Nintedanib in Lung Transplant Recipients With Bronchiolitis Obliterans Syndrome Grade 0p-1-2

Inclusion Criteria: 1. Written informed consent signed prior to entry into the trial 2. Patients ≥18 years of age when signing his/her informed consent 3. Patients at least at 6 months post-LTx 4. Single- or double-LTx or combined cardio-pulmonary LTx are eligible 5. Patients must have diagnosis of BOS defined as a decrement of 10% or more in forced expiratory volume in 1 seconde (FEV1) compared to post-transplant baseline FEV1 individualized for each patient according to ISHLT definition. The documented post-LTx baseline value of FEV1 is defined as the mean of the 2 highest values measured at least 3 weeks apart according to ISHLT criteria, and post-LTx VC measurements 6. Patients must have BOS grade 0p, 1 or 2 7. Patients must have documented progressive BOS as demonstrated by the following criteria: at least 3 FEV1 and VC measurements in the last 12 months prior V1, each at least 3 weeks apart, with a total decline of at least 200ml in FEV1 in these last 12 months AND FEV1/VC\<0.7 8. Azithromycin therapy for at least 4 weeks prior to V1, with an Azithromycin dose of minimum 250 mg/day at least 3 times per week as this is considered standard therapy for bronchiolitis obliterans syndrome Exclusion Criteria: Related to LTx 1. Criteria of restrictive allograft syndrome (RAS) at V0, including the following: (1) Decline of VC \< 20% of best post-LTx value (FVCBest is defined as the average of the two FVCs associated with the two PFTs used in FEV1 baseline calculation for CLAD diagnosis) AND FEV1/VC \> 0.7 AND (2) Thorax HRCT at entry demonstrate new significant findings which are compatible with RAS like interstitial fibrosis, consolidation, appearances suggesting Restrictive Allograft Syndrome (RAS) 2. FEV1 and/or FV and/or TLC decline related to other nonCLAD causes (eg Diaphragm dysfunction, pneumothorax or pleural effusion, evolutive bronchial stricture within the previous 3 months) 3. At V0, patients who already have developed severe BOS grade 3 4. Patients with severe comorbidity complicating CLAD which might determine the prognosis and functional level of the patient (e.g. evolutive invasive aspergillosis or mycobacterial infection within the last 3 months, active malignant disease within the last 12 months) 5. At visit V1 (end of screening period), diagnosis of documented acute cellular (AR) perivascular rejection higher than grade A1 within the 4 prior weeks OR diagnosis of acute antibody-mediated rejection within the 4 prior weeks, based on presence of all 4 following criteria: 1) acute lung allograft dysfunction, 2) detection of donor-specific antibodies, 3) histological findings compatible with AMR on transbronchial lung biopsy TBBx, and 4) detection of C4d \> 50% on TBBx 6. At visit V1 (end of screening period), diagnosis of documented acute pulmonary infection within the 2 prior weeks, on the basis of the following: 1) clinical, radiological and physiological deterioration; AND 2) isolation of an organism from a clinically relevant BAL fluid culture; AND 3) antibiotic therapy resulting in a full recovery and return to pre-morbid lung function 7. Previous treatment with Nintedanib after the date of lung transplantation (Treatment with Nintedanib before lung transplantation is not an exclusion criteria) 8. Ongoing treatment with photopheresis at V1 or planned treatment with photopheresis within the study period. Laboratory parameter thresholds 9. Within the 2 weeks prior to V1, renal insufficiency with following criteria: Creatinine clearance \<30 ml/min estimated by the Cockcroft-Gault equation 10. Within the 2 weeks prior to V1, any of the following liver test criteria above the specified limit: Total bilirubin \> 1.5 above the upper limit of the normal range (ULN), except in patients with predominantly unconjugated hyperbilirubinemia (e.g., Gilbert's syndrome). Aspartate or alanine aminotransferase (AST or ALT) \>3 × ULN (refer to the protocole, for the management of liver enzyme elevation). General exclusion criteria 11. Pregnancy or lactation (women of childbearing capacity are required to have a negative serum pregnancy test before treatment and must agree to maintain highly effective contraception by practicing abstinence or by using at least two methods of birth control from the date of consent to three months after the end of the patient study participation) 12. Other investigational therapy received within 1 month or 6 half-lives (whichever was greater) prior to screening visit (V0) 13. Alcohol or drug abuse which in the opinion of the treating physician would interfere with treatment 14. Patients not able to understand and follow study procedures including completion of self-administered questionnaires without help. Other diseases 15. Cardiac disease: (1) History of myocardial infarction within 6 months of visit 1 or unstable angina within 6 months of visit 1; (2) Presence of aortic stenosis (AS) per investigator judgement at visit 1; (3) Severe chronic heart failure: defined by left ventricular ejection fraction (EF) \< 25% per investigator judgement at visit 1 16. Known allergy or hypersensitivity to Nintedanib or intolerance to nintedanib, peanut or soya, or any other components of the study medication 17. Bleeding Risk: Known genetic predisposition to bleeding; Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin, etc.) or high dose antiplatelet therapy (acetyl salicylic acid \>325 mg/day, or clopidogrel \>75 mg/day) \[NB: Prophylactic low dose heparin or heparin flush as needed for maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. per day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other antiplatelet therapy) are not prohibited\]; History of haemorrhagic central nervous system (CNS) event within 12 months prior to visit 1; History of haemoptysis or haematuria within 3 months prior to visit 1, active gastro-intestinal bleeding or ulcers and/or major injury or surgery within 3 months prior to visit 1; International normalised ratio (INR) \> 2 at visit 1; Prothrombin time (PT) and activated partial thromboplastin time (aPTT) \> 150% of institutional ULN at visit 1 18. Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment) 19. Planned major surgery during the trial participation 20. History of thrombotic event (including stroke and transient ischemic attack) within 6 months of visit 1 21. Second-degree or third-degree atrioventricular (AV) block on electrocardiogram (ECG) per investigator judgement at visit 1 22. i) Hypotension (systolic blood pressure \[SBP\] \< 90 mm Hg or diastolic blood pressure \[DBP\] \< 50 mm Hg) (symptomatic orthostatic hypotension) at visit 1 ii) Uncontrolled systemic hypertension (SBP \> 160 mmHg; DBP \> 100 mmHg) at visit 1 23. Known penile deformities or conditions (e.g., sickle cell anemia, multiple myeloma, leukemia) that may predispose to priapism 24. Retinitis pigmentosa, or History of vision loss, or History of nonarteritic ischemic optic neuropathy 25. Ongoing treatment with pirfenidone at V1 or planned treatment with pirfenidone within the study period.