Clinical trial NCT03656926: Efficacy + Safety of Liposome Cyclosporine A to Treat Bronchiolitis Obliterans Post Double Lung Transplant (BOSTON-2)
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 Double Lung Transplant
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Bronchiolitis Obliterans
Chronic Rejection of Lung Transplant
Lung Transplant Rejection
Lung Transplant; Complications
Lung Transplant Failure and Rejection
Chronic Lung Allograft Dysfunction
Lead sponsor: Zambon SpA
Sponsor class: INDUSTRY
First posted: 2018-09-04
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 double lung transplant recipients.

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 double lung transplant. Patients will receive either L-CsA (10 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-2.

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.

Eligibility criteria: Inclusion Criteria:

1. Adult patients ≥ 18 years who received a double 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.

   In case a patient is also receiving concomitant azithromycin for prophylaxis or treatment of BOS, in addition to the previously described immunosuppressive regimen, azithromycin must be 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 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).

Exclusion Criteria:

1. Patients with confirmed other causes for loss of lung function, such as acute infection, acute rejection, restrictive allograft syndrome (RAS) (CLAD - RAS phenotype, see Protocol Specific Definition ), etc.
2. Cystic Fibrosis patients with multi-drug resistant infections not responding to available anti-microbial therapies.
3. 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.
4. 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.
5. Mechanical ventilation (including CPAP) within 12 weeks prior to Randomization.
6. Patients with uncontrolled hypertension.
7. Patient has baseline resting oxygen saturation of \< 89% on room air or use of supplemental oxygen at rest.
8. 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 Randomization Visit.
9. Known hypersensitivity to L-CsA or to cyclosporine A.
10. Patients with chronic renal failure, defined as serum creatinine \> 2.5 mg/dL at screening, or requiring chronic dialysis.
11. Patients with liver disease and serum bilirubin \> 3-fold upper limit of normal range or transaminases \> 2.5 upper limit of normal range.
12. 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.
13. Pregnant women or women who are unwilling to use appropriate birth control to avoid pregnancy through their End of Study Visit.
14. Women who are currently breastfeeding.
15. 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.
16. Patients who have received extracorporeal photophoresis (ECP) for treatment of BOS within 1 month prior to Randomization.
17. Patients who are currently participating in an interventional clinical trial.
18. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary procedures.
19. 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.

Primary outcomes:
measure: Mean change in FEV1 (mL) from baseline to Week 48)
timeFrame: Baseline to Week 48
Secondary outcomes:
measure: Mean change in FEV1/FVC from baseline to Week 48
timeFrame: Baseline to Week 48
measure: Time to Progression of BOS
timeFrame: 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.
Other outcomes:
measure: Adverse Events
timeFrame: Baseline through study completion (52 weeks)
measure: Acute tolerability of L-CsA
timeFrame: Baseline through Week 48
Locations:
city: Phoenix
country: United States
facility: Banner Health
state: Arizona
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Palo Alto
country: United States
facility: Stanford University Hospital
state: California
city: San Francisco
country: United States
facility: UC San Francisco
state: California
city: Gainesville
country: United States
facility: University of Florida Medical Center
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky Albert B. Chandler Hospital
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University Hospital
state: Maryland
city: Saint Louis
country: United States
facility: Barnes Jewish Hospital
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Pittsburg
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Vienna
country: Austria
facility: Waehringer Guertel
city: Brussels
country: Belgium
facility: CHU Erasme
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital
city: Marseille
country: France
facility: CHU Hopital Nord
city: Paris
country: France
facility: Marie-Lannelongue
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg
city: Hannover
country: Germany
facility: Hannover Medical School
city: Munich
country: Germany
facility: LMU Klinikum Großhadern
city: Petah tikva
country: Israel
facility: Rabin Medical Center
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Coruña
country: Spain
facility: Complexo Hospitalario de A Coruna
city: Madrid
country: Spain
facility: Hospital Puerta de Hierro
city: Santander
country: Spain
facility: Hospital Marques de Valdecilla
city: Valencia
country: Spain
facility: University Hospital LA Fe
city: Cambridge
country: United Kingdom
facility: Royal Papworth Hospital
city: Manchester
country: United Kingdom
facility: University of Manchester
Study officials:
affiliation: Zambon SpA, Chief Medical Officer
name: Paola Castellani, MD
role: STUDY_DIRECTOR
References: