Efficacy + Safety of Liposome Cyclosporine A to Treat Bronchiolitis Obliterans Post Double Lung Transplant (BOSTON-2)

The objective of the trial is to assess efficacy and safety of add-on aerosolized liposomal cyclosporine A (L-CsA) to Standard of Care (SoC) therapy as compared to SoC therapy alone in the treatment of Bronchiolitis obliterans syndrome (BOS) in double lung transplant recipients.

This is a Phase III randomized, controlled clinical trial of L-CsA for the treatment of bronchiolitis obliterans syndrome in adults diagnosed with BOS following double lung transplant. Patients will receive either L-CsA (10 mg) via the PARI Investigational eFlow® Device twice daily plus Standard of Care (SoC) treatment, or SoC alone, for a period of 48 weeks. All patients will be eligible to continue in an open-label extension trial of L-CsA following completion of BOSTON-2.

Regardless of treatment allocation, all patients will continue to receive their SoC regimen for maintenance of the lung allograft. Eligible patients for the clinical trial must have a tacrolimus-based triple-drug therapy in combination with mycophenolate mofetil or its equivalent and a corticosteroid.

A total of 11 visits will be performed during the clinical trial. After informed consent has been obtained, a Screening Visit will be carried out in order to check general eligibility for participation. At the Randomization Visit, inclusion and exclusion criteria will be re-checked and spirometry performed. During the 48-week treatment period, visits are scheduled every 4-8 weeks. If a patient has an event that meets one of the criteria for progression of BOS, he/she will return to the clinic at least 2-weeks later for an unscheduled visit to have spirometry and other procedures performed.

Eligibility Criteria:
Inclusion Criteria:

1. Adult patients ≥ 18 years who received a double lung transplant at least 12 months prior to Screening.
2. Patients with BOS diagnosis defined as CLAD-BOS phenotype with:

   1. Screening FEV1 between 85-51% of personal best FEV1 value post transplant. OR
   2. Screening FEV1 \>85% of personal best FEV1 associated with EITHER a ≥ 200 mL decrease in FEV1 in the previous 12 months OR according to medical history showing BOS progression.
3. Diagnosis of CLAD-BOS must be made at least 12 months after lung transplantation and

   1. within 12 months prior to the screening visit OR
   2. more than 12 months from screening and patient must have shown a decline in FEV1 ≥ 200ml in the previous 12 months before screening, which is not due to acute infection or acute organ rejection
4. Patients in whom the diagnosis of BOS has been confirmed by the elimination of other possible causes of obstructive or restrictive lung disease (CLAD - RAS phenotype, see Protocol Specific Definitions).
5. Patients should be on a maintenance regimen of immunosuppressive agents including tacrolimus, a second agent such as but not limited to MMF or azathioprine, and a systemic corticosteroid such as prednisone as third agent.

   The regimen must be stable within 4 weeks prior to randomization with respect to the therapeutic agents.

   In case a patient is also receiving concomitant azithromycin for prophylaxis or treatment of BOS, in addition to the previously described immunosuppressive regimen, azithromycin must be on a stable regimen for at least 4-weeks prior to randomization.
6. Patients capable of understanding the purposes and risks of the clinical trial, who have given written informed consent and agree to comply with the clinical trial requirements/visit schedules, and who are capable of aerosol inhalation. Patients must consent to retrieve prespecified data from the historic medical record (e.g., information related to the transplant surgery; spirometry data; medication use).

Exclusion Criteria:

1. Patients with confirmed other causes for loss of lung function, such as acute infection, acute rejection, restrictive allograft syndrome (RAS) (CLAD - RAS phenotype, see Protocol Specific Definition ), etc.
2. Cystic Fibrosis patients with multi-drug resistant infections not responding to available anti-microbial therapies.
3. Patients with acute antibody-mediated rejection at Screening. In this context, clinically stable patients (as judged by the Investigator) with detectable levels of donor specific antibodies (DSA) at the Screening Visit are eligible for the study.
4. Active acute bacterial, viral, or fungal infection not successfully resolved at least 4 weeks prior to the Screening Visit. Patients with chronic infection or colonization who are clinically stable as per judgement of the Investigator are eligible for the study.
5. Mechanical ventilation (including CPAP) within 12 weeks prior to Randomization.
6. Patients with uncontrolled hypertension.
7. Patient has baseline resting oxygen saturation of \< 89% on room air or use of supplemental oxygen at rest.
8. Evidence of functional airway stenosis (e.g., bronchomalacia/tracheomalacia, airway stents, or airways requiring balloon dilatations to maintain patency) with onset after the initial diagnosis of BOS and ongoing at Screening and/or Randomization Visit.
9. Known hypersensitivity to L-CsA or to cyclosporine A.
10. Patients with chronic renal failure, defined as serum creatinine \> 2.5 mg/dL at screening, or requiring chronic dialysis.
11. Patients with liver disease and serum bilirubin \> 3-fold upper limit of normal range or transaminases \> 2.5 upper limit of normal range.
12. Patients with active malignancy within the previous 2 years, including post-transplant lymphoproliferative disorder, with the exception of treated, localized basal and squamous cell carcinomas.
13. Pregnant women or women who are unwilling to use appropriate birth control to avoid pregnancy through their End of Study Visit.
14. Women who are currently breastfeeding.
15. Receipt of an investigational drug as part of a clinical trial within 4 weeks prior to the Screening Visit. This is defined as any treatment that is implemented under an Investigational New Drug (IND) or compassionate use.
16. Patients who have received extracorporeal photophoresis (ECP) for treatment of BOS within 1 month prior to Randomization.
17. Patients who are currently participating in an interventional clinical trial.
18. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary procedures.
19. Any co-existing medical condition that in the Investigator's judgment will substantially increase the risk associated with the patient's participation in the clinical trial.