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 forcedexpiratory volume in 1 seconde (FEV1) compared to post-transplant baseline FEV1individualized for each patient according to ISHLT definition. The documentedpost-LTx baseline value of FEV1 is defined as the mean of the 2 highest valuesmeasured at least 3 weeks apart according to ISHLT criteria, and post-LTx VCmeasurements

6. Patients must have BOS grade 0p, 1 or 2

7. Patients must have documented progressive BOS as demonstrated by the followingcriteria: at least 3 FEV1 and VC measurements in the last 12 months prior V1, eachat 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 ofminimum 250 mg/day at least 3 times per week as this is considered standard therapyfor 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 thetwo FVCs associated with the two PFTs used in FEV1 baseline calculation for CLADdiagnosis) AND FEV1/VC > 0.7 AND (2) Thorax HRCT at entry demonstrate newsignificant 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 Diaphragmdysfunction, pneumothorax or pleural effusion, evolutive bronchial stricture withinthe 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 theprognosis and functional level of the patient (e.g. evolutive invasive aspergillosisor mycobacterial infection within the last 3 months, active malignant disease withinthe 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 ofacute antibody-mediated rejection within the 4 prior weeks, based on presence of all 4 following criteria: 1) acute lung allograft dysfunction, 2) detection ofdonor-specific antibodies, 3) histological findings compatible with AMR ontransbronchial lung biopsy TBBx, and 4) detection of C4d > 50% on TBBx

6. At visit V1 (end of screening period), diagnosis of documented acute pulmonaryinfection within the 2 prior weeks, on the basis of the following: 1) clinical,radiological and physiological deterioration; AND 2) isolation of an organism from aclinically relevant BAL fluid culture; AND 3) antibiotic therapy resulting in a fullrecovery and return to pre-morbid lung function

7. Previous treatment with Nintedanib after the date of lung transplantation (Treatmentwith Nintedanib before lung transplantation is not an exclusion criteria)

8. Ongoing treatment with photopheresis at V1 or planned treatment with photopheresiswithin 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 thespecified 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 anegative serum pregnancy test before treatment and must agree to maintain highlyeffective contraception by practicing abstinence or by using at least two methods ofbirth control from the date of consent to three months after the end of the patientstudy participation)

12. Other investigational therapy received within 1 month or 6 half-lives (whichever wasgreater) prior to screening visit (V0)

13. Alcohol or drug abuse which in the opinion of the treating physician would interferewith treatment

14. Patients not able to understand and follow study procedures including completion ofself-administered questionnaires without help. Other diseases

15. Cardiac disease: (1) History of myocardial infarction within 6 months of visit 1 orunstable angina within 6 months of visit 1; (2) Presence of aortic stenosis (AS) perinvestigator judgement at visit 1; (3) Severe chronic heart failure: defined by leftventricular ejection fraction (EF) < 25% per investigator judgement at visit 1

16. Known allergy or hypersensitivity to Nintedanib or intolerance to nintedanib, peanutor soya, or any other components of the study medication

17. Bleeding Risk: Known genetic predisposition to bleeding; Patients who requirefibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists,direct thrombin inhibitors, heparin, hirudin, etc.) or high dose antiplatelettherapy (acetyl salicylic acid >325 mg/day, or clopidogrel >75 mg/day) [NB:Prophylactic low dose heparin or heparin flush as needed for maintenance of anindwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. per day), as well asprophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 325mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other antiplatelettherapy) 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 majorinjury or surgery within 3 months prior to visit 1; International normalised ratio (INR) > 2 at visit 1; Prothrombin time (PT) and activated partial thromboplastintime (aPTT) > 150% of institutional ULN at visit 1

18. Patients with underlying chronic liver disease (Child Pugh A, B or C hepaticimpairment)

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) Uncontrolledsystemic 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 ischemicoptic neuropathy

25. Ongoing treatment with pirfenidone at V1 or planned treatment with pirfenidonewithin the study period.