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Purpose

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).

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

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 Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Single (Outcomes Assessor)
Masking Description
This was an open-label clinical trial. Clinical trial monitors, treating physicians, study nurses, study coordinators, and enrolled patients were not blinded to treatment assignment. However, the pulmonary function technicians, respiratory therapists, or physiotherapists who conducted spirometry on-site were blinded to treatment assignment.

Arm Groups

ArmDescriptionAssigned Intervention
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

Recruiting Locations

More Details

NCT ID
NCT03657342
Status
Completed
Sponsor
Zambon SpA

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]).

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.