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

NCT ID: NCT03657342

Last Updated: 2025-10-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-26
• Study Completion Date: 2024-04-16

Brief Summary

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).

Detailed Description

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]).

Conditions

Bronchiolitis Obliterans; Chronic Rejection of Lung Transplant; Lung Transplant Rejection; Lung Transplant; Complications; Lung Transplant Failure and Rejection; Chronic Lung Allograft Dysfunction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

L-CsA treatment plus SoC

Liposomal Cyclosporine A 5 mg twice daily for 48 weeks + Standard of Care Therapy

Group Type: EXPERIMENTAL

Liposomal Cyclosporine A

Intervention Type: DRUG

This formulation is developed for inhalation use and delivered via the PARI eFlow® Device, which is a new technology of nebulizing liquid drugs with a perforated vibrating membrane resulting in an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm

Control treatment

In this arm only the standard of care is administered. Standard of care is a maintenance regimen of immunosuppressive agents.

Group Type: ACTIVE_COMPARATOR

standard of care

Intervention Type: DRUG

Standard of Care Therapy. Eligible 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. Patients receiving azithromycin for prophylaxis or treatment of BOS, must be on a stable regimen for a least 4-weeks prior to randomization and will continue to receive azithromycin during the trial as deemed appropriate by the investigator.

Interventions

Liposomal Cyclosporine A

This formulation is developed for inhalation use and delivered via the PARI eFlow® Device, which is a new technology of nebulizing liquid drugs with a perforated vibrating membrane resulting in an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm

Intervention Type: DRUG

standard of care

Standard of Care Therapy. Eligible 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. Patients receiving azithromycin for prophylaxis or treatment of BOS, must be on a stable regimen for a least 4-weeks prior to randomization and will continue to receive azithromycin during the trial as deemed appropriate by the investigator.

Intervention Type: DRUG

Other Intervention Names

L-CsA; SoC

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Zambon SpA

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Paola Castellani, MD

Role: STUDY_DIRECTOR

Zambon SpA, Chief Medical Officer and R&D

Locations

Banner Health

Phoenix, Arizona, United States

Norton Thoracic Institute at St. Joseph's Hospital

Phoenix, Arizona, United States

UCLA Medical Center

Los Angeles, California, United States

Stanford University Hospital

Palo Alto, California, United States

UC San Francisco

San Francisco, California, United States

University of Florida Medical Center

Gainesville, Florida, United States

Mayo Clinic Jacksonville

Jacksonville, Florida, United States

University of South Florida

Tampa, Florida, United States

Indiana University Health Methodist Hospital

Indianapolis, Indiana, United States

University of Kentucky Albert B. Chandler Hospital

Lexington, Kentucky, United States

University of Maryland

Baltimore, Maryland, United States

Johns Hopkins University Hospital

Baltimore, Maryland, United States

110

St Louis, Missouri, United States

Columbia University Medical Center

New York, New York, United States

113

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Cleveland Clinic

Cleveland, Ohio, United States

119

Columbus, Ohio, United States

108

Philadelphia, Pennsylvania, United States

Temple University Hospital

Philadelphia, Pennsylvania, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Baylor University Medical Center

Dallas, Texas, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Baylor St. Luke's Medical Center

Houston, Texas, United States

Houston Methodist Hospital

Houston, Texas, United States

Universitair Ziekenhuis Leuven

Leuven, , Belgium

Hôpitaux Universitaires de Strasbourg

Strasbourg, , France

Hannover Medical School - MHH Klinik für Pneumologie

Hanover, , Germany

LMU Klinikum Großhadern

Munich, , Germany

Rabin Medical Center

Petah Tikva, , Israel

Complexo Hospitalario de A Coruna

A Coruña, , Spain

Hospital Universitari Vall d'Hebron

Barcelona, , Spain

Hospital Universitario Reina Sofia

Córdoba, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Hospital Universitario Puerta de Hierro

Madrid, , Spain

Hospital Marques de Valdecilla

Santander, , Spain

Hospital Universitario y Politécnico La Fe

Valencia, , Spain

Royal Papworth Hospital NHS Foundation Trust

Cambridge, , United Kingdom

University Hospital of South Manchester NHS Foundation Trust

Manchester, , United Kingdom

Countries

United States; Belgium; France; Germany; Israel; Spain; United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2018-003204-39

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

BT - L-CsA - 301 - SLT

Identifier Type: -

Identifier Source: org_study_id