BT–L-CsA–302–DLT

Zambon S.p.A.

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

Sponsor Contact Point, Zambon SpA, Zambon SpA, +39 0266524513, clinicaltrials@zambongroup.com

Sponsor Contact Point, Zambon SpA, Zambon SpA, +39 0266524513, clinicaltrials@zambongroup.com

No

No

No

Final

12 Mar 2024

Yes

12 Mar 2024

Yes

12 Mar 2024

No

To assess the efficacy and safety of add-on aerosolized L-CsA to Standard of Care therapy as compared to SoC therapy alone in the treatment of BOS in double lung transplant recipients.

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 insured 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: 61

Israel: 5

Spain: 36

United Kingdom: 6

Austria: 5

Belgium: 6

Denmark: 4

France: 12

Germany: 34

169

97

0

0

0

0

0

0

122

47

0

Overall study (overall period)

Randomised - controlled

This was an opel-label study hence clinical monitors, physicians, nurses, study coordinators & patients were not blinded to treatment assignment. However, pulmonary function technicians, respiratory therapists, or physiotherapists who conducted spirometry on-site were blinded to treatment assignment. Patients and other unblinded personnel were asked not to share treatment assignment infos with them. The statistician who made the blinded interim sample size re-assessment was blinded as well.

Yes

L-CsA

liposomal cyclosporine A

Inhalation solution

Inhalation use

Liposomal Cyclosporine A (L-CsA) 10 mg twice daily for 48 weeks, plus Standard of Care Therapy. 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. The L-CsA was administered as 10 mg/2.4 mL inhalation via the PARI eFlow device BID (morning/evening, approximately 12 hours apart) for 48 weeks. Nebulization time per inhalation dose was approximately 6 to 17 minutes. Patients received training on the use of the device and the first dose of L-CsA was self-administered by each patient under the supervision of trained personnel. In addition, during all subsequent scheduled visits the L-CsA inhalation was self-administered by the patient and under the supervision of trained study personnel.

Standard of care

SoC

Inhalation solution

Inhalation use

This is a maintenance regimen of immunosuppressive agents. Standard of Care: Standard of Care Therapy (SoC). The SoC included maintenance immunosuppressive medication including tacrolimus, a second agent such as but not limited to MMF or azathioprine, and a systemic corticosteroid such as prednisone as third agent; but also a prophylaxis against common opportunistic infections, and all other necessary medications and therapies for the optimal care of the patient. This also included vaccination against COVID-19 All changes in concurrent treatment or medication were administered according to site's SoC. 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, should be on a stable regimen for a least 4-weeks prior to randomization and continued to receive azithromycin during the trial as deemed appropriate by the inves

Standard of Care

SoC

Inhalation solution

Inhalation use

This is a maintenance regimen of immunosuppressive agents. Standard of Care: Standard of Care Therapy (SoC). The SoC included maintenance immunosuppressive medication including tacrolimus, a second agent such as but not limited to MMF or azathioprine, and a systemic corticosteroid such as prednisone as third agent; but also a prophylaxis against common opportunistic infections, and all other necessary medications and therapies for the optimal care of the patient. This also included vaccination against COVID-19 All changes in concurrent treatment or medication were administered according to site's SoC. 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, should be on a stable regimen for a least 4-weeks prior to randomization and continued to receive azithromycin during the trial as deemed appropriate by the investigator.

Group A

Group B

Group A - Full analysis set

The FAS was defined as all randomized patients. Patients were analyzed according to the treatment group to which they were randomized.

Group A - Safety analysis set

Safety Analysis Set (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 - Per protocol set

Per Protocol Set (PPS): The PPS was defined as all patients included in the FAS • who completed randomized treatment as scheduled or who were withdrawn prematurely due to lack of efficacy or lack of tolerability of the clinical trial treatment, and • for whom no major PDs interfering with the assessment of treatment efficacy were observed.

Group B - Full analysis set

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

Group B - Safety analysis set

Safety Analysis Set (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 - Per protocol set

Per Protocol Set (PPS): The PPS was defined as all patients included in the FAS • who completed randomized treatment as scheduled or who were withdrawn prematurely due to lack of efficacy or lack of tolerability of the clinical trial treatment, and • for whom no major PDs interfering with the assessment of treatment efficacy were observed.

Group A

Group B

Group A - Full analysis set

The FAS was defined as all randomized patients. Patients were analyzed according to the treatment group to which they were randomized.

Group A - Safety analysis set

Safety Analysis Set (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 - Per protocol set

Per Protocol Set (PPS): The PPS was defined as all patients included in the FAS • who completed randomized treatment as scheduled or who were withdrawn prematurely due to lack of efficacy or lack of tolerability of the clinical trial treatment, and • for whom no major PDs interfering with the assessment of treatment efficacy were observed.

Group B - Full analysis set

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

Group B - Safety analysis set

Safety Analysis Set (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 - Per protocol set

Per Protocol Set (PPS): The PPS was defined as all patients included in the FAS • who completed randomized treatment as scheduled or who were withdrawn prematurely due to lack of efficacy or lack of tolerability of the clinical trial treatment, and • for whom no major PDs interfering with the assessment of treatment efficacy were observed.

FEV1 is the Forced Expiratory Volume in One Second. The FEV1 data collected from the on-site COMPACTTM spirometer were to be considered primary, while data collected with the In2itiveTM home spirometer were to be used for supportive analyses.

Primary

Week 48

V9 - week 48

Group A - Full analysis set v Group B - Full analysis set

144

Pre-specified

-0.028

2-sided

An untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine. Please note that in Group B, participants in SoC were not asked to report study treatment-related TEAE. Hence, on the platform, at the category "with any study treatment-related TEAE" and "with any serious treatment-related TEAE" a "000" is reported since the expression "NA" is not accepted by the system.

Secondary

Baseline through study completion (52 weeks)

Forced Expiratory Volume in One Second on Forced Vital Capacity. It was analysed in the FAS using a LMM for repeated measurements, 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.

Secondary

Week 48 (V9)

Estimates were from a Linear Mixed Model 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/FVC, the interactions of time splines with baseline FEV1/FVC, region (North America versus all other countries together), age (<55 versus > or = 55), use of azithromycin at randomization, and time as random effect.

Group A - Full analysis set v Group B - Full analysis set

144

Pre-specified

-0.016

2-sided

Time to progression of BOS, defined as the earliest of the following: Absolute decrease from Baseline in FEV1 ≥10% or ≥ 200 mL (0.2 L) and absolute decrease in FEV1/FVC of > 5% OR Worsening of BOS grade, OR Re-transplantation, OR Death from respiratory failure. 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. Please note: in the descriptive statistics median and confidence interval limits were not achieved due to the low number of events. On the platform this is indicated with "000", because the system doesn't accept the expression "NA" (not applicable).

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.

For the statistical analysis, the estimand was the log hazard ratio of the L-CsA + SoC group relative to the SoC alone group. The treatment policy strategy was adopted for handling the IEs of treatment discontinuation. Dropouts due to other reasons and death from respiratory failure were to be treated as non-informative censoring.

Group A - Full analysis set v Group B - Full analysis set

169

Pre-specified

1.19

2-sided

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

Secondary

Baseline/V1

From baseline throughout the study, till week 52.

Serious TEAEs by System Organ Class and Preferred Term Reported by at Least 2 Patients Overall while non serious adverse events are reported with a 0% threshold.

23.1

Group B - SAF

Group A - SAF