Efficacy + Safety of Liposome Cyclosporine A to Treat Bronchiolitis Obliterans Post Single Lung Transplant (BOSTON-1)

A Phase III Clinical Trial to Demonstrate Efficacy / Safety of Liposomal Cyclosporine A + Standard of Care (SoC) vs SoC Alone in Treating Chronic Lung Allograft Dysfunction / Bronchiolitis Obliterans in Patients Post Single Lung Transplant

The objective of this trial is to assess the efficacy and safety of aerosolized liposomal cyclosporine A (L-CsA) as add-on therapy to standard of care (SoC) as compared to SoC alone in single lung transplant recipients with chronic lung allograft dysfunction (CLAD)-bronchiolitis obliterans syndrome (BOS).

BOSTON-1 was a Phase III, prospective, multicenter, randomized, open-label, controlled clinical trial of L-CsA for the treatment of BOS in adults diagnosed with CLAD-BOS following single lung transplant.

Eligible patients were randomized to receive either L-CsA (5 mg) via the PARI eFlow® Device (L-CsA eFlow) twice daily plus SoC treatment or SoC alone for a period of 48 weeks.

Regardless of treatment allocation, all patients continued to receive their SoC regimen for maintenance of the lung allograft. Maintenance immunosuppressive therapy including tacrolimus, a second agent such as, but not limited to, MMF or azathioprine, and a systemic corticosteroid such as prednisone as third agent was administered according to institutional standards.

Up to 11 study visits (screening, V1 through V10) were planned. Spirometry was measured at all visits according to American Thoracic Society/European Respiratory Society 2005 guidelines. Spirometry measurements on-site were performed by pulmonary function technicians, respiratory therapists, or physiotherapists who were blinded to each patient's study treatment assignment.

Safety assessments at every study visit included physical examination, vital signs, adverse event (AE) reporting, and clinical laboratory tests. Acute tolerability of L-CsA was assessed by spirometry before and 1 hour and 4 hours after inhalation of L-CsA at initial dosing.

All patients who completed the study were eligible to continue in an open-label extension trial of L-CsA (BOSTON-3 [Study BT-L-CsA-303-FU]).

Inclusion Criteria:

1. Adult patients ≥ 18 years who received a single 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 have been 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 was not due to acute infection or acute organ rejection.

4. Patients in whom the diagnosis of BOS had 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 have been on a maintenance regimen of immunosuppressive agents including tacrolimus, a second agent such as but not limited to mycophenolate mofetil (MMF) or azathioprine, and a systemic corticosteroid such as prednisone as third agent. The regimen must have been stable within 4 weeks prior to randomization with respect to the therapeutic agents. In case a patient was also receiving concomitant azithromycin for prophylaxis or treatment of BOS in addition to the previously described immunosuppressive regimen, azithromycin must have been 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 had given written informed consent and agreed to comply with the clinical trial requirements/visit schedules, and who were capable of aerosol inhalation. Patients must have consented to retrieve prespecified data from the historic medical record (e.g., information related to the transplant surgery; spirometry data; medication use).

7. Women of childbearing potential must have had a negative serum or urine pregnancy test within 7 days prior to randomization and must agree to use one of the methods of contraception listed in Appendix II of the Protocol through their End of Study (EoS) Visit.

8. Patients had no concomitant diagnoses that were considered fatal within one year (12 months) of Screening.

Exclusion Criteria:

1. Patients with confirmed other causes for loss of lung function, such as acute infection, acute rejection, restrictive allograft syndrome (CLAD - RAS phenotype, see Protocol Specific Definition ), etc.
2. 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 were eligible for the study.
3. 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 were clinically stable as per judgement of the Investigator are eligible for the study.
4. Mechanical ventilation (including CPAP) within 12 weeks prior to Randomization.
5. Patients with uncontrolled hypertension.
6. Patient had baseline resting oxygen saturation of < 89% on room air or use of supplemental oxygen at rest.
7. 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 Baseline Visit.
8. Known hypersensitivity to L-CsA or to cyclosporine A.
9. Patients with chronic renal failure, defined as serum creatinine > 2.5 mg/dL at screening, or requiring chronic dialysis.
10. Patients with liver disease and serum bilirubin > 3-fold upper limit of normal range or transaminases > 2.5 upper limit of normal range.
11. 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.
12. Pregnant women or women who were unwilling to use appropriate birth control to avoid pregnancy through their End of Study (EoS) Visit.
13. Women who were currently breastfeeding.
14. Receipt of an investigational drug as part of a clinical trial within 4 weeks prior to the Screening Visit. This was defined as any treatment that was implemented under an Investigational New Drug (IND) or compassionate use.
15. Patients who had received extracorporeal photophoresis (ECP) for treatment of BOS within 1 month prior to Randomization.
16. Patients who were currently participating in an interventional clinical trial.
17. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary procedures.
18. Any co-existing medical condition that in the Investigator's judgment would substantially increase the risk associated with the patient's participation in the clinical trial.