was 175 µg×h·L−1 (85.1) in patients aged 6–11 years and 160 µg×h·L−1 (82.7) in patients aged 12–17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean (se) changes in FVC % predicted at week 24 were 0.3 (1.3) in the nintedanib group and −0.9 (1.8) in the placebo group. In conclusion, in children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population.

Introduction

Childhood interstitial lung disease (chILD) comprises a spectrum of rare and heterogeneous lung disorders affecting infants, children and adolescents that may be associated with significant morbidity [1, 2]. The pathophysiology of chILD often involves a genetic component, sometimes combined with exposure-related injury or autoimmune dysregulation, although in some cases the aetiology remains unknown [1, 3–6]. Some children with ILD develop pulmonary fibrosis. As in adults, in chILD, pulmonary fibrosis involves tissue damage, excessive deposition of extracellular matrix, and aberrant remodelling of the lung, although fibroblastic foci are not seen histologically in children with fibrosis [1, 7]. In the absence of licensed drugs for the treatment of chILD, treatment typically involves immunomodulation [8], but the evidence to support this approach is lacking.

Nintedanib is an intracellular inhibitor of tyrosine kinases that inhibits processes fundamental to the progression of pulmonary fibrosis [9, 10]. Randomised controlled trials demonstrated that in adults with idiopathic pulmonary fibrosis (IPF), other forms of progressive pulmonary fibrosis, and fibrosing ILD associated with systemic sclerosis, nintedanib consistently reduced the rate of decline in forced vital capacity (FVC), a surrogate measure of ILD progression in adults [11], compared with placebo, with an adverse event profile characterised predominantly by gastrointestinal events [12–15]. Based on the clinical efficacy of nintedanib in adults, and presumed similarities in the pathophysiology of fibrotic lung remodelling in adults and children, it was postulated that nintedanib may provide similar benefit in a paediatric population with clinically significant or progressive pulmonary fibrosis. As a confirmatory trial of the efficacy of nintedanib in paediatric patients was deemed not feasible, the InPedILD trial (ClinicalTrials.gov NCT04093024; Eudra-CT 2018-004530-14) was designed with the primary objectives of evaluating the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. In addition, data on efficacy endpoints were collected to support evaluation of the benefit-risk of nintedanib in the paediatric population.

Materials and methods

Patients

The InPedILD trial enrolled children or adolescents aged 6–17 years with fibrosing ILD on a high-resolution computed tomography (HRCT) scan performed ≤12 months before screening, confirmed by central review (see Supplementary Material), FVC ≥25% predicted and clinically significant disease [16]. Clinically significant disease was defined as a Fan score ≥3 [17] or documented evidence of clinical progression over any time frame. The Fan score assesses disease severity in children and adolescents with ILD based on symptoms, oxygen saturation and pulmonary hypertension; scores range from 1 to 5, with higher scores indicating greater disease severity [17]. Evidence of clinical progression was based on a relative decline in FVC ≥10% predicted, a relative decline in FVC of 5–10% predicted with worsening symptoms, worsening fibrosis on HRCT, or other measures of clinical worsening attributed to progressive pulmonary fibrosis (e.g. increased oxygen requirement, decreased diffusion capacity). Key exclusion criteria are listed in the Supplementary Material.

Trial design

The InPedILD trial was a phase 3 trial conducted at 43 sites in 21 countries [16]. After a 4-week screening period, patients were randomised 2:1 to receive nintedanib or placebo using interactive response technology, stratified by age group (6–11 years, 12–17 years) (figure 1). Dosing was based on weight-dependent allometric scaling. Starting doses were 50 mg, 75 mg, 100 mg, or 150 mg twice daily and the dose was adjusted during treatment based on the patient's weight (table 1). Dose reductions to the dose below and treatment interruptions were permitted to manage adverse events. The lowest dose was 25 mg twice daily. Dose re-escalation was allowed within 4 weeks of dose reduction for adverse events considered related to trial drug, or within 8weeks for adverse events not considered related to trial drug.

FIGURE 1
FIGURE 1

Trial design.

View this table:
TABLE 1

Dosing and dose adjustments

The trial consisted of a placebo-controlled double-blind period of 24 weeks followed by a variable period during which all patients received open-label nintedanib (figure 1). Patients who prematurely discontinued study drug were asked to attend all visits as originally planned. Once ≥30 patients (including ≥20 patients aged 12–17 years) had completed pharmacokinetic sampling at week 26 or had prematurely discontinued the trial, recruitment was closed. Following confirmation that sufficient pharmacokinetic data had been collected, all patients were scheduled for an end-of-treatment visit, after which they entered a 4-week follow-up period or rolled over into an open-label extension trial in which all patients received nintedanib (InPedILD-ON; ClinicalTrials.gov NCT05285982; Eudra-CT 2020-005554-23).

A Steering Committee provided scientific advice on the design of the trial. A Safety Monitoring Committee reviewed pharmacokinetic and safety data to determine the safety profile and benefit-risk of nintedanib and advise on dose modification, additional assessments, and the appropriateness of further enrolment and continuation of the trial. An Adjudication Committee was established to adjudicate deaths due to cardiac, respiratory or other causes and review adverse events categorized as major adverse cardiovascular events. The trial was carried out in compliance with the protocol, the principles of the Declaration of Helsinki and the Harmonised Tripartite Guideline for Good Clinical Practice from the International Conference on Harmonisation, EU directive 2001/20/EC/EU regulation 536/2014 and other relevant guidelines. The trial was initiated at each site (listed in the Supplementary Material) following approval by the respective institutional review board/independent ethics committee and competent authority according to national and international regulations. Written informed consent and assent (where applicable) were obtained prior to trial entry.

Endpoints

The co-primary endpoints were the area under the plasma concentration–time curve at steady state (AUCτ,ss) at week 2 of nintedanib treatment (i.e. at week 2 in patients randomised to receive nintedanib and at week 26 in patients randomised to receive placebo for 24 weeks followed by nintedanib) and the proportion of patients with treatment-emergent adverse events at week 24, which were defined as events with onset from the first intake of trial drug until the day prior to first intake of open-label nintedanib or the last intake of randomised treatment plus 28 days (whichever occurred first). Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 25.

Pathological findings on bone imaging and stunted growth of the dental root on dental imaging were defined as adverse events of special interest. Secondary safety endpoints included the proportion of patients with pathological findings of epiphyseal growth plate on imaging and pathological findings on dental examination or imaging at week 24. Follow-up imaging of epiphyseal growth plates was only conducted in patients with open physes. Change from baseline in height-for-age z-score at week 24 was a further endpoint.

Secondary efficacy endpoints included changes in FVC % predicted, oxygen saturation (SpO2) at rest, 6-minute walk test (6MWT) distance and Pediatric Quality of Life™ (PedQL™) questionnaire scores at week 24. Spirometry was performed using standardised spirometers supplied to each site and according to ATS/ERS guidelines [18]. FVC % predicted values were calculated using equations published by the European Respiratory Society Global Lung Function Initiative [19]. The PedsQL questionnaire comprised the young child report (5–7 years), the child report (8–12 years) and the teen report (>12 years), as well as a parent report for each age range; each of these scores ranges from 0 to 100, with higher scores indicating better health-related quality of life [20].

Analyses

For the primary pharmacokinetic analysis, AUCτ,ss was calculated using non-compartmental and compartmental analyses and descriptive statistics. In patients randomised to nintedanib, the AUCτ,ss at week 2 was used; if this value was missing, the value at week 26 was used. In patients randomised to placebo, the AUCτ,ss at week 26 (corresponding to week 2 of nintedanib treatment) was used. Pharmacokinetic analyses were conducted in patients who received ≥1 dose of trial medication and provided evaluable data for ≥1 pharmacokinetic endpoint without protocol violations relevant to the evaluation of pharmacokinetics. Safety analyses were conducted in patients who received ≥1 dose of trial medication. Adjusted mean changes from baseline in FVC % predicted, SpO2, 6MWT distance, PedsQL questionnaire scores and height-for-age z-score at week 24 were analysed using a mixed model for repeated measures, with fixed categorical effects of treatment at each visit and age group and fixed continuous effects of baseline at each visit, and random effect for patient. Adverse events are presented descriptively.

Sample size was calculated based on the evaluation of the primary pharmacokinetic endpoint and the need for the clearance parameter to be estimated with adequate precision. Assuming a coefficient of variation (CV) of 70.8% (based on the geometric CV of apparent clearance of nintedanib in the plasma at steady state [CL/Fss] following extravascular multiple dose administration), ≥20 patients with pharmacokinetic measurements per age group (6–11 years and 12–17 years) would be needed to achieve ≥80% probability (loosely referred to as power [21]) of having the 95% confidence interval of the CL/Fss and the AUCτ,ss within 60% and 140% of the geometric mean estimate. Based on the inclusion criteria and a preliminary feasibility assessment, it was anticipated that the study would only enrol enough patients aged ≥12 years to achieve this probability; however, pharmacokinetic data from children aged 6–11 years were also collected and analysed. A sample size of ≥30 patients (≥10 aged 6–11 years, ≥20 aged 12–17 years) was targeted.

Results

Patients

Of 87 patients screened, 39 patients (12 aged 6–11 years, 27 aged 12–17 years) were randomised and treated (26 with nintedanib, 13 with placebo) (figure 2, Table S1). Baseline characteristics were generally balanced between the treatment groups (table 2). The majority of patients were female (61.5%) and white (79.5%). Mean (sd) age was 12.6 (3.3) years, weight was 42.2 (17.8) kg and FVC was 59.4 (21.9) % predicted. The most common diagnostic category was surfactant protein deficiency (30.8%). The most frequent criterion met for clinically significant disease was a Fan score ≥3 (59.0%) (Table S2).

FIGURE 2
FIGURE 2

Disposition of patients during double-blind period.

View this table:
TABLE 2

Baseline characteristics.

Exposure

Mean (sd) exposure to trial medication during the double-blind period was 22.3 (4.8) weeks in the nintedanib group and 22.6 (4.2) weeks in the placebo group (table 3). During this period, four patients (15.4%) in the nintedanib group and one patient (7.7%) in the placebo group had ≥1 dose reduction and three patients (11.5%) in the nintedanib and none in the placebo group had ≥1 treatment interruption; three patients (11.5%) in the nintedanib group and none in the placebo group discontinued treatment (figure 2). Mean (sd) exposure to trial medication over the whole trial was 46.4 (22.3) weeks for patients randomised to nintedanib and 49.6 (23.6) weeks for patients who received placebo followed by open-label nintedanib (Table S3).

View this table:
TABLE 3

Exposure to trial medication during double-blind period.

Pharmacokinetics

The geometric mean (gMean) (gCV%) AUCτ,ss for nintedanib was 175 µg×h·L−1 (85.1) in patients aged 6 to 11 years and 160 µg×h·L−1 (82.7) in patients aged 12 to 17 years. Additional pharmacokinetic data are shown in Table S4.

Adverse events

During the double-blind period, adverse events were reported in 22 patients (84.6%) in the nintedanib group and 11 patients (84.6%) in the placebo group (table 4). Diarrhoea was the most frequent adverse event associated with nintedanib, reported in 10 patients (38.5%) in the nintedanib group and two patients (15.4%) in the placebo group. Two patients (7.7%) had adverse events that led to discontinuation of nintedanib (reported as epiphyses premature fusion [not confirmed by central review of imaging] and liver injury). Two patients (7.7%) in the nintedanib group and one patient (7.7%) in the placebo group had serious adverse events (see table 4 for details).

View this table:
TABLE 4

Adverse events during double-blind period

Over the whole trial, adverse events were reported in all patients randomised to nintedanib and in 12 patients (92.3%) who received placebo as randomised treatment and then open-label nintedanib; serious adverse events were reported in five patients (19.2%) randomised to nintedanib and in three patients (23.1%) who received placebo followed by open-label nintedanib (See Table S5 for details). No patients had adverse events leading to treatment discontinuation during the open-label period. Two patients (7.7%) randomised to nintedanib had aspartate transaminase and/or alanine transaminase ≥3 times the upper limit of the normal range; none met criteria for Hy's law.

Epiphyseal growth plate and dental examinations

At week 24, 20 patients (76.9%) and nine patients (69.2%) in the nintedanib and placebo groups, respectively, had epiphyseal growth plate imaging. Pathological findings were observed in two patients (7.7%) in the nintedanib group and one patient (7.7%) in the placebo group (Table S6).

At week 24, dental examination was performed in 23 patients (88.5%) and 10 patients (76.9%), and dental imaging in 22 (84.6%) and 10 (76.9%) patients, in the nintedanib and placebo groups, respectively. On dental examination, new pathological findings were reported in five patients (19.2%) treated with nintedanib and one patient (7.7%) who received placebo. On dental imaging, stunted growth of the dental root was reported in six patients (23.1%) treated with nintedanib and none who received placebo (Table S7). Review by the safety monitoring committee and a dental expert determined that in three patients, root development was completed (i.e. stunted growth was implausible) and in three patients, different angulations between assessments had led to an overread. Treatment was reinitiated in all cases. In five of the six patients, no indication of stunted growth of dental root was identified in central review of dental imaging at week 52. Details of these cases are provided in Table S8.

Height-for-age z-score

Adjusted mean (se) changes from baseline in height-for-age z-score at week 24 were −0.05 (0.03) in the nintedanib group and −0.03 (0.04) in the placebo group (difference −0.02 [95% CI: −0.12, 0.09]; nominal p=0.75) (Figure S1).

Forced vital capacity

Adjusted mean (se) changes from baseline in FVC % predicted at week 24 were 0.3 (1.3) in the nintedanib group and −0.9 (1.8) in the placebo group (difference 1.2 [95% CI: −3.4, 5.8]; nominal p=0.60) (figure 3). The treatment effect of nintedanib observed in this trial was within the range of the effect observed in trials conducted in adults with fibrosing ILDs over 24 weeks (Figure S2).

FIGURE 3
FIGURE 3

Change in FVC % predicted over 24 weeks.

Spo2, 6MWT distance and PedsQL

Adjusted mean (se) changes from baseline in SpO2 at rest at week 24 were 0.07% (0.77) in the nintedanib group and −2.25% (1.08) in the placebo group (difference 2.31% [95% CI: −0.39, 5.02]; nominal p=0.09) (figure 4). Adjusted mean (se) changes from baseline in 6MWT distance at week 24 were 17.6 (16.5) m in the nintedanib group and 10.5 (22.9) m in the placebo group (difference 7.2 [95% CI: −50.7, 65.0]; nominal p=0.80) (Table S9).

FIGURE 4
FIGURE 4

Change in SpO2 at rest over 24 weeks.

Adjusted mean (se) changes from baseline in the PedsQL patient report score at week 24 were 6.5 (1.9) and 5.5 (2.7) in the nintedanib and placebo groups, respectively (difference 1.0 [95% CI: −5.8, 7.9]; nominal p=0.76) (Table S8). Adjusted mean (se) changes from baseline in the PedsQL parent report score at week 24 were 5.5 (2.5) and 5.6 (3.5) in the nintedanib and placebo groups, respectively (difference −0.1 [95% CI: −9.0, 8.7]; nominal p=0.98) (Table S10).

Discussion

The main objectives of the InPedILD trial were to determine the dosing of nintedanib that would result in an exposure in children and adolescents comparable to adults, and to assess the safety of nintedanib in children and adolescents with clinically significant fibrosing ILD. The results demonstrated that nintedanib had an acceptable safety profile in this patient population. As in adults [12–14, 22], the most common adverse event associated with nintedanib in the InPedILD trial was diarrhoea, but the proportion of children who experienced diarrhoea was lower than that observed in adults, and there were no discontinuations due to diarrhoea during the double-blind period.

Inhibition of the vascular endothelial growth factor receptor (VEGFR) results in decreased angiogenesis, which is essential for bone growth and development [23]. Data from animal models have suggested that nintedanib, an inhibitor of VEGFR [24], may have reversible effects on the epiphyseal growth plates of large bones and an impact on tooth development [25]. Thus, close monitoring of growth, bone and tooth development was implemented in the InPedILD trial. Pathological findings on epiphyseal growth plate imaging showed no evidence of premature closure of the physes. Changes in height-for-age z-scores suggested normal linear growth. Although six cases of stunted dental root growth were reported, these could not be confirmed by an expert paediatric dentist taking into account additional clinical and demographic data. Although reassuring, the potential effects of nintedanib on epiphyseal growth plates and dentition will continue to be monitored in the open-label extension study.

During the double-blind period of the InPedILD trial, five patients in the nintedanib group had COVID-19 compared with one patient in the placebo group. Three patients (11.5%) in the nintedanib group and four patients (30.8%) in the placebo group received a COVID-19 vaccine during the double-blind period; a further patient (7.7%) in the placebo group had COVID-19 before the trial. Based on mechanism of action, non-clinical and clinical data, there is no indication that nintedanib would increase the risk of infection or worsen the disease course of COVID-19.

A dose of 150 mg bid was investigated in the pivotal trials of nintedanib in adults with pulmonary fibrosis [12–14] and is the recommended dose for adult patients [26]. Studies investigating the impact of exposure on the efficacy and safety of nintedanib in adults support this dose [27, 28]. In the InPedILD trial, dosing was based on weight-dependent allometric scaling. In adults treated with nintedanib 150 mg bid, the derived gMean (gCV%) AUCτ,ss of nintedanib is 203 µg×h·L−1 (67.5) and the median (5th, 95th percentile) AUCτ,ss is 181 µg*h·L−1 (81.5, 398) [Boehringer Ingelheim data on file]. Thus, the pharmacokinetic data from the InPedILD trial show that the weight-based dosing regimen achieved exposure in paediatric patients that was comparable to that observed in adults treated with 150 mg bid, supporting the use of this dosing regimen in the paediatric population.

FVC was an exploratory endpoint in the InPedILD trial. The mean change (se) in FVC % predicted at week 24 was 0.3% (1.3) in the nintedanib group versus −0.9% (1.8) in the placebo group. We also observed a stabilisation of SpO2 at rest over 24 weeks in the nintedanib group compared with a decline in the placebo group (mean [se] changes of 0.07% [0.77] versus −2.25% [1.08]). These observations need to be interpreted with caution given the paucity of data on the natural history of lung function in children with ILD [7, 29, 30] and the short duration of the trial. However, the observed reduction in decline in FVC % predicted with nintedanib versus placebo in this paediatric population was within the range observed in adults with fibrosing ILDs treated for 24 weeks.

Conducting clinical trials in children with fibrosing ILD is challenging due to factors including its rarity and a lack of consensus on how to measure the progression of pulmonary fibrosis in children [1]. Other than the InPedILD trial, the only randomised placebo-controlled trial of an intervention in children with fibrosing ILD to have published results is a trial of hydroxychloroquine conducted in Germany, which differed substantially from the InPedILD trial in its design [31]. The InPedILD trial is the first international placebo-controlled trial to have been conducted in children with ILD and as such represents a landmark in the field. However, it also has limitations, including the small sample size and short duration, which limit interpretation of the data. Of note, randomisation of 39 patients in the InPedILD trial required the involvement of dozens of sites, with a failure to meet radiological criteria based on central review the main reason for screen failure.

In conclusion, data from the InPedILD trial demonstrate that nintedanib has an acceptable safety and tolerability profile in children and adolescents with fibrosing ILD, with no new safety signals observed compared with adult patients. Exposure levels achieved with weight-based allometric dosing were within the range observed in adults. These data provide a scientific basis for the use of nintedanib in children and adolescents with fibrosing ILD.

Plain language summary

A plain language summary of these data is available here: https://www.globalmedcomms.com/respiratory/ERS2022/Deterding/plain-language-summary

Acknowledgments

We thank the patients who participated in the InPedILD trial and their parents and caregivers. The InPedILD trial was supported by Boehringer Ingelheim International GmbH (BI). The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment for development of this manuscript. Writing assistance was provided by Julie Fleming and Wendy Morris of FleishmanHillard, London, UK, which was contracted and funded by BI. BI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Footnotes

  • ClinicalTrials.gov NCT04093024; Eudra-CT 2018-004530-14 “cd_value_code=”text

  • Data availability: Data sharing statement 
To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, BI grants all external authors access to relevant clinical study data. In adherence with the BI Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a journal, regulatory activities are complete and other criteria are met. Researchers should use https://vivli.org/ to request access and visit https://www.mystudywindow.com/msw/datasharing for further information.
&#10 ;“cd_value_code=”text

  • Data sharing statement To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, BI grants all external authors access to relevant clinical study data. In adherence with the BI Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a journal, regulatory activities are complete and other criteria are met. Researchers should use https://vivli.org/ to request access and visit https://www.mystudywindow.com/msw/datasharing for further information.

  • Funder: Boehringer Ingelheim; DOI: http://dx.doi.org/10.13039/100001003.

  • Conflict of interest: Robin Deterding reports consultancy fees, fees for participation on the Steering Committee of the InPedILD trial and support for travel from Boehringer Ingelheim (BI) and consultancy fees from Roche.

  • Conflict of interest: Lisa R Young reports grants paid to her institution from the National Institutes of Health (NIH) and Orphan Disease Center at the University of Pennsylvania; royalties from UpToDate; consultancy fees and fees for participation on the Steering Committee of the InPedILD trial from Boehringer Ingelheim (BI); consultancy fees from Roche and Sanofi; and honoraria from NYU Langone Health.

  • Conflict of interest: Emily M DeBoer reports fees from BI for participation on the Steering Committee of the InPedILD trial. Steven Cunningham reports fees paid to his institution by BI for his participation on the Steering Committee of the InPedILD trial.

  • Conflict of interest: David Warburton reports a grant re: the RECOVER (COVID-19) initiative from the National Heart, Lung, and Blood Institute (NHLBI) and fees from BI for participation on the Steering Committee of the InPedILD trial.

  • Conflict of interest: Nicolaus Schwerk reports consultancy fees from Novartis; payment for lectures from AbbVie, Allergopharma, Chiesi, Infectopharm, Novartis, Pfizer, Sanofi; fees for participation in Data Safety Monitoring Boards or Advisory Boards for BI and Novartis; fees from BI for participation on the Steering Committee of the InPedILD trial; he is a member of the German Society for Pediatric Pneumology, European Respiratory Society, Children's Interstitial Lung Disease Clinical Research Collaboration (chILD-EU), European Cooperation in Science and Technology (COST) network for translational research in children's and adult ILD (ENTeR-chILD) and Secretary of Kinderlungenregister.

  • Conflict of interest: Kevin R Flaherty reports grants paid to his institution from BI; royalties from UpToDate; consultancy fees from Arrowhead, AstraZeneca, Bellerophon, BI, CSL Behring, Daewoong, DevPro, Dispersol, FibroGen, Horizon, Immunet, Lupin, NeRRe Therapeutics, Pliant, Polarean, Pure Health, PureTech, Respivant, Roche/Genentech, Shionogi, Sun Pharmaceuticals, Trevi, United Therapeutics; he is a Steering Committee Chair for the Pulmonary Fibrosis Foundation and reports fees from BI for participation on the Steering Committee of the InPedILD trial.

  • Conflict of interest: Kevin K Brown reports grants from NHLBI; consultancy fees, speaker fees, support for travel and/or has served as an advisor or on the data monitoring committee for AbbVie, Biogen, Blade Therapeutics, BI, Bristol Myers Squibb, CSL Behring, DevPro Biopharma, Dispersol, Eleven P15, Galapagos, Galecto, Huitai Biomedicine, Humanetics, the Open Source Imaging Consortium (OSIC), Pliant, Redx Pharma, Sanofi, Third Pole, Translate Bio; he reports fees from BI for participation on the Steering Committee of the InPedILD trial; he holds leadership or fiduciary roles with the Fleischner Society and OSIC.

  • Conflict of interest: Mihaela Dumistracel, Elvira Erhardt, Julia Bertulis, Martina Gahlemann and Susanne Stowasser are employees of BI.

  • Conflict of interest: Matthias Griese reports grants from BI for analysis of the chILD-EU register; has received fees from BI for membership of the InPedILD Steering Committee, an advisory board and an adjudication board and for a web-based series.

  • Received July 29, 2022.
  • Accepted August 25, 2022.
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Nintedanib in children and adolescents with fibrosing interstitial lung diseases
Robin Deterding, Lisa R Young, Emily M DeBoer, David Warburton, Steven Cunningham, Nicolaus Schwerk, Kevin R Flaherty, Kevin K Brown, Mihaela Dumistracel, Elvira Erhardt, Julia Bertulis, Martina Gahlemann, Susanne Stowasser, Matthias Griese, for the InPedILD trial investigators
European Respiratory Journal Jan 2022, 2201512; DOI: 10.1183/13993003.01512-2022
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