Nintedanib in progressive bronchiolitis obliterans syndrome (BOS) grade 0p-1-2 in lung transplant recipients (INFINITIx-BOS): protocol of a French multicenter randomized controlled trial.

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Learn more: PMC Disclaimer | PMC Copyright Notice Trials . 2026 Apr 11;27:298. doi: 10.1186/s13063-025-09314-7 Search in PMC Search in PubMed View in NLM Catalog Add to search Nintedanib in progressive bronchiolitis obliterans syndrome (BOS) grade 0p-1-2 in lung transplant recipients (INFINITIx-BOS): protocol of a French multicenter randomized controlled trial Olivier Brugière Olivier Brugière 1 Service de Pneumologie Et Transplantation Pulmonaire, Hôpital Foch, Suresnes, France 2 U976 HIPI, IRSL, Université Paris Cité, Paris, France Find articles by Olivier Brugière 1, 2, ✉ , Sandrine Hirschi Sandrine Hirschi 3 Department of Pneumology, Strasbourg Lung Transplant Program, Strasbourg University Hospital, Strasbourg, France Find articles by Sandrine Hirschi 3 , Martine Reynaud-Gaubert Martine Reynaud-Gaubert 4 Service de Pneumologie Et Transplantation Pulmonaire, CHU de Marseille, Marseille, France Find articles by Martine Reynaud-Gaubert 4 , Vincent Bunel Vincent Bunel 5 APHP.Nord-Université de Paris, Hôpital Bichat-Claude Bernard, Service de Pneumologie B Et Transplantation Pulmonaire, Paris, France Find articles by Vincent Bunel 5 , Xavier Demant Xavier Demant 6 Service de Pneumologie Et Transplantation Pulmonaire, CHU de Bordeaux, Bordeaux, France Find articles by Xavier Demant 6 , Jérôme Le Pavec Jérôme Le Pavec 7 Service de Pneumologie Et Transplantation Pulmonaire, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France Find articles by Jérôme Le Pavec 7 , Loic Falque Loic Falque 8 Service Hospitalier Universitaire de Pneumologie Et Physiologie, Pôle Thorax Et Vaisseaux, CHU Grenoble Alpes, Grenoble, France Find articles by Loic Falque 8 , Nassima Si Mohammed Nassima Si Mohammed 9 Unité de Recherche Clinique Paris Nord Val de Seine, URC PNVS, Hôpital Bichat, Paris, France Find articles by Nassima Si Mohammed 9 , Coralie Tardivon Coralie Tardivon 9 Unité de Recherche Clinique Paris Nord Val de Seine, URC PNVS, Hôpital Bichat, Paris, France Find articles by Coralie Tardivon 9 , Camille Couffignal Camille Couffignal 9 Unité de Recherche Clinique Paris Nord Val de Seine, URC PNVS, Hôpital Bichat, Paris, France Find articles by Camille Couffignal 9 ; the INFINITIx-BOS Consortium Author information Article notes Copyright and License information 1 Service de Pneumologie Et Transplantation Pulmonaire, Hôpital Foch, Suresnes, France 2 U976 HIPI, IRSL, Université Paris Cité, Paris, France 3 Department of Pneumology, Strasbourg Lung Transplant Program, Strasbourg University Hospital, Strasbourg, France 4 Service de Pneumologie Et Transplantation Pulmonaire, CHU de Marseille, Marseille, France 5 APHP.Nord-Université de Paris, Hôpital Bichat-Claude Bernard, Service de Pneumologie B Et Transplantation Pulmonaire, Paris, France 6 Service de Pneumologie Et Transplantation Pulmonaire, CHU de Bordeaux, Bordeaux, France 7 Service de Pneumologie Et Transplantation Pulmonaire, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France 8 Service Hospitalier Universitaire de Pneumologie Et Physiologie, Pôle Thorax Et Vaisseaux, CHU Grenoble Alpes, Grenoble, France 9 Unité de Recherche Clinique Paris Nord Val de Seine, URC PNVS, Hôpital Bichat, Paris, France ✉ Corresponding author. Received 2025 Feb 7; Accepted 2025 Nov 16; Collection date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13072616  PMID: 41964069 Abstract Background Long-term survival after lung transplantation (LTx) is still hampered by the development of chronic allograft dysfunction (CLAD). Bronchiolitis obliterative syndrome (BOS), the most common phenotype of CLAD, is thought to arise from repeated injuries to graft epithelial cells, leading to fibrous scarring of small airways. Thus far, there is no approved treatment for BOS disease. Based on both animal/human studies in LTx and the demonstrated efficacy of the TKI nintedanib treatment in idiopathic pulmonary fibrosis (IPF), nintedanib is a candidate molecule capable of stopping the fibroproliferative process in BOS. Hence, the rationale to conduct a nintedanib trial in LTx recipients with BOS is based on (i) an unmet medical need due to poor survival after BOS diagnosis; (ii) the demonstrated fibrotic pathways in BOS; and (iii) the proven efficacy of nintedanib in IPF. Methods The INFINITIx-BOS study is an investigator-initiated, national multicentric, phase II, superiority, parallel-group, double-blind, comparative randomized clinical trial. A total of 80 recipients with progressive BOS within the prior year, at least at 6 months post-LTx, will be randomized to receive either nintedanib (150 mg bid) or placebo for a period of 6 months, in addition to maintenance immunosuppressive therapy left to their physician’s discretion with 4 dedicated visits. The primary endpoint is the slope of decline over 6 months of treatment. The secondary endpoints are change in 6-min walk test, SGRQ, graft failure, SPO2, and safety events over 6 months, which will be compared between the two arms. Discussion Based on a fibrotic pattern partially shared between IPF and BOS, this randomized INFINITIx-BOS trial has the potential to demonstrate an additional strategy with nintedanib as a targeted-fibrotic pathway associated with BOS. Trial registration number NCT03283007 , first posted 11 September 2017. Protocol version identifier No. 6–0, 8 September 2023. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-025-09314-7. Keywords: Lung transplantation, Bronchiolitis obliterans syndrome (BOS), Nintedanib, Randomized controlled study (RCT), Placebo Introduction Lung transplantation (LTx) is now a widely accepted procedure for end-stage pulmonary diseases. Nevertheless, long-term graft and patient survival after lung transplantation are hampered by the development of chronic allograft dysfunction (CLAD) which affects more than 50% of recipients in the long-term follow-up [ 1 , 2 ]. CLAD remains the most common cause of graft failure and death after LTx [ 1 , 2 ]. Obliterative bronchiolitis (OB), the obstructive CLAD, is the most common manifestation of CLAD. OB is thought to arise from repeated injury to graft epithelial cells, leading to fibrous scarring and obliteration of the small airway lumen, as a result of dysregulated fibrotic repair [ 3 ] and loss of peribronchial microvasculature [ 2 , 4 , 5 ]. The patchy histopathological distribution at onset makes it difficult to confirm the diagnosis of OB from specimens obtained by transbronchial or open lung biopsy. Hence, bronchiolitis obliterans syndrome (BOS) has become a generally accepted surrogate of OB, characterized physiologically by progressive airflow limitation. In the absence of confounding variables, lung transplant recipients are considered to suffer from BOS grade ≥ 1 if they experience a sustained >20% decline in forced expiratory volume in 1 s (FEV1) from baseline defined by the average of the 2 best FEV1 measurements obtained at least 3 weeks apart [ 5 ]. The most important risk factors for BOS are lymphocytic bronchiolitis and repeated acute rejection episodes [ 1 ]. Non-immunologic factors, such as infections, gastro-esophageal reflux, and ischemic injury [ 1 ], have also been implicated as cofactors. Therapeutic successes have been achieved in reversing the progressive loss of lung function using azithromycin in some cases [ 1 , 6 ], which has led to consider the prior use of azithromycin in every LTx patient before establishing the definitive diagnosis of BOS [ 2 ]. Therapeutic strategies in established BOS disease, which greatly vary between centers, have been focused on increased immunosuppression or immunomodulatory therapy, with poor efficacy in most patients [ 7 ]. Pharmacological treatments in patients with established BOS have previously used multiple different agents, including (1) high doses of steroids, which should be avoided in the long term due to their deleterious and harmful effects according to the recommendations of ISHLT/ATD/ERS (1); (2) conversion from ciclosporin to tacrolimus [ 1 , 2 , 8 , 9 ]; (3) a trial of azithromycin at least for 8 weeks [ 1 , 10 ]; (4) inhaled steroids; (5) montelukast [ 11 , 12 ]; (6) alemtuzumab (anti-CD52 therapy) [ 13 , 14 ]; and (7) thymoglobulins [ 14 ] and other T-cell-depleting agents. Nevertheless, intensification of immunosuppression has been reported with little effect on established BOS in the absence of confounders such as acute cellular or antibody-mediated rejection episodes (1). Other non-pharmacological therapies have also been assessed such as (1) anti-reflux surgery in selected patients with gastro-esophageal reflux disease with sufficient ventilatory reserves (1); (2) extracorporeal photopheresis (ECP) with experiences showing some benefit in non-randomized studies [ 15 – 19 ]; and (3) total lymphoid irradiation (TLI) [ 20 , 21 ]. The crucial role of a dysregulated fibrotic repair has also been shown in OB. Architectural remodeling with fibrosis and scarring of airways and blood vessels is the most prominent histologic feature seen in allograft dysfunction [ 22 – 24 ]. OB lesions demonstrate luminal or subintimal infiltration by myofibroblasts, which play a central role in the fibrotic pathology [ 25 ]. Investigation of mesenchymal cells after LTx suggests their alteration in patients with BOS, with increased extracellular matrix synthesis [ 24 ]. Bronchial epithelial cells (BEC) are able to secrete fibrotic factors (PDGF, FGF) that play a role in the development of BOS [ 24 ]. Also, the cellular mechanisms involved during bronchial remodeling in BO have been linked to the epithelial-mesenchymal transition process (EMT), which has been identified as a new source of fibroblasts that could contribute to the remodeling of the airways [ 26 , 27 ]. Moreover, observations have linked platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) to the development of experimental obliterative airway disease (OAD) [ 28 – 33 ], and, similarly, growth factor pathways, as fibroblast growth factor beta, PDGF, and IGF-1, seem to be involved in human BO [ 24 , 34 – 36 ]. Together, these data suggest the potential role of novel receptor tyrosine kinase inhibitors targeting these growth factors to inhibit the progression of BOS. Accordingly, nintedanib may be able to suppress this fibroproliferative pathway and attenuate the development of CLAD in human Tx recipients [ 37 – 43 ]. Nintedanib is a small molecule that inhibits a distinct spectrum of receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs) including VEGFR (vascular endothelial growth factor receptor), PDGFR (platelet-derived growth factor receptor), FGFR (fibroblast growth factor receptor), and Src family kinases (Src, Lck, and Lyn belonging to a family of proto-oncogene tyrosine-protein kinases). All these growth factor pathways and their downstream signal cascades have been demonstrated to be involved in the pathogenesis of fibrotic tissue remodeling. The clinical efficacy of nintedanib has been studied in patients with idiopathic pulmonary fibrosis (IPF) in one phase II dose-finding trial (TOMORROW) including four different doses of nintedanib and two replicate phase III (INPULSIS 1 and 2) trials [ 44 – 46 ]. These were randomized, double-blind, placebo-controlled trials comparing treatment with nintedanib twice daily to placebo for 52 weeks. A statistically significant reduction in the annual rate of decline of FVC (in mL) was demonstrated in patients receiving nintedanib 150 mg bid compared to patients receiving placebo. The treatment effect of nintedanib compared to placebo on FVC was consistent in all three studies, i.e., a relative reduction of decline of approximately 50%. Supporting the effect of nintedanib on slowing disease progression, nintedanib 150 mg bid significantly reduced the risk of first acute exacerbation compared with placebo in INPULSIS-2 and in the TOMORROW trial and reduced the risk of acute exacerbations (adjudicated) by 68% in a pre-specified sensitivity analysis of pooled data from the INPULSIS trials [ 44 – 46 ]. Nintedanib was first developed in IPF and approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2014 and 2015, respectively. We hypothesize that an additional strategy with nintedanib as compared to placebo could improve the treatment of LTx recipients with progressive BOS grade 0p-1–2 while maintaining an acceptable safety profile. Aims and objectives The primary aim of the INFINITIx-BOS trial is to assess nintedanib efficacy in the reduction of the rate of decline of FEV1 (forced expiratory volume in 1 s) in BOS 0p-1–2 post-LTx added with a dose of 150 mg twice daily to the standard-of-care (SOC) compared to placebo over 6 months. The secondary aims of this trial are presented in Table 1 . Table 1. Secondary objectives and associated outcomes Secondary objectives Secondary outcomes To assess nintedanib efficacy and tolerance in the treatment of BOS grade 0p-1–2 post-lung transplantation, are the following: • To assess the efficacy of nintedanib on exercise tolerance as assessed by the change of 6-min walking test (6-WT) over 6 months • To assess the efficacy of nintedanib on quality of life (QOL) improvement as assessed by change in the SGRQ (Saint George’s Respiratory Questionnaire) over 6 months • To assess the efficacy of nintedanib to hamper FEV1 decrease, as assessed by a repeated FEV1 measurements method over 6 months • To assess the efficacy of nintedanib to hamper progression of BOS, as assessed by change in BOS grade and graft failure (defined as death or re-transplantation) • To assess the efficacy of nintedanib on the change of oxygen saturation (SpO2) over 6 months • To assess nintedanib tolerance in lung transplant recipients over 6 months, comparing occurrence of adverse events between both arms • To assess explanatory parameters of fibrotic pathways (KL-6, SPD, VEGF, PDGF) • Change of 6-min walking test (6-WT) over 6 months, as assessed by absolute change from baseline in the 6-min walking test (6-WT) at month 6 (V4) • Quality of life (QOL) improvement as assessed by absolute change in the SGRQ (Saint George’s Respiratory Questionnaire) from baseline to month 6 (V4) • Reduction in FEV1 decline as assessed by absolute change of FEV1 in mL at month 6 by a repeated FEV1 measurements (month 0 (V1), month 1 (V2), month 3 (V3), month 6 (V4)) • Change in BOS grade and graft failure (defined as death or re-transplantation) as assessed by proportion of patients with disease progression of BOS disease with change in BOS grade and/or graft failure from baseline to month 6 (V4) (defined as death or re-transplantation) • Change in oxygen saturation (SpO2) over 6 months • Nintedanib tolerance in LTx recipients over 6 months, comparing occurrence of adverse events between both arms • Change in explanatory parameters of fibrotic pathways over 6 months (KL-6, SPD, VEGF, PDGF) Open in a new tab Methods and analysis Design overview The INFINITIx-BOS study is an investigator-initiated, national multicentric, phase II, superiority, parallel-group, double-blinded, comparative randomized clinical trial, in which lung transplant recipients diagnosed with chronic active BOS grade 0p-1–2 are allocated in a 1:1 ratio to nintedanib (intervention group) or to placebo (control group). The trial design is summarized in Table 2 and in Fig. 1 . We report the study protocol according to the Standard Protocol Items: Recommendations for Interventional Trials statement [ 47 ]. Table 2. Summary of the chronology of the study with data collected V0 Screening visit ≤8 weeks before V1 V1 Inclusion visit V2 1 month ± 2 weeks V3 3 months ± 2 weeks V4 6 months ± 2 weeks (last visit) Additional visits between V1 and V4 Patient information (with leaflets) √ √ Location: LTx center √ √ √ √ √ √ Informed consent with form signature √ Randomization √ Patient demographics √ Medical history* √ Concomitant medication √ √ √ √ √ √ Clinical interview and examination by pulmonologist √ √ √ √ √ √ 6-Month treatment (nintedanib or placebo) dispensed 1 month at V1, 2 months at V2, and at 3 months at V3 √ √ √ √ In case of dose adaptation Treatment compliance (patient diary) √ √ √ √ Pre-screening PFTs (see inclusion criterion no. 7) and pre-screening HRCT-scan (<6 months) review √ Biological evaluation: - Renal assessment < 8 weeks before V1 - Liver assessment < 8 weeks before V1 - Hematologic assessment < 8 weeks before V1 √ √ AE/SAE √ Efficacy and safety event collection * √ √ √ √ √ Blood sampling: renal, liver, hematologic assessment, and anticalcineurin trough level √ √ √ √ √ Local urine pregnancy test √ √ √ √ √ PFTs: FEV1, FVC √ √ √ √ √ 6-WT √ √ SpO2 √ √ √ SGRQ √ √ Blood samples for explanatory blood biomarker assessment √ √ ECG √ HR thoracic CT-scan √ (or ≤8 weeks) √ Chest X-ray √ √ √ √ √ Open in a new tab V visit, V0 screening visit within 8 weeks before V1, V1 visit 1 post-lung transplantation, LTx center lung transplant center of the patient (= LTx hospital); Medical history* , including also collection of information about baseline pretransplant characteristics, transplant-related characteristics, and review of previous post-LTx PFT; Physical examination* , physical examination by a physician that includes weight, height, body mass index, and vital signs; Local urine pregnancy test , only for women of childbearing potential (urine); AE/SAE adverse events, serious adverse events, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, 6-WT 6-min walk test, SpO2 oxygen saturation, SGRQ Saint-Georges Respiratory Questionnaire, ECG electrocardiogram, HR thoracic CT-scan, high-resolution CT-scan Fig. 1. Open in a new tab Study flow chart After one screening period (V0), four visits are planned within the 6-month treatment period (V1 inclusion, V2 (month 1), V3 (month 3), V4 (month 6)). The trial will last until V4 of the last randomized patient after the completion of 6 months of treatment with 28 days of adverse events recorded after the last dose. Visits V2, V3, and V4 will be scheduled over 6 months with planned investigations including physical examination, blood sampling, PFTs, ECG, chest X-ray, and/or CT-scan, as described in Table 2 . If necessary, and at the discretion of clinicians caring for the patients, additional visits can be performed. Patient screening, inclusion, and randomization will be conducted either by the principal investigator or by a physician representing the investigator. Patient eligibility will be assessed in accordance with the predefined inclusion and exclusion criteria (Table 3 ). All eligible patients will be informed about the study before randomization both verbally and with a written document, in accordance with French law. At the time of randomization, written informed consent will be obtained from patients. Each center will maintain a screening log for all eligible patients. Table 3. Main inclusion and exclusion criteria of INFINITIx-BOS study Inclusion criteria 1. Written informed consent 2. Patients ≥ 18 years 3. Patients at least at 6 months post-LTx 4. Single- or double- or combined CP-LTx 5. BOS diagnosis grade 0p-1–2 (ISHLT 2014) (3) 6. Decline of ≥200 mL in FEV1 last 12 months 7. Azithromycin therapy ≥ 4 weeks prior to V1 Exclusion criteria 1. Lung redo transplantation 2. RAS diagnosis at V0 [ 49 ] 3. FEV1 decline related to non-CLAD causes 4. BOS with grade ≥ 3 5. Non-controlled infection 6. Active malignant disease 7. ACR episode grade ≥ A1 within 4 weeks < V1 [ 51 ] 8. AMR episode within 4 weeks < V1 [ 52 ] 9. Pulmonary infection within 2 weeks prior V1 10. Previous nintedanib treatment post-LTx 11. Ongoing treatment with ECP at V1 12. eGFR < 30 mL/min/1.73 m 2 13. Bilirubin > 1.5 × ULN or AST or ALT > 3 × ULN 14. Other investigational therapy at V0 15. Alcohol or drug abuse 16. Inability to understand study procedures 17. MI or AS or severe HF within 6 months ≤ V1 18. Known allergy to nintedanib 19. Full-dose therapeutic anticoagulation or high-dose antiplatelet therapy Open in a new tab LTx lung transplantation, CP cardio-pulmonary, LTx; BOS bronchiolitis obliterans syndrome, ISHLT International Society for Heart and Lung Transplantation, FEV1 forced expiratory volume in 1 s, V1 visit 1, RAS restrictive allograft syndrome, CLAD chronic allograft dysfunction, ACR acute cellular rejection, AMR antibody-mediated rejection, ECP extracorporeal photopheresis, eGFR estimated glomerular filtration rate, ULN upper limit of the normal range, AST or ALT aspartate or alanine aminotransferase, MI myocardial infarction, AS presence of aortic stenosis (AS) per investigator judgment at visit 1, HF heart failure: defined by left ventricular ejection fraction (EF) < 25% per investigator judgment at visit 1 Every patient with criteria of progressive BOS 0p-1–2 within the last year of follow-up can be assessed for inclusion in the INFINITIx-BOS trial in each participating center. Patients at V0 will enter a screening period and be proposed a visit 1 (inclusion V1) as soon as possible, with a maximum duration of the screening period of 8 weeks, whereas no minimal duration of the screening period is required. Investigations during screening include pre-therapeutic pulmonary function tests and an HRCT-scan (not older than 6 months) for the diagnosis of BOS disease in accordance with inclusion criteria, and biological sampling (Table 3 ). Azithromycin administration > 4 weeks prior to anticipated drug administration has to be checked. A preliminary check of in-/exclusion criteria is performed at the time of informed consent to avoid unnecessary procedures in non-eligible patients. At visit 1, an informed consent form (ICF) will be signed by the patient, with collection of clinical and safety laboratory parameters, reviewing all in- and exclusion criteria. Included patients will be randomized to either nintedanib or placebo. At the end of 6-month follow-up, visit 4 will be performed and after the last dose, a phone recording of any adverse effects will be recorded after 28 days. The study treatment will be continued for 6 months after which both groups will be proposed, at the discretion of their physician and considering the risk-benefit ratio, the administration of nintedanib as a non-blinded drug at the same last daily dose administered at the last visit V4 (month 6). Study setting and population Participants will be prospectively recruited among patients LTx recipients transplanted and followed in reference centers. They will be invited to participate by the pneumonologist during a SOC visit in 7 French university and non-university centers including Foch hospital (Suresnes—coordinator site), Bichat hospital (Paris), Marie-Lannelongue hospital (Le Plessis-Robinson), CHU of Marseille hospital, CHU of Strasbourg hospital, CHU of Grenoble hospital, and CHU of Bordeaux hospital. Patients will be considered eligible for randomization if they fulfill the inclusion criteria and none of the exclusion criteria, as defined in Table 3 (and Table S1). The key eligibility criteria include single- or double-LTx or combined cardio-pulmonary LTx and the diagnostic for a BOS grade 0p-1–2. Intervention Experimental group From randomization up to 6 months after, nintedanib 150 mg will be self-administered by the patient orally twice daily (bid). To manage adverse events, the dose may be reduced to 100 mg bid temporarily or permanently. Control group From randomization up to 6 months after, placebo 150 mg will be self-administered by the patient orally twice daily (bid). To manage adverse events, the dose may be reduced to 100 mg bid temporarily or permanently. Concomitant treatment Maintenance immunosuppressive therapy at the date of inclusion and during the whole period of the study is left to the discretion of the physicians excepting extracorporeal photopheresis (ECP) which is not allowed during the period of INFINITIx-BOS study. Outcome parameters Primary outcome The primary endpoint is the reduction in the rate of decline of forced expiratory volume in 1 s (FEV1) after the start of treatment at a dose of 150 mg twice daily (bid) compared to placebo over 6 months in LTx recipients with BOS. The absolute difference of FEV1 in mL over 6 months of treatment defined by the rate of decline between inclusion (V1) and month 6 (V4) will be compared between nintedanib and placebo groups. Secondary endpoints See Table 1 for the full list of secondary outcomes. Assessment of endpoints Assessment of FEV1. FEV1 will be measured at visit 1 (inclusion), month 1 (V2), month 3 (V3), month 6 (V4), and additional visits if they occur. Spirometry measurements must be performed according to ATS/ERS 2005 guidelines [ 48 ], including daily calibration of the spirometer and regular calibration of the calibration pump. Spirometry will be conducted while the patient is in a seated position. The test will be done in triplicate (three curves to be provided), and the best result selected according to guidelines. On days of clinic visits, if patients are treated with bronchodilators, a washout of 24 h for long acting and 8 h for short acting bronchodilators should be observed before spirometry. Assessment of FVC. FVC will be measured at V1 and V4, according to ATS/ERS 2005 guidelines [ 48 ]. It does not represent an endpoint per se, but will be used both to meet exclusion criteria at visit 1, and at V4 to check the absence of RAS onset superimposed to the initial BOS phenotype. It will be used by the adjudication committee for the reviewing of the cases. Assessment of 6-WT. 6-WT must be performed according to American Thoracic Society guidelines [ 49 ] (on days of clinic visits, by the patient at visit 1 (inclusion) and after 6 months (V4)). Assessment of Saint George’s Respiratory Questionnaire (SGRQ). The SGRQ measures health status in patients with chronic airflow limitation, as observed in LTx patients with BOS. It comprises two parts which cover three domains (symptoms, activities, and impacts) with scores ranging from 0 (no impairment) to 100 (worst possible). The French version of the SGRQ [ 50 ] will be self-administered by the patient at visit 1 (inclusion) and after 6 months (M6) indicated in the flowchart. Assessment of SpO2. Oxygen saturation (SPO2) will be measured at rest by standard pulse oximetry at visit 1 (inclusion), month 1 (V2), month 3 (V3), and month 6 (V4). Assessment of thoracic CT-scan. CT-scan will be performed with the high-resolution (HR) technique commonly used for BOS assessment during the screening period, at inclusion (V1), and at month 6 (V4). Thoracic CT-scan will be blinded for a centralized interpretation by two thoracic expert radiologists. Assessment of adherence. A recorded diary book will be provided to allow the self-monitoring of adherence to the blinded treatment. Assessment of explanatory serum markers (KL6, SPD, VEGF, PDGF). For these explanatory markers, plasma samples collected at V1 and V4 will be stored at −80°C in a dedicated local biologic resource center and centralized to Foch hospital at the end of the study for a single round analysis (no biological collection planned). Randomization and sequence generation The randomization will be performed using CleanWEB, an online centralized procedure service running 24 h/24. The randomization sequence will be computer-generated in advance by a statistician of the coordinating office. It will only be stratified by center. No stratification variable was chosen based on the grade. Allocation concealment The number of experimental units per block will be kept confidential to avoid prediction of future patient’s allocation. Only the independent statistician and the computer programmer who will implement the sequence assignment in the secure electronic case report form (eCRF) will have access to the randomization list. Allocation concealment will be ensured, as CleanWeb services will not release the randomization code until the patient has been recruited into the trial. Blinding Neither the patients nor the medical staff will be aware of the randomization arm. The study statistician, also, will be blinded to the groups. Trial medication is identified by a medication code number. Packaging and labeling will be otherwise identical. The booklet cover page for 150 mg and 100 mg nintedanib and the respective corresponding placebo is differently colored. The color, size, and shape of nintedanib and placebo capsules are indistinguishable within dose strength, but differ between dose strengths. The situations in which the blinding must be lifted urgently are left at the discretion of physicians . The investigating doctor may request unblinding for any reason he or she considers essential, by contacting the sponsor in non-urgent situations, on working days, or the drug safety center of Fernand Widal Hospital (Paris, France), in the case of an emergency (24H/24H). Feasibility of patient recruitment The anticipated population that will be screened for inclusion encompasses all LTx recipients transplanted and followed in the 7 participating centers, with around 400 LTx performed in total per year in these French LTx centers. The total planned duration of the study is 56 months. Adherence to the treatment will be evaluated at each visit with patient interviews and checking of returned empty treatment boxes. Prohibited/permitted interventions The only treatment which is prohibited for the duration of the study in either arm for the treatment of BOS 0p-1–2 is ECP. Experience of ECP in patients with progressive BOS has been reported in an increasing number of LTx centers, with stabilization of lung function in about half of responder-patients in the medium-term follow-up. All immunosuppressive or immunomodulatory therapies added to the maintenance IS regimen are permitted before and for the duration of the study and left at the discretion of physicians. In cases of administration of immunosuppressive therapy in order to stabilize BOS disease, such as high-dose steroids or T-cell-depleting agents, clinicians can include the patients after a minimum of at least 1 month following these specific BOS-directed treatments. Additionally, in case of the necessity of planned surgery within the duration of the study, the drug of each arm will be stopped 3 weeks before and withheld until complete post-surgical wound healing. Safety considerations Anticipated methods and timetable for measuring, collecting, and analyzing the parameters for assessing the safety include complete physical examination, blood samples, local urine pregnancy test (V1), and ECG, PFTs, chest X-ray, and/or CT-scan, as indicated at timepoints of scheduled or additional visits in the flowchart (Table 2 and Fig. 1 ). If laboratory values indicate abnormalities, adequate and more frequent blood sampling may be performed at the discretion of the investigator. According to article R.1123-49 of the French Public Health Code (CSP, Code de Santé Publique), the investigator must notify the sponsor without delay on the day when the investigator becomes aware of any serious adverse event which occurs during the trial, related to the studied treatment or not, except those which are listed below as not requiring a notification without delay. The study drug, nintedanib, has been approved for treatment of IPF in large phase III trials [ 51 ], and its adverse effects (AEs) profile has been observed mainly as gastrointestinal (GI) side effects, with diarrhea [ 44 ]. A list of drugs with potential interaction with nintedanib is shown in Table S5 (Supplemental), with their corresponding precautions for use. Recommendations of experts for surveillance of patients under nintedanib [ 52 ] include the following which were planned in the INFINITIx-BOS study: (i) the surveillance of hepatic tests monthly with treatment discontinuation in case of liver enzyme elevation of 3 to 5 times the upper limit of normal (ULN); (ii) a close monitoring of cytochrome P450 3A4 (CYP3A4) in case of coadministration with nintedanib, such as calcineurin inhibitors used in a maintenance IS regimen post-LTx (Table S3, Supplemental); (iii) the holding of nintedanib in case of planned abdominal surgery; (iv) the management of mild to moderate diarrhea with loperamide (Table S4, Supplemental). If eGFR falls below 30 mL/min after inclusion of the patients, the decision to continue the treatment study should be at the investigator’s discretion, after assessment of the risk/benefit for each participant. The study drug treatment will be discontinued prematurely if the patients experience any of the following: pregnancy, diverticulitis, gastrointestinal perforations, persistent neutropenia < 0.5 cells Å ~ 10 9 /L, thrombocytopenia < 50 cells Å ~ 10 9 /L, elevated liver enzymes ALT or AST > 3 to 5 Å ~ ULN or malignancies (except for local basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that have been excised and cured). Adverse events relating to gastrointestinal perforation and hepatic injury grade 3, thromboembolic events, and bleeding will be considered AESIs (adverse events of special interest) in the INFINITIx-BOS trials. All adverse events that occur during the trial will be reported and compared between the 2 arms of the trial in the analysis of results of the INFINITIx-BOS trial. Their severity will be graded according to their type with predefined classification, notably for liver enzyme elevation (Table S3), and occurrence of diarrheas (Table S4). Comparison of adverse events (including AESIs) between the 2 arms will be stratified according to the type and severity, which will be assessed looking at the proportions of patients who experienced harms in each group based on MedDRA classification. Adverse events relating to gastrointestinal perforation and grade 3 hepatic injury, thromboembolic events, and bleeding will be considered AESIs in the INFINITIx-BOS trials. The investigator can temporarily or permanently withdraw a subject from the study for any safety reason or if it is in the subject’s best interests. Criteria and procedures for prematurely terminating the study treatment are as follows: (i) in case of temporary suspension of treatment, the investigator must document the reason for suspending and resuming the treatment in the subject’s source file and the case report form; (ii) in case of premature termination of treatment but with a patient who remains enrolled in the study until the end of the subject’s participation, the investigator must document the reason; (iii) in case of premature termination of treatment and exit from the study, any data collected prior to the date of premature exit may still be used. The case report form must list the various reasons why the subject exited or was withdrawn from the study as follows: lack of efficacy, adverse reaction, other medical problem, subject’s personal reasons, explicit withdrawal of consent, or lost to follow-up. Follow-up of subjects after 6 months. If there are serious adverse events, the investigator must notify the sponsor and monitor the subject until the completion of the study by the patient. A serious adverse event notification form will be sent by fax to the sponsor. The serious adverse event will be monitored until it is resolved. The sponsor or the competent authority can prematurely terminate all or part of the research, temporarily or permanently, upon the recommendations of the data and safety monitoring board (DSMB). Statistical analysis Sample size calculation Assuming an FEV1 decrease of 50 mL per month in the placebo group and a standard deviation (SD) of FEV1 of 35 mL in both randomized groups based on the retrospective local database from Bichat hospital center (Paris, France), the enrollment of 34 patients in each group will allow detection of a 50% reduction in FEV1 decline over 6 months of nintedanib, with a bilateral type I error of 5% and a power of 80%. A two-sided t -test will be used to compare the decline of both treatment groups, defined as the difference between FEV1 measured at 6 months and baseline FEV1. Imputation techniques will be used to cope with missing data. An estimated 80 patients will be recruited to the trial allowing for a drop-out rate of 15% (observed data from the reference centers). Statistical analyses The absolute difference of FEV1 in mL over 6 months of treatment defined by the rate of decline between inclusion (V1) and month 6 (V4) will be compared between nintedanib versus placebo groups according to the normality distribution by the Student t -test or the non-parametric Wilcoxon rank-sum test in the intention-to-treat population. Secondary analysis For secondary endpoints, change of variables for 6-WT, SGRQ, graft failure and incidence of hospital admission, SPO2, and safety events over 6 months will be compared between the two arms using a non-parametric Wilcoxon rank-sum test for continuous variables and Fisher’s exact test for qualitative variables. The repeated measures for the primary endpoint, change in FEV1 (mL) over 6 months will be compared between the nintedanib and placebo groups, using the method of repeated measures at each visit by a linear mixed-effects model. Analysis of the outcome of FVC and FEV1/FVC will be performed for each patient independently, to check the lack of restrictive allograft syndrome (RAS) onset during the study duration, as defined in the exclusion criteria. Secondary analyses will be performed for the following sub-group populations: Per-protocol population (restricted to the patients who fulfill the protocol in terms of the eligibility, randomized arms, treatment compliance, and outcome assessment) Population excluding patients with diagnosis of RAS at the end of study The analyses will follow the intention-to-treat (ITT) principle. The ITT population will be all the patients randomized, who take at least one dose of assigned treatment and have at least one follow-up with measurements, analyzed in their allocated group, irrespective of the intervention eventually received or lost to follow-up. Two other populations are also defined. The per-protocol (PP) population, i.e., the patients will fulfill the protocol in terms of eligibility, treatment, and outcome assessment. The PP population will include all ITT patients without any major protocol deviations, who did not have to stop the study drug for >4 weeks due to side effects, and who had ≥80% compliance with the study drug (with dose adjustments if required) while on treatment (up to discontinuation for patients whose treatment is terminated early). The PP analysis will be used to assess the robustness of the ITT analysis results of primary and secondary efficacy data. The treatment-compliant population, i.e., the patients will take all the tablets during the 6 months according to the pharmacy’s stock and the recorded diary book. A sensitivity analysis population excluding patients with a diagnosis of RAS at the end of the study will also be performed. All analyses results will be reported according to the Consolidated Standards of Reporting Trials 2025 [ 53 ]. The estimated treatment difference with an associated 95% confidence interval (CI) and P value will be presented with a significant level of all statistical analyses at two-sided 5%. All statistical analyses will be performed using SAS software (SAS Institute) V.9.4 or later, or R software (R Foundation for Statistical Computing, Vienna, Austria. http://www.r-project.org/) V.4.0 or later. Data collection and management Data collection will be done in electronic format; the statistical software CleanWeb for data entry will be used. The software will fulfill the regulatory requirements and security norms. Data will be handled according to French law. All original records (including consent forms, reports of suspected unexpected serious adverse reactions, and relevant correspondences) will be archived at trial sites for 15 years. The clean trial database file will be anonymized and maintained for 15 years. Comprehensive monitoring at the patient level will be conducted to ensure the acquisition of high-quality data regarding adherence to the intervention (nintedanib) or control (placebo) arm, as well as to assess potential cross-contamination. We will collect data on primary and secondary endpoints, as well as the potential risk of adverse effects detailed in Table 2 . The data of this study will be available on reasonable request from the corresponding author. The data will not be publicly available due to privacy and ethical restrictions. Patients and public involvement Patients and public were not involved in any of the phases of this study. Results of the trial will be made available to all participants via ClinicalTrials.gov as well as by email notification. Trial status The final version of the INFINITIx-BOS study protocol has been registered in the public clinical trial database, ClinicalTrials.gov ( NCT03283007 ), first posted on 14 September 2017. The date the study started was 2019-10-30, the last patient was included in August 2024, and the study was primarily completed in January 2025. Patient recruitment was initially planned to be extended beyond August 2024, due to recruitment difficulties related to the COVID-19 pandemic in France since 2020, but this extension could not ultimately be implemented. Ethics and dissemination Legal obligations and approval Sponsorship has been agreed by Assistance Publique—Hôpitaux de Paris (AP-HP, Clinical Research and Innovation Department) for this drug human interventional research study. The sponsor has obtained the favorable opinion of a French institutional review board (Comité de Protection des Personnes (CPP) Ile-de-France 19.01863.068659—Version No. 6.0 of 08/09/2023). The CPP approval and the summary of the protocol were communicated to the French National Agency for Medicines and Health Products Safety (ANSM). The trial will be carried out in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. Any substantial modifications to the protocol must be sent by the sponsor to the IRB for approval. The information sheet and the consent form can be revised if necessary, particularly if there is a substantial amendment to the study or if adverse reactions occur. AP-HP is the owner of the data. The data cannot be used or disclosed to a third party without its prior permission. Methods for obtaining information and consent from research participants In accordance with Article L.1122-1-1 of the French Public Health Code, no research can be carried out on a person without his/her free and informed consent, obtained in writing after the person has been given the information specified in Article L.1122-1 of said Code. The person will be given a reflection period during the screening period (≤8 weeks) where they will receive the oral and written information, and be asked to sign the consent form at V1 (see online supplemental material 3). The person’s free and informed written consent will be obtained by the investigator, or by a medical doctor representing the investigator, before the person is enrolled in the trial, during the baseline visit. The information sheet and a copy of the consent form, signed and dated by the research subject and by the investigator or the doctor representing the investigator, will be given to the individual prior to being enrolled in the trial. In addition, the investigator will specify in the research participant’s medical file the methods used for obtaining their consent as well as the methods used for providing information with a view to obtaining consent. The investigator will retain the original signed and dated consent form. Subjects may exit the study at any time and for any reason. Data collection and quality control The persons responsible for the quality control of clinical matters will take all necessary precautions to ensure the confidentiality of information relating to the study participants. These persons, as well as the investigators themselves, are bound by professional confidentiality. During or after the research, all data collected about the participants and sent to the sponsor by the investigators (or any other specialized collaborators) will be anonymized. Under no circumstances should the names, addresses, and other protected identifiers of the subjects involved be shown. In any case of premature withdrawals and exits, the investigator must document their reason(s) and try to collect the primary endpoint, secondary endpoints, and safety assessment, if the participant agrees. If a participant exits the study prematurely or withdraws consent, any data collected prior to the date of premature exit may still be used except if the participant refuses in writing. To monitor compliance, all treatment blisters will be stored after use for counting and auditing. All processing units (used or not) will be stored in the medical ward and sent to the site pharmacy at study end for destruction. To ensure the safety of the population studied in the INFINITIx-BOS study as well as the integrity of the study, all data will be examined regularly by a data and safety monitoring board (DSMB), an independent committee responsible for monitoring this data. The research data will be collected and monitored using an eCRF through CleanWEB Electronic Observation Book and will be centralized on a server hosted by the AP-HP Operations Department. This research is governed by the CNIL (Commission Nationale de l’Informatique et des Libertés, national commission for informatic and liberty) “Reference Method for processing personal data for clinical studies” (MR-001, amended). AP-HP, the sponsor, has signed a declaration of compliance with this “Reference Method.” Research staff will work with local investigators to obtain data that are as complete and accurate as possible. An independent Clinical Research Associate appointed by the sponsor will be responsible for the proper running of the study, for collecting, documenting, recording, and reporting all handwritten data, in accordance with the Standard Operating Procedures applied within the Clinical Research and Innovation Department of AP-HP. The investigators agree to accept the quality assurance audits carried out by the sponsor as well as the inspections carried out by the competent authorities. All data, documents, and reports may be subject to regulatory audits. These audits and inspections cannot be refused on the grounds of medical secrecy. An audit can be carried out at any time by independent individuals appointed by the sponsor. The aims of the audits are to ensure the quality of the study, the validity of the results, and compliance with the legislation and regulations in force. The persons who manage and monitor the study agree to comply with the sponsor’s audit requirements. The audit may encompass all stages of the study, from the development of the protocol to the publication of the results and the storage of the data used or produced as part of the study. The sponsor is responsible for access to the study database. Ethical considerations Meetings scheduled by the data and safety monitoring board ensure the monitoring and safety of patients included in the study, as well as the quality of data collected. Patients will receive oral and written information on the nature of the study, its objective, as well as the potential risks and benefits before being included. Information on the inclusion and exclusion criteria will also be given to patients before their inclusion in the trial, as well as the informed consent form by the doctors of the transplant centers. Discussion The onset of BOS in LTx recipients represents a huge challenge of treatment, since there is currently no definite treatment for this threatening disease. Due to this lack of established effective treatment in BOS, we initiated this randomized controlled trial (RCT) to assess the efficacy of nintedanib in stabilizing functional decline after BOS onset following LTx. At the date of design of the INFINITIx-BOS trial in 2019, treatments used by LTx centers in case of BOS diagnosis greatly varied, except for the initiation of azithromycin. Non-controlled studies in which azithromycin was used have shown either an improvement or even normalization of the FEV1 in a significant proportion of patients diagnosed with BOS [ 54 – 56 ]. Hence, most centers already initiate azithromycin therapy in case of BOS onset in their usual clinical practice, in an attempt to rule out a reversible cause of functional decline such as neutrophilic reversible allograft dysfunction disease (NRAD) [ 10 ], and to consolidate the definite diagnosis of BOS. Additionally, once the diagnosis of BOS is established, many different treatments have been used since the beginning of LTx programs in the late 1980 s, in an attempt to stabilize the declining lung function, although the efficacy has been reported as remaining poor in this indication. These treatments have included (1) intensification of immunosuppression with lymphocyte depletion (such as anti-thymoglobulin globulin, alemtuzumab, or total lung irradiation), (2) immunomodulatory treatment (montelukast, extracorporeal photopheresis), (3) change of maintenance immunosuppression (switch of ciclosporin to tacrolimus, or use of m-TOR inhibitor), (4) inhaled therapy such as nebulized ciclosporin, or (5) antifibrotic agents (pirfenidone or nintedanib) [ 3 , 8 , 9 , 11 – 21 , 57 ]. The vast majority of these treatments were mostly reported in clinical cases or series, with a low level of proof regarding their efficacy, in parallel with a persistent low survival after diagnosis of BOS. First, conversion of ciclosporin to tacrolimus is usually performed in patients with BOS, because tacrolimus has been shown to be superior in preventing BOS onset in randomized studies [ 8 , 9 ]. Nevertheless, it should be underlined that no RCT has assessed the impact of conversion of ciclosporin to tacrolimus in patients already with an established BOS onset. Immunomodulatory treatment such as with montelukast, which is a cysteinyl leukotriene receptor antagonist, has been added in the treatment of patients with BOS, showing an association with a significant decrease in the rate of FEV1 decline in a small series as compared to a control group [ 11 ]. A RCT was thereafter conducted but did not show a significant difference in graft loss at 1 year between patients treated with montelukast versus placebo [ 12 ]. Cytolytic anti-lymphocyte therapies have been used in LTx patients after occurrence of BOS, either with alemtuzumab or anti-thymocyte globulins. Their efficacy has been reported in case reports or uncontrolled retrospective studies, which showed a decrease in decline or stabilization of FEV1 in a variable proportion of patients after alemtuzumab [ 13 , 14 ] or thymoglobulins [ 14 ]. Nevertheless, although these treatments are still used, their efficacy remained largely incomplete, with most patients showing persistent decline of function during follow-up after the date of therapeutic intervention [ 14 ]. Another depleting lymphoid treatment can be achieved with total lymphoid irradiation (TLI), which has been administered in patients with progressive or refractory BOS [ 20 , 21 ]. Several of these studies reported significant attenuation of FEV1 decline, although graft survival post-TLI remained poor during follow-up in these studies [ 20 , 21 ]. In the last decade, a growing interest in the LTx community has also been paid to the use of extracorporeal photopheresis (ECP) for treating LTx recipients with BOS. ECP is an immunomodulatory therapy which involves isolation of leukocytes of patients treated with methoxsalen and ultraviolet light, before returning the cells to the patient [ 15 ]. Several uncontrolled single-center studies have reported a significantly lower rate of functional decline or even an improvement of FEV1 value after initiation of ECP in BOS patients [ 16 – 18 ]. This was also shown in an open-label non-randomized study with a control group, which showed a favorable response to ECP in 61% of cases [ 19 ]. Due to this encouraging signal, a multicenter RCT of phase 3 will start recruiting in 2025 in the USA, in order to better clarify the efficacy of ECP in BOS patients ( NCT02181257 ). Hence, because of an increasing use of ECP among LTx centers at the date of design of the INFINITIx-BOS study, it was decided to exclude patients previously treated or treated with ECP at the date of screening of BOS patients. Apart from these immunosuppressive/immunomodulatory treatments assessed in BOS disease, attention has also been paid to the potential therapeutic effect of antifibrotic agents in CLAD, notably of the two drugs already approved for the treatment of IPF disease, that is, pirfenidone and nintedanib. It has been shown that BOS disease shares some common histological patterns with IPF, with first an inflammatory phase and tissue injuries, followed by a second phase of tissue repair, with both diseases considered with an injuries/repair process as the main mechanisms of lung tissue structure impairment [ 28 – 33 ]. Additionally, and of note, the crucial role of fibrotic pathways has been demonstrated in the early stage of BOS development, as in patients with a grade of BOS as low as BOS 1 [ 3 ]. First, pirfenidone efficacy was assessed in cohorts including BOS patients. A large European RCT of pirfenidone administered in new-onset progressive BOS patients (EPOS study) failed to demonstrate a significant beneficial effect of pirfenidone versus placebo on pulmonary function decline in LTx (Persch M, et al. J Heart Lung Transplant 2020; 39: S12). Furthermore, recent results of the STOP-CLAD study, a RCT investigating the effects of pirfenidone in patients with BOS or RAS, had no apparent effect in attenuating the accumulation of radiographic evidence of allograft dysfunction or spirometric decline [ 57 ]. Nevertheless, this single-center randomized trial did not meet enrollment goals and some patients did not have criteria for progressive BOS at the date of inclusion, which prevents a definite conclusion [ 57 ]. In a similar way, nintedanib may be able to suppress this fibroproliferative pathway and attenuate the development of BOS in human Tx recipients [ 37 – 43 ]. To the best of our knowledge, there is no data yet available on the potential efficacy of nintedanib as a treatment of BOS validating the study design against placebo. Hence, the INFINITIx-BOS study is the first controlled prospective RCT for the treatment of BOS patients with nintedanib in LTx recipients. Another trial with nintedanib in LTx is currently underway with another design, which is a single-center RCT that will investigate the continuation of nintedanib after single-LTx in patients with ( NCT03562416 ), and the results of which have not yet been reported. Hence, no systematic assessment has been carried out so far, underscoring the need for RCTs with nintedanib. In the INFINITIx-BOS study, patients will be randomly assigned to nintedanib and standard of care (SOC) or SOC treatment for 6 months. SOC before inclusion in the study will be left to the choice of the physician and will allow other treatment until 1 month before inclusion, except for the use of ECP, which is a criterion of non-inclusion. For the primary endpoint of the study, we have chosen FEV1 decline, since its variation remains the main criterion for assessing the impact of therapeutic intervention on lung function in LTx patients with BOS. A criterion of progressive BOS has been selected in the inclusion criteria, since functional outcome in some patients with a BOS diagnosis may display a transient stabilization of their FEV1 value after the initial decline of their function [ 1 , 2 ]. Secondary end points will include other functional items, such as exercise tolerance (6-WT), gas exchange (oxygen saturation), change in grade of BOS [ 1 , 2 ], graft failure (with death of patients or re-transplantation), and also an assessment of the variation of parametric response mapping analysis of CT-scan for analysis of small airway disease [ 58 ]. Additionally, the variation of explanatory parameters of fibrotic pathways (KL6, SPD, VEGF, and PDGF) will be analyzed from baseline to month 6. The safety of a treatment in a new indication is always of concern in clinical trials. Although nintedanib has already been used safely in large cohorts of IPF patients [ 44 – 46 ], it has infrequently been used in patients under long-term intake of anticalcineurin therapy. Nintedanib has limited drug–drug interaction potential, based on the minor role of CYP pathways in its metabolism and the lack of induction or inhibition of CYP enzymes [ 59 ]. Nevertheless, since nintedanib is a substrate of P-gp, coadministration of potent inhibitors and inducers of this efflux transporter can potentially modify its exposure (AUC and Cmax), so that patients should be monitored closely for tolerability of nintedanib if a potent P-gp inhibitor is being coadministered as exposure to nintedanib may be increased [ 59 ]. A list of these drugs is included in the protocol to contraindicate some drugs or to highlight the precaution for their use in combination (see Table S5: drugs with interaction with nintedanib). The most frequently reported adverse event in the INPULSIS® trials was diarrhea, which was reported in 62% of patients treated with nintedanib compared to 18% in the placebo group. Diarrhea adverse events were mild to moderate in intensity in the vast majority of patients and led to premature treatment discontinuation in fewer than 5% of nintedanib-treated patients [ 44 ]. A table for management of diarrhea for included patients was provided for investigators (see Table S3). In a similar manner, in the case of the concomitant use of other drugs known to cause liver enzyme elevations, a detailed guidance on how to manage liver enzyme elevations was provided for investigators (Table S4). To the best of our knowledge, the INFINITIx-BOS trial is the first controlled prospective RCT for the treatment of progressive BOS disease with nintedanib in LTx recipients. Therefore, in case of positive results with a benefit demonstrated of nintedanib on lung graft outcome as compared with placebo, it will have significant clinical implications by identifying a novel effective therapy for treatment of patients with early BOS, with the aim to stabilize the graft function in the long term. This trial could improve graft survival, therefore reducing patient morbidity and improving their quality of life. Furthermore, this could identify a new target of injuries targeted by the alloimmune response during the development of BOS disease, which could lead to an improvement in patient management. Dissemination policy The trial results of INFINITIx-BOS will be disseminated to the healthcare professional’s community via a medical publication that will be submitted after a complete analysis of results. Results of the INFINITIx-BOS trial will be disseminated regardless of the magnitude or direction of the effect. The design and initiation of this study were carried out under the unique responsibility of the authors of the study and in complete independence from the Boehringer Ingelheim laboratory. The author(s) of any publication relating to this study must include the APHP among their affiliations and name the sponsor AH-HP (DRCD) and the source of funding (Programme Hospitalier de Recherche Clinique PHRC). Supplementary Information Supplementary Material 1. (45.3KB, docx) Supplementary Material 2. (49.8KB, docx) Supplementary Material 3. (274.8KB, pdf) Acknowledgements Not applicable. Authors’ contributions OB and CC developed the concept and designed the trial; OB and CC wrote the manuscript. OB is the PI of the trial. SH, MR-G, VB, XD, JLP, and LF are co-investigators of the trial and performed a critical review of the manuscript. NM is the project manager of the sponsor and CT is the dedicated statistician. All authors contributed to the critical revision of the manuscript and gave final approval for its publication. Funding 1. This study received funding from the “Direction Générale de l’offre de soins (DGOS)” in France, through a grant obtained via an academic clinical research hospital program, called “Programme Hospitalier de Recherche Clinique (PHRC)” in 2016 in France (number of the grant: AOR16076). 2. The study drugs, i.e., nintedanib and the placebo, were provided by the Boehringer Ingelheim laboratory. The design and initiation of this study were carried out under the unique responsibility of the authors of the study and in complete independence from the Boehringer Ingelheim laboratory. Data availability Principal investigator (OB) and co-investigators only will have access to the final trial dataset, and this access will be limited to investigators. Declarations Competing interests The authors declare no competing interests. Footnotes Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Meyer KC, Raghu G, Verleden GM, Corris PA, Aurora P, Wilson KC, Brozek J, Glanville AR, Committee IAEBTF, Committee IAEBTF. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. Eur Respir. J 2014; 44: 1479–1503. [ DOI ] [ PubMed ] 2. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. 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[ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Supplementary Materials Supplementary Material 1. (45.3KB, docx) Supplementary Material 2. (49.8KB, docx) Supplementary Material 3. (274.8KB, pdf) Data Availability Statement Principal investigator (OB) and co-investigators only will have access to the final trial dataset, and this access will be limited to investigators. 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