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

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ClinicalTrials.gov Identifier: NCT03657342
Recruitment Status : Recruiting
First Posted : September 5, 2018
Last Update Posted : March 31, 2022
Sponsor:
Information provided by (Responsible Party):
Zambon SpA

Brief Summary:
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 single lung transplant recipients.

Condition or disease Intervention/treatment Phase
Bronchiolitis Obliterans Chronic Rejection of Lung Transplant Lung Transplant Rejection Lung Transplant; Complications Lung Transplant Failure and Rejection Chronic Lung Allograft Dysfunction Drug: Liposomal Cyclosporine A Drug: standard of care Phase 3

Detailed Description:

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 single lung transplant. Patients will receive either L-CsA (5 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-1.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : April 2, 2019
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : June 2024

Resource links provided by the National Library of Medicine


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 Name: 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 Name: SoC




Primary Outcome Measures :
  1. Mean change in FEV1 (mL) from baseline to Week 48 [ Time Frame: Baseline to Week 48 ]

Secondary Outcome Measures :
  1. Mean change in FEV1/FVC from baseline to Week 48 [ Time Frame: Baseline to Week 48 ]
  2. Time to Progression of BOS [ Time Frame: 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 52 weeks. ]

    defined as the earliest of the following:

    • Absolute decrease from baseline in FEV1 >/= 10% or >/= 200 mL and absolute decrease in FEV1/FVC of > 5% OR
    • Change in BOS Severity, OR
    • Re-transplantation, OR
    • Death from respiratory failure This endpoint will be assessed in a combined analysis with a similar Phase III clinical trial, BT - L-CsA - 302 - DLT (BOSTON-2) which will be conducted in the same investigational centers in patients who have undergone double-lung transplantations.


Other Outcome Measures:
  1. Adverse Events [ Time Frame: Baseline through study completion (52 weeks) ]
  2. Acute tolerability of L-CsA [ Time Frame: Baseline through Week 48 ]
    change in forced expiratory volume in one second (FEV1); reports of cough or shortness of breath

  3. Hematology and Serum Chemistry Parameters [ Time Frame: From date of randomization until end of study participation (52 weeks) ]
    Number of patients with treatment-related changes in hematology or serum chemistry parameters assessed by CTCAE v5.0.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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.
  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).
  7. Women of childbearing potential must have 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 through their End of Study Visit.
  8. Patients have no concomitant diagnoses that are 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 are 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 are clinically stable as per judgement of the Investigator are eligible for the study.
  4. Mechanical ventilation within 12 weeks prior to Randomization.
  5. Patients with uncontrolled hypertension.
  6. Patient has 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 are unwilling to use appropriate birth control to avoid pregnancy through their End of Study Visit.
  13. Women who are currently breastfeeding.
  14. 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.
  15. Patients who have received extracorporeal photophoresis (ECP) for treatment of BOS within 1 month prior to Randomization.
  16. Patients who are 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 will substantially increase the risk associated with the patient's participation in the clinical trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03657342


Contacts
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Contact: Ferdinando Ceravolo, MD +39 02 583831 ferdinando.ceravolo@zambongroup.com

Locations
Show Show 33 study locations
Sponsors and Collaborators
Zambon SpA
Investigators
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Study Director: Paola Castellani, MD Zambon SpA, Chief Medical Officer
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Responsible Party: Zambon SpA
ClinicalTrials.gov Identifier: NCT03657342    
Other Study ID Numbers: BT - L-CsA - 301 - SLT
2018-003204-39 ( EudraCT Number )
First Posted: September 5, 2018    Key Record Dates
Last Update Posted: March 31, 2022
Last Verified: March 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Bronchiolitis
Bronchiolitis Obliterans
Bronchitis
Respiratory Tract Infections
Infections
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Cyclosporine
Cyclosporins
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Calcineurin Inhibitors