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

Study Overview

• Status: Completed
• Conditions: Bronchiolitis Obliterans; Lung Transplant Rejection; Lung Transplant; Complications; Lung Transplant Failure and Rejection; Chronic Rejection of Lung Transplant; Chronic Lung Allograft Dysfunction
• Intervention / Treatment: Drug: Liposomal Cyclosporine A; Drug: standard of care

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]).

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Universitair Ziekenhuis Leuven
• France
  • Strasbourg, France
    • Hôpitaux Universitaires de Strasbourg
• Germany
  • Hanover, Germany
    • Hannover Medical School - MHH Klinik für Pneumologie
  • Munich, Germany
    • LMU Klinikum Großhadern
• Israel
  • Petah Tikva, Israel
    • Rabin Medical Center
• Spain
  • A Coruña, Spain
    • Complexo Hospitalario de A Coruna
  • Barcelona, Spain
    • Hospital Universitari Vall d'Hebron
  • Córdoba, Spain, 14004
    • Hospital Universitario Reina Sofía
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de octubre
  • Madrid, Spain
    • Hospital Universitario Puerta de Hierro
  • Santander, Spain
    • Hospital Marques de Valdecilla
  • Valencia, Spain
    • Hospital Universitario y Politécnico La Fe
• United Kingdom
  • Cambridge, United Kingdom
    • Royal Papworth Hospital NHS Foundation Trust
  • Manchester, United Kingdom
    • University Hospital of South Manchester NHS Foundation Trust
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Banner Health
    • Phoenix, Arizona, United States, 85013
      • Norton Thoracic Institute at St. Joseph's Hospital
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
    • Palo Alto, California, United States, 94305
      • Stanford University Hospital
    • San Francisco, California, United States, 94143
      • UC San Francisco
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida Medical Center
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Tampa, Florida, United States, 33606
      • University of South Florida
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Methodist Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40508
      • University of Kentucky Albert B. Chandler Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University Hospital
  • Missouri
    • St Louis, Missouri, United States, 63110
      • 110
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 22042
      • 113
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • 119
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • 108
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
    • Houston, Texas, United States, 77030
      • Baylor St. Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: L-CsA treatment plus SoC; Liposomal Cyclosporine A 5 mg twice daily for 48 weeks + Standard of Care Therapy	Drug: 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; Other Names: L-CsA
Active Comparator: Control treatment; In this arm only the standard of care is administered. Standard of care is a maintenance regimen of immunosuppressive agents.	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.; Other Names: SoC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in FEV1 (L) From Baseline to Week 48	FEV1 is the Forced Expiratory Volume in One Second. For FEV1 were considered primary the data collected from the on site COMPACT study spirometer. Baseline is the mean of the best FEV1 obtained with the study spirometer at Screening Visit and the pre-randomization best FEV1 obtained at the Baseline Visit (V1).The primary efficacy analysis was carried out using a Linear Mixed Model (LMM) for repeated measures, using all observed available FEV1 measurements. In case of death or re-transplantation events, FEV1 was imputed as zero at each nominal day post event. PS: Estimates are from a LMM on the response variable with factors for time splines, treatment, the interactions of time splines by treatment, baseline FEV1, the interactions of time splines with baseline FEV1, region, underlying indication for lung transplant (COPD vs all others), use of azithromycin at randomization, and time as random effect.	Week 48 (V9)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in FEV1/FVC From Baseline to Week 48	Forced Expiratory Volume in One Second on Forced Vital Capacity. It was analysed in the FAS using a LMM for repeated measurements and COMPACT data, with baseline FEV1/FVC among covariates. In case of death or re- transplantation events, FEV1/FVC was imputed as zero at each nominal day post event. FEV1/FVC is a calculated ratio used to diagnose obstructive and restrictive lung disease. It represents the proportion of a patient's vital capacity that he/she is able to expire in the first second of forced expiration to the full forced vital capacity.	Week 48
Time to Progression of Bronchiolitis Obliterans Syndrome (BOS)	The progression of BOS is defined as the earliest of the following: Absolute decrease from baseline in FEV1 by at least 10% or 200 mL and a decrease in FEV1/FVC by at least 5% (if a patient had an event that met this criterion for progression of BOS, progression of BOS must have been confirmed by measurements that were taken with COMPACT spirometer at least 2 weeks apart) OR; Worsening of BOS grade, OR; Re-transplantation, OR; Death from respiratory failure. Rules for censoring progression of BOS are set. More than one type of event might correspond to the event of BOS progression (even those occurring on the same date). In case progression of BOS was defined by more than one criterion on different dates, the earliest event date was considered, i.e., the date closer to randomization was used as the progression date.	From date of randomization until the date of first documented progression of BOS, or date of retransplantation, or date of death from respiratory failure, whichever came first, assessed up to 48 weeks.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Adverse Events (AE)	An AE is an untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine.	Baseline through study completion (week 48)
Acute Tolerability of L-CsA: Change From Pre-dose to 1 hr and 4h Post-dose	Acute tolerability of IMP (L-CsA) during initial dosing was determined by measuring spirometry 1 hour and 4 hours after treatment. The FEV1 was measured prior to dosing with L-CsA. A decline of ≥20% associated with symptoms could have warranted IMP discontinuation. Parameters reflecting acute tolerability of IMP were: spirometry, cough, or dyspnea.	Baseline through study completion Week 48

Collaborators and Investigators

• Sponsor: Zambon SpA
• Investigators: Study Director: Paola Castellani, MD, Zambon SpA, Chief Medical Officer and R&D

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2019
• Primary Completion (Actual): April 16, 2024
• Study Completion (Actual): April 16, 2024

Study Registration Dates

• First Submitted: August 30, 2018
• First Submitted That Met QC Criteria: August 31, 2018
• First Posted (Actual): September 5, 2018

Study Record Updates

• Last Update Posted (Estimated): October 27, 2025
• Last Update Submitted That Met QC Criteria: October 10, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchiolitis; Bronchitis; Behavior; Social Behavior; Bronchiolitis Obliterans; Rejection, Psychology; Health Services Administration; Health Care Quality, Access, and Evaluation; Quality of Health Care; Quality Indicators, Health Care; Standard of Care
• Other Study ID Numbers: BT - L-CsA - 301 - SLT; 2018-003204-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No