A phase II, multicentre,randomised, double-blind, placebo controlled, parallel group, dose-finding clinical trial to investigate the efficacy and safety of 10 and 20 mg/day aerosolised liposomal ciclosporin A (L-CsA) versus aerosolised placebo in the prevention of bronchiolitis obliterans syndrome (BOS) in lung transplant (LT) patients

INTERVENTION: Product Name: Aerolised Liposomal Ciclosporin A Product Code: L‐CsA Pharmaceutical Form: Powder for nebuliser solution INN or Proposed INN: Ciclosporin CAS Number: 59865‐13‐3 Current Sponsor code: 081400 Other descriptive name: Ciclosporine, Ciclosporina Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 4‐ Pharmaceutical form of the placebo: Powder for nebuliser solution Route of administration of the placebo: Inhalation use Product Name: Aerolised Liposomal Ciclosporin A Product Code: L‐CsA Pharmaceutical Form: Powder for nebuliser solution INN or Proposed INN: Ciclosporin CAS Number: 59865‐13‐3 Current Sponsor code: 081400 Other descriptive name: Ciclosporine, Ciclosporina Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 4‐ Pharmaceutical form of the placebo: Powder for nebuliser solution Route of administration of the placebo: Inhalation use Product Name: Sodium Chloride Solution Product Code: Sodium Chloride Solvent Pharmaceutical Form: Nebuliser solution Current Sponsor code: Sodium Chloride Other descriptive name: Sodium Chloride Concentration unit: % (W/W) percent weight/weight Concentration type: equal Concentration number: 0.25‐ Product Name: Sodium Chloride Solution Product Code: Sodium Chloride Solvent Pharmaceutical Form: Nebuliser solution Current Sponsor code: Sodium Chloride Other descriptive name: Sodium Chloride Concentration unit: % (W/W) percent weight/weight Concentration type: equal Concentration number: 0.25‐ CONDITION: Prevention of bronchiolitis obliterans syndrome in lung transplant ; MedDRA version: 9.1 Level: LLT Classification code 10049202 Term: Bronchiolitis obliterans PRIMARY OUTCOME: Main Objective: To establish a dosage with the most favourable risk/benefit ratio for the prevention of Bronchiolitis Obliterans Syndrome in lung transplant patients Primary end point(s): Efficacy Endpoints:; • Mean forced expiratory volume in one second (FEV1) at baseline,12, 18 and 24; months after first IMP administration; • Mean FEV1 slope from baseline to 12, 18 and 24 months after first IMP administration; • Mean forced midexpiratory flow (FEF25‐75), vital capacity (VC) and total lung capacity; (TLC) at baseline, 12, 18 and 24 months after first IMP administration; • Mean single breath diffusion capacity (DLCO) and capillary blood gases at 6, 12, 18; and 24 months after first IMP administration; • Cumulative mean incidence of BOS 12, 18 and 24 months after first IMP; administration; • Cumulative mean incidence of acute rejection grade A2 or higher 12, 18 and 24; months after first IMP administration; • Cumulative mean incidence of invasive bacteria, viral or fungal infection 12, 18 and; 24 months after first IMP administration; • Cumulative mean incidence of lung graft lost 12, 18 and 24 after first IMP; administration; • Mean walking distance from 6 min walk test at baseline, 12, 18 and 24 months after first IMP administration; • Mean cumulative dose of maintenance immunosuppressant 12, 18 and 24 months after first IMP administration; • Mean cumulative number of overnight hospital stays 12, 18 and 24 months after first IMP administration; • Mean level of inflammatory markers and L‐CsA from bronchoalveolar lavage (BAL); from at least two visits during the clinical trial period; • Cumulative overall survival during the clinical trial period; ; Safety Endpoints:; • Incidence of AEs including clinically relevant laboratory findings until EoS; • Mean L‐CsA blood levels at baseline and 6 month after first IMP administration Secondary Objective: To compare efficacy and safety data from the IMP versus placebo and to evaluate IMP PK data in whole blood and BAL samples INCLUSION CRITERIA: 1. Subject’s written informed consent obtained prior to any screening procedure. 2.Received a single lung, bilateral lung or heart/lung transplantation within four weeks prior to first investigational medicinal product (IMP) administration 3.Male or female, >/= 18 years of age 4.Capable of self‐administration medications 5.Capable of understanding the purpose and risk of the clinical trial 6.Received within one week prior to first IMP administration the following immunosuppressive agents and dosages for maintenance therapy: a) Tacrolimus approximately 0.1 to 0.2 mg/kg/day adjusted to a target serum level (C0, trough) of 8 to 15 µg/L and b) Mycophenolate mofetil (MMF) 1 to 3 g/day and c) Prednisone orally; tapered down within the first 3 months after transplantation 7.Female patients with reproductive potential must have a negative serum pregnancy test within 3 days prior to screening. Both women and men must agree to use a