BOSTON 1

Zambon S.p.A.

Via Lillo del Duca 10, Bresso (Mi), Italy, 20091

Sponsor Contact Point, Zambon SpA , Zambon SpA, +39 02 39 02 665241, clinicaltrials@zambongroup.com

Sponsor Contact Point, Zambon SpA , Zambon SpA, +39 02 39 02 665241, clinicaltrials@zambongroup.com

No

No

No

Final

16 Apr 2024

Yes

16 Apr 2024

Yes

16 Apr 2024

No

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).

The clinical study was performed in accordance with the principles that have their origin in the Declaration of Helsinki, and with local regulations. The study was carried out in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) notes for guidance on Good Clinical Practice (GCP). Investigators ensured a close follow-up of safety signals, and that everything has been done to reduce the burden of study procedures (e.g. no painful procedures, etc.).

26 Mar 2019

No

Yes

United States: 41

Israel: 6

Spain: 9

United Kingdom: 3

Germany: 3

62

12

0

0

0

0

0

0

14

48

0

Overall study (overall period)

Randomised - controlled

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.

Yes

L-CsA

Liposomal Cyclosporine A

Inhalation powder

Inhalation use

5 mg L-CsA, powder for nebulization solution for inhalation use, administered with the nebulizer eFlow. L-CsA 5 mg/1.25 mL was administered twice daily for 48 weeks. More precisely, each patient received two L-CsA administrations per day, one in the morning and one in the evening. The inhalations were scheduled to be taken approximately 12 hours apart, e.g., at 8:00 a.m. and 8:00 p.m. each day. 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.

Standard of care

SoC

Not assigned

Oral use

In this active-comparator arm only the standard of care (SoC) is administered. SoC is a maintenance regimen of immunosuppressive agents. 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.

Group A (L-CsA + SoC)

Group B (SoC alone)

Group A (L-CsA Treatment Plus SoC) (SAF)

The SAF was defined as all randomized patients receiving SoC and/or at least one dose of L-CsA, independently of the treatment allocation at randomization. Independently of the treatment allocation at randomization, patients were analyzed according to the treatment they actually received. All safety and tolerability data were summarized and analyzed using the SAF.

Group B (SoC alone) (SAF)

The SAF was defined as all randomized patients receiving SoC and/or at least one dose of L-CsA, independently of the treatment allocation at randomization. Independently of the treatment allocation at randomization, patients were analyzed according to the treatment they actually received. All safety and tolerability data were summarized and analyzed using the SAF.

Group A (L-CsA + SoC) (FAS)

The FAS was defined as all randomized patients. Patients were analyzed according to the treatment group to which they were randomized. All primary and secondary endpoints were performed using the FAS, unless otherwise specified.

Group B (SoC Alone) (FAS)

The FAS was defined as all randomized patients. Patients were analyzed according to the treatment group to which they were randomized. All primary and secondary endpoints were performed using the FAS, unless otherwise specified.

Group A (L-CsA + SoC)

Group B (SoC alone)

Group A (L-CsA Treatment Plus SoC) (SAF)

The SAF was defined as all randomized patients receiving SoC and/or at least one dose of L-CsA, independently of the treatment allocation at randomization. Independently of the treatment allocation at randomization, patients were analyzed according to the treatment they actually received. All safety and tolerability data were summarized and analyzed using the SAF.

Group B (SoC alone) (SAF)

The SAF was defined as all randomized patients receiving SoC and/or at least one dose of L-CsA, independently of the treatment allocation at randomization. Independently of the treatment allocation at randomization, patients were analyzed according to the treatment they actually received. All safety and tolerability data were summarized and analyzed using the SAF.

Group A (L-CsA + SoC) (FAS)

The FAS was defined as all randomized patients. Patients were analyzed according to the treatment group to which they were randomized. All primary and secondary endpoints were performed using the FAS, unless otherwise specified.

Group B (SoC Alone) (FAS)

The FAS was defined as all randomized patients. Patients were analyzed according to the treatment group to which they were randomized. All primary and secondary endpoints were performed using the FAS, unless otherwise specified.

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.

Primary

Week 48 (V9)

at V9. Estimates are from a LMM for repeated measurements on the response variable change from baseline in FEV1 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.

Group A (L-CsA + SoC) (FAS) v Group B (SoC Alone) (FAS)

50

Pre-specified

-0.095

2-sided

Forced Expiratory Volume in One Second on Forced Vital Capacity. FEV1/FVC is a calculated ration used to diagnose obstructive and restrictive lungo 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.

Secondary

Week 48 (V9)

At V9. Estimates are - as for the primary outcome - from a LMM for repeated measurements on the response variable change from baseline in FEV1/FVC 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.

Group A (L-CsA + SoC) (FAS) v Group B (SoC Alone) (FAS)

50

Pre-specified

-0.064

2-sided

The progression of BOS is 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% (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.

Secondary

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.

Group A (L-CsA + SoC) (FAS) v Group B (SoC Alone) (FAS)

62

Pre-specified

2.601

2-sided

An AE is an untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine.

Secondary

Baseline through study completion (week 48)

Acute tolerability of IMP (L-CsA) during initial dosing was determined by measuring spirometry prior to administration of L-CsA as well as 1 hour and 4 hours after completion of IMP inhalation. A decline of ≥20% in FEV1 associated with symptoms could have warranted IMP discontinuation. Parameters reflecting acute tolerability of IMP were: spirometry, cough, or dyspnea.

Secondary

Baseline through study completion Week 48

Permanent assessment throughout the complete clinical trial period, from baseline (Week 0, Day 1, V1) till week 48 (V9)

23.1

Group A (L-CsA + SoC) - SAF

Group B (SoC alone) - SAF