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
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
Sponsor: Zambon SpA

 
C LI NI C A L  T RI A L  P R O T O C O L  
A P h ase III, Pr os pecti ve, M ultice nter, R a n d o mize d, C o ntr olle d Cli nic al Tri al t o 
De m o nstr ate t he Effic ac y a n d S afet y of Li p os o m al C ycl os p ori ne A ( L -Cs A) I n h al ati o n 
S ol uti o n Deli vere d vi a t he 
 
 pl us St a n d ar d of C are 
vers us St a n d ar d of C are Al o ne i n t he Tre at me nt of C hr o nic L u n g All o gr aft D ysf u ncti o n / 
Br o nc hi olitis O bliter a ns S y n dr o me i n P atie nts p ost Si n gle L u n g Tr a ns pl a nt ati o n  
Pr ot oc ol N o: B T –  L -Cs A –  3 0 1 –  S L T 
( B O S T O N-1)  
Versi o n:  5. 0  
Date: 2 Fe br uar y 2 0 2 3 
Pr ot oc ol A me n d m e nt N u m ber 4 
I N D N u m ber:  7 8, 8 5 4  
E U D R A C T  N u m ber:  2 0 1 8 -0 0 3 2 0 4 -3 9  
S P O N S O R  
Za m b o n  S p A  
Via  Lill o  del  D uca,  1 0 
Bress o ( MI) 2 0 0 9 1 
Ital y 
I N V E S TI G A TI O N A L M E DI CI N A L  P R O D U C T  
Li p os o mal C ycl os p ori ne A ( L -Cs A) 
 
C CI
C CI

L -Cs A:
Pr ot oc ol  N u m ber:  
S p o ns or:  
Versi o n 5 .0 _ 2 -Fe br uar y -2 0 2 3 
 
Treat me nt  of  B O S  after S L T
B T -L -Cs A -3 0 1 -S L T  
Za m b o n  S p A  
1  SI G N A T O RI E S  
S P O N S O R  
Za m b o n  S p A  
Vi a  Lill o  d el  D u c a, 1 0 
Br ess o ( Ml) 2 0 0 9 1 
It al y 
 
 
P h o ne:
 
E mail:  
 
 
 
P h o n e: 
 
E mail:  
 
Date  
Si g nat ure  
Pa ge  2  of 1 0 6  
Cli ni cal Tri al  Pr ot oc ol  B T - L -Cs A - 3 0 1  - S L T  
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  3  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
Pr ot oc ol  Ac k n o wle d g me nt  / C o nfi de nti alit y  
A P h ase III, Pr os pecti ve, M ultice nter, R a n d o mize d, C o ntr olle d Cli nic al Tri al t o 
De m o nstr ate t he Effic ac y a n d S afet y of Li p os o m al C ycl os p ori ne A ( L -Cs A) I n h al ati o n 
S ol uti o n Deli vere d vi a t he 
 
 pl us St a n d ar d of C are 
vers us St a n d ar d of C are Al o ne i n t he Tre at me nt of C hr o nic L u n g All o gr aft D ysf u ncti o n / 
Br o nc hi olitis O bliter a ns S y n dr o me i n P atie nts p ost Si n gle L u n g Tr a ns pl a nt ati o n  
( Pr ot oc ol N o.:  B T  –  L -Cs A  –  3 0 1  –  S L T)  
B y  si g ni n g t his Pr ot oc ol,  t he Pri nci pal  I n vesti gat or ac kn o wle d ges  a n d a grees: 
T he Pr ot oc ol c o ntai ns all necessar y details f or c o n d ucti n g t he cli nical trial. T he Pri nci pal 
I n vesti gat or will c o n d uct t his cli nical trial as detaile d herei n, i n c o m plia nce wit h G o o d Cli nical 
Practice ( G C P) a n d t he a p plica ble re g ulat or y re q uire me nts, a n d w ill ma ke e ver y reas o na ble eff ort 
t o c o m plete t he cli nical trial wit hi n t he ti me desi g nate d. 
T he  Pr ot oc ol  a n d all rele va nt i nf or mati o n o n  t he dr u g  a n d de vice  relati n g t o n o ncli nical  a n d cli nical 
e x perie nce, w hic h was f ur nis he d b y t he S p o ns or, Za m b o n S p A., w ill be ma de a vaila ble t o all 
p h ysicia ns, n urses a n d ot her pers o n nel w h o partici pate i n t he c o n d uct of t his cli nical trial. T he 
I n vesti gat or will disc uss t his material wit h t he m t o ass ure t hat t he y are f ull y i nf or me d re gar di n g 
t he I n vesti gati o nal Me dici nal Pr o d uct a n d t he c o n d uct of t he cli nical trial.  
T his d oc u me nt c o ntai ns i nf or mati o n t hat is pri vile ge d or c o nfi de ntial. As s uc h, it ma y n ot be 
discl ose d u nless s pecific pri or per missi o n is gra nte d i n writi n g b y t he S p o ns or or s uc h discl os ure  
is re q uire d b y fe deral or ot her la ws or re g ulati o ns. Pers o ns t o w h o m a n y of t his i nf or mati o n is t o  
be discl ose d m ust first be i nf or me d t hat t he i nf or mati o n is c o nfi de ntial. T hese restricti o ns o n 
discl os ure will a p pl y e q uall y t o all f ut ure  i nf or mati o n s u p plie d, w hic h is i n dicate d as pri vile ge d or 
c o nfi de ntial. 
Za m b o n S p A or its desi g nee will ha ve access t o a n y s o urce d oc u me nts fr o m w hic h Case Re p ort 
F or m i nf or mati o n ma y ha ve bee n ge nerate d. T he Case Re p ort F or ms a n d ot her data perti ne nt t o 
t his cli nical trial are t he s ole pr o pert y of Za m b o n S p A w hic h ma y utilize t he data i n vari o us wa ys, 
s uc h as f or s u b missi o n t o g o ver n me nt re g ulat or y a ut h orities, or i n p u blicati o n of t he res ults of t he 
cli nical trial. 
T he c o n d uct a n d res ults of t his cli nical trial will be ke pt c o nfi de ntial.  T he res ults of t his cli nical 
trial ma y be p u blis he d. U p o n c o m pleti o n of t he cli nical trial it is t he i nte nti o n of t he parties t o 
pre pare a j oi nt p u blicati o n re gar di n g or descri bi n g t he cli nical trial a n d all t he res ults t here fr o m 
a n d b ot h parties s hall c o -o perate i n t his re gar d.  
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 4 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
I have read and agree to the protocol numbered BT – L-CsA – 301 – SLT. I am aware of my 
responsibilities as a Principal Investigator and agree to conduct this clinical trial according to US 
and international standards of Good Clinical Practice (FDA Title 21 part 312 and International 
Conference on Harmonisation guidelines), applicable government regulations, and Institutional 
research policies and procedures under the guidelines of International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP), national regulations, and the protocol. I agree 
to appropriately direct and assist the staff under my control, who will be involved in the clinical 
trial. 
Principal Investigator’s Signature 
Name & Title 
(Print) 
Date 
Signature 
Center Name 
(Print) 

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  5  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
2  T A B L E  O F  C O N T E N T S  
1  
SI G N A T O RI ES  
2  
2  
T A BL E  O F  C O N T E N T S  
5  
3  
A B B R E VI A TI O NS  
9  
4  
P R O T O C OL -S P E CI FI C  D EFI NI TI O N S  
1 3  
5  
P R O T O C OL  S Y N O P SI S  
1 5  
6  
I N T R O D U C TI O N 
2 9  
6. 1  B R O N C HI OLI TI S  O BLI T E R A N S  A N D  B R O N C HI OLI TI S  O BLI T E R A N S  S Y N D R O M E
2 9  
7  
B A C K G R O U N D  I NF O R M A TI O N 
3 4  
7. 1  IN V E S TI G A TI O N AL  M E DI CI N AL  P R O D U C T  
3 4  
7. 1. 1  D R U G  C O M P O N E N T  
3 4  
7. 1. 2  D E VI C E  C O M P O N E N T  
3 4  
7. 1. 3  N O N CLI NI C AL  D A T A  
3 4  
7. 1. 4  C LI NI C AL E X P E RI E N C E  
3 5  
7. 1. 5  S U M M A R Y  OF  K N O W N  A N D  P O T E N TI AL  R I S KS A N D  B E N EFI TS  
3 6  
7. 1. 6  JU S TI FI C A TI O N  O F  D O S E  R E GI M E N
3 6  
7. 1. 7  S T A T E M E N T  OF  C O M PLI A N C E  
3 7  
7. 1. 8  P O P UL A TI O N  
3 8  
8  
T RI AL  O BJ E C TI V E S  A N D  P U R P O S E  
3 9  
8. 1  T RI AL  O BJ E C TI V E S  
3 9  
8. 2  P U R P O S E  O F  T H E  T RI AL  
3 9  
9  
T RI AL  D E SI G N  
4 0  
9. 1  E N D P OI N T S  
4 0  
9. 1. 1  P RI M A R Y  E N D P OI N T  
4 0  
 
 
 
 
 
 
9. 2  T RI AL  D ESI G N  
4 1  
9. 3  S T R A TI FI C A TI O N  A N D  R A N D O MI Z A TI O N
4 2  
9. 3. 1  B LI N DI N G 
4 2  
9. 4  IN V E S TI G A TI O N AL  M E DI CI N AL  P R O D U C T : T R E A T M E N T , D O S A G E  A N D  A D MI NI S T R A TI O N  
4 2  
9. 4. 1  F O R M UL A TI O N  OF  L-C SA  
4 2  
9. 4. 2  T R E A T M E N T  A N D  D OS A G E  
4 3  
9. 4. 3  A D MI NI S T R A TI O N  OF  L-C SA  
4 4  
9. 5  IN V E S TI G A TI O N AL  M E DI CI N AL  P R O D U C T  P A C K A GI N G , LA B ELI N G  A N D  S T O R A G E  
4 6  
9. 5. 1  P A C K A GI N G  A N D  LA B ELI N G  O F  L-C SA  
4 6  
9. 5. 2  S T O R A G E
4 7  
C CI

L- Cs A: 
Pr ot o c ol N u m b er:
S p o ns or: 
Treat me nt of B O S after S L T 
B T – L- Cs A – 3 0 1 – S L T 
Z a m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 6  of 1 0 6  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 3 0 1 – S L T 
Versi o n 5. 0 _ 2- Fe br u ar y- 2 0 2 3 
 
9. 5. 3 
 
4 7 
9. 6  S T O P PI N G R UL E S A N D D I S C O N TI N U A TI O N C RI T E RI A  
4 7  
9. 6. 1 
P A TI E N T L E V EL 
4 7 
9. 6. 2 
C E N T E R L E V EL  
4 8 
9. 6. 3 
S T U D Y L E V EL  
4 9 
9. 7  IN V E S TI G A TI O N AL M E DI CI N AL P R O D U C T : S U P PL Y A N D A C C O U N T A BILI T Y  
4 9  
1 0  S EL E C TI O N A N D WI T H D R A W AL O F P A TI E N T S 
5 0  
1 0. 1  P A TI E N T IN CL U SI O N C RI T E RI A  
5 0  
1 0. 2  P A TI E N T E X CL U SI O N C RI T E RI A  
5 1  
1 0. 3  P A TI E N T W I T H D R A W AL C RI T E RI A  
5 2  
1 0. 3. 1 
P R O C E D U R E S F O R P A TI E N T W I T H D R A W AL A N D T Y P E A N D T I MI N G O F D A T A C OLL E C TI O N  
5 2 
1 0. 3. 2 
R E PL A C E M E N T O F W I T H D R A W N P A TI E N T S  
5 3 
1 0. 3. 3 
F OLL O W -U P O F W I T H D R A W N P A TI E N T S  
5 3 
1 0. 3. 4 
C O M PL E TI O N OF C LI NI C AL T RI AL A N D L O S T T O F OLL O W -U P  
5 3 
1 1  T R E A T M E N T O F P A TI E N T S 
5 4  
1 1. 1  S T A N D A R D O F C A R E A L O N E 
5 4  
1 1. 2  L- C SA  PL U S S T A N D A R D O F C A R E  
5 4  
1 1. 3  C O N C U R R E N T T R E A T M E N T O R M E DI C A TI O N  
5 4  
1 1. 3. 1 I M M U N O S U P P R E SSI V E M E DI C A TI O N  
5 4 
1 1. 3. 2 
P R O P H YL A XI S A N D T H E R A P Y O F IN F E C TI O N S  
5 5 
1 1. 3. 3 
A ZI T H R O M Y CI N 
5 5 
1 1. 3. 4 
O T H E R M E DI C A TI O N 
5 5 
1 1. 3. 5 
  
 
 
 
 
5 5 
1 2  A S S E S S M E N T O F E FFI C A C Y 
5 7  
1 2. 1  M E T H O D S A N D T I MI N G O F E FFI C A C Y A S S E S S M E N T S A N D A N AL Y S E S  
5 7  
1 2. 1. 1 
S PI R O M E T R Y  
5 7 
1 2. 1. 2 
P R O G R E S SI O N O F B O S 
5 9 
1 2. 1. 3 
A U G M E N T A TI O N O R C H A N G E O F IM M U N O S U P P R E SSI O N  
6 0 
1 2. 1. 4 
R E -T R A N S PL A N T A TI O N 
6 0 
1 2. 1. 5 
D E A T H  
6 0 
1 2. 1. 6 
A C U T E R EJ E C TI O N A N D I T S S E V E RI T Y  
6 0 
1 2. 1. 7 
A N TI B O D Y - ME DI A T E D R EJ E C TI O N  
6 1 
1 2. 1. 8 
Q U ALI T Y O F L I F E Q U E S TI O N N AI R E ( E Q- 5 D- 5L) 
6 1 
1 2. 1. 9 
H O S PI T ALI Z A TI O NS  
6 1 
1 3  A S S E S S M E N T O F S A F E T Y 
6 2  
1 3. 1  S A F E T Y P A R A M E T E R S  
6 2  
1 3. 1. 1 
A D V E R S E E V E N T S ( A ES) 
6 2 
1 3. 1. 2 
A C U T E T OL E R A BILI T Y O F L- CSA 
6 6 
1 3. 1. 3 I N F E C TI O NS  
6 6 
1 3. 1. 4 
M ALI G N A N CI E S  
6 7 
C CI
C CI

L-CsA: 
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 7 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
 
 
 
 
13.1.5 CLINICAL LABORATORY 
67 
13.1.6 VITAL SIGNS 
69 
13.1.7 PHYSICAL EXAMINATIONS 
70 
13.2 DATA MONITORING COMMITTEE (DMC) 
70 
13.3 ADJUDICATION COMMITTEE (AC) 
70 
14 VISIT SCHEDULE 
71 
14.1 CLINICAL TRIAL FLOW CHART 
75 
14.2 VISITS 
76 
14.2.1 SCREENING 
76 
14.2.2 VISIT 1 / BASELINE VISIT 
77 
14.2.3 VISIT 2 THROUGH VISIT 9 / EOT 
78 
14.2.4 VISITS 1, 4, 6, AND 9 / EOT 
79 
14.2.5 VISIT 10 / END OF STUDY (EOS) 
79 
14.2.6 PERMANENTLY THROUGHOUT THE COMPLETE CLINICAL TRIAL PERIOD 
79 
14.2.7 UNSCHEDULED VISITS 
79 
14.2.8 REMOTE VISITS (V2-V8) 
79 
15 STATISTICS 
81 
15.1 ANALYSIS DATA SETS 
81 
15.2 STATISTICAL AND ANALYTICAL METHODS 
82 
15.2.1 DESCRIPTIVE STATISTICS 
82 
15.2.2 CHARACTERIZATION AND BASELINE COMPARABILITY OF TREATMENT GROUPS 
83 
15.2.3 ANALYSES OF EFFICACY 
83 
15.2.4 CUMULATIVE MAINTENANCE IMMUNOSUPPRESSION 
85 
15.2.5 ANALYSIS OF SAFETY 
85 
15.3 INTERIM ANALYSIS 
86 
15.4 MISSING DATA 
86 
15.5 SAMPLE SIZE CONSIDERATIONS 
86 
16 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
87 
17 QUALITY CONTROL AND QUALITY ASSURANCE 
88 
18 INSTITUTIONAL REVIEW BOARD (IRB)/ETHICS COMMITTEE (EC) 
89 
19 PATIENT INFORMED CONSENT 
90 
20 NOTIFICATION TO AUTHORITIES 
91 
21 DATA HANDLING AND RECORD KEEPING 
92 
21.1 CONFIDENTIALITY 
92 
21.2 COMPLETION OF ELECTRONIC CASE REPORT FORMS 
92 
21.3 SOURCE DATA AND PATIENT FILES 
94 
21.4 INVESTIGATOR FILE AND ARCHIVING 
94 
21.5 MONITORING, QUALITY ASSURANCE, AND INSPECTION BY AUTHORITIES 
94 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 8 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
21.6 DATA MANAGEMENT AND DATA CONTROL
95 
22 FINANCING AND INSURANCE 
96 
23 PUBLICATIONS 
97 
24 REFERENCES 
98 
25 APPENDIX I – CORE INFORMED CONSENT FORM 
100 
26 APPENDIX II – ACCEPTABLE METHODS OF CONTRACEPTION 
102 
27 APPENDIX III – ANTIBODY-MEDIATED REJECTION 
103 
28 APPENDIX IV – STUDY PROTOCOL VERSIONS HISTORY OF CHANGES 
105 
LIST OF TABLES 
Table 1. CLAD Staging of Lung Allograft Disease Following Lung Transplantation 
14 
Table 2. Basic Phenotypes of Chronic Lung Allograft Dysfunction 
14 
Table 3. Bronchiolitis obliterans syndrome (BOS) classification 
31 
Table 4. Basic Phenotypes of Chronic Lung Allograft Dysfunction 
31 
Table 5. Qualitative Composition of the IMP 
43 
Table 6. Revised Working Formulation for Classification and Grading of Pulmonary Allograft Rejection 
61 
Table 7. Terminology of renal disorders 
69 
Table 8. Definition and diagnostic certainty of clinical pulmonary AMR 
103 
Table 9. Definition and diagnostic certainty of sub-clinical pulmonary AMR 
104 
LIST OF FIGURES 
Figure 1: Freedom from bronchiolitis obliterans syndrome by diagnosis [ISHLT Registry 2017] 
29 
Figure 2: Relative incidence of leading causes of death [ISHLT Registry 2017] 
32 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 9 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
3 ABBREVIATIONS 
AC 
Adjudication Commitee 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AMR 
Antibody Mediated Rejection 
AST 
Aspartate Aminotransferase 
ATG 
Anti-Tymocyte Globulin 
ATS 
American Thoracic Society 
AZA 
Azathioprine 
BAL 
Bronchoalveolar Lavage 
BID, b.i.d. 
Bis in die, twice daily 
BO 
Bronchiolitis Obliterans 
BOS 
Bronchiolitis Obliterans Syndrome 
BDRM 
Blind Data Review Meeting 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulation 
CLAD 
Chronic Lung Allograft Dysfunction 
CMV 
Cytomegalovirus 
CNI 
Calcineurin Inhibitor 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CsA 
Cyclosporine A 
CsA-PG 
Cyclosporine A Propylene Glycol 
CRS 
Clinical Study Report 
CT 
Computed Tomography 
CTC 
Common Toxicity Criteria 
dL 
Deciliter 
DLT 
Double Lung Transplant 
DMC 
Data Monitoring Committee 

L -Cs A:  
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  1 0  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
 
 
 
D S A  
D o n or  s pecific A nti b o dies  
E B V  
E pstei n  Barr  Vir us  
E C  
Et hics  C o m mittee  
E C P  
E xtrac or p oreal  P h ot o p heresis  
e C R F 
Electr o nic  Case  Re p ort  F or m  
E o S  
E n d  of  St u d y  
E o T  
E n d  of  Treat me nt  
E Q -5 D -5 L  
E ur o  Q O L  Healt h  Q uesti o n naire  
E R S  
E ur o pea n  Res pirat or y  S ociet y  
F A S  
F ull  A nal ysis  Set  
F D A  
F o o d  a n d Dr u g  A d mi nistrati o n  
 
 
F E V 1  
F orce d  E x pirat or y  V ol u me  i n O ne  Sec o n d  
F V C  
F orce d  Vital  Ca pacit y  
G D R P  
Ge neral  Data  Pr otecti o n  Re g ulati o n  
G E R D  
Gastr o -Es o p ha geal  Refl u x  Disease  
G C P  
G o o d  Cli nical  Practice  
HI P A A  
Healt h  I ns ura nce P orta bilit y  a n d Acc o u nta bilit y  Act  
H L A  
H u ma n  Le u k oc yte  A nti ge n  
I B 
I n vesti gat or Br oc h ure  
I C H 
I nter nati o nal C o u ncil  of  Har m o nisati o n  
I C U 
I nte nsi ve Care  U nit  
I g M 
I m m u n o gl o b uli n M  
I M P 
I n vesti gati o nal Me dici nal  Pr o d uct  ( L-Cs A)  
I N D 
I n vesti gati o nal Ne w  Dr u g  
I R B 
I nstit uti o nal Re vie w  B oar d  
I S H L T 
I nter nati o nal S ociet y  of  Heart  a n d L u n g  Tra ns pla ntati o n  
I U D 
I ntra uteri ne De vice  
K g  
Kil o gra m  
L  
Liter  
C CI

L -Cs A:  
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  1 1  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
 
 
 
L A B A  
L o n g -Acti n g  Beta  A g o nist  
L A M A  
L o n g -Acti n g  M uscari nic  A nta g o nist  
L -Cs A  
Li p os o mal  C ycl os p ori ne  A  
 
 
 
L M M  
Li near  Mi xe d  M o del  
M A R  
Missi n g  At  Ra n d o m  
Me d D R A  
Me dical  Dicti o nar y  f or Re g ulat or y  Acti vities  
M g  
Milli gra m  
µ m  
Micr o meter  
Mi n  
Mi n ute  
m L  
Milliliter  
M M F  
M yc o p he n olate  M ofetil  
m T O R  
Ma m malia n  Tar get  of  Ra pa m yci n  
N  ( n) 
N u m ber  
N g  
Na n o gra m  
N O A E L  
N o  O bser va ble  A d verse  Effect  Le vel  
O B  
O bliterati ve  Br o nc hi olitis  
P G  
Pr o p yle ne  Gl yc ol  
PI  
Pri nci pal  I n vesti gat or 
P h E ur  
E ur o pea n  P har mac o peia  
P K  
P har mac o ki netics  
P P S  
Per  Pr ot oc ol  Set  
Q  
Q uartile  
R A S  
Restricti ve  All o graft  S y n dr o me  
S A E  
Seri o us  A d verse  E ve nt  
S A P  
Statistical  A nal ysis  Pla n  
S A S  
Statistical  A nal ysis  S oft ware  
 
 
S L T  
Si n gle  L u n g  Tra ns pla nt  
S m P C  
S u m mar y  of  Pr o d uct  C haracteristics  
C CI
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 12 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
SOC 
Standard of Care 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAC 
Tacrolimus 
TDT 
Triple Drug Therapy 
TEAE 
Treatment-Emergent Adverse Event 
USA 
United States of America 
USP 
United States Pharmacopeia 
WHO-DD 
World Health Organization Drug Dictionary 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 13 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
4 PROTOCOL-SPECIFIC DEFINITIONS 
Acute Rejection: Acute rejections are classified according to the revised working formulation for 
classification and grading of pulmonary allograft rejection and will be assessed at any time of 
occurrence throughout the clinical trial period. 
Antibody Mediated Rejection: Diagnosis of antibody mediated rejection is performed 
according to the International Society of Heart and Lung Transplantation (ISHLT) consensus 
guidelines and assessed at any time of occurrence throughout the clinical trial period. In this 
context, clinically stable patients displaying low and stable levels of Donor Specific Antibodies 
at Screening (as judged by the Investigator) are eligible for the study. 
BOS diagnosis: The Investigator will have used the site’s clinical spirometer to determine that 
the patient has clinically defined BOS (CLAD – BOS phenotype) (for definitions, please see 
below) before referring patients to the study. In this context, FEV1 values are defined as follows: 
•
Personal Best FEV1: The highest FEV1 value following transplant surgery - this can
be derived from one single spirometry session or the mean of two best FEV1 values
derived from two spirometry sessions (as per the usual practice by the site; see also
Meyer 2014).
•
FEV1 confirming diagnosis of BOS: The FEV1 value used by the clinician to
confirm the diagnosis of BOS - this can be derived from one single spirometry session
or the mean of two best FEV1 values derived from two spirometry sessions (as per the
usual practice by the site; see also Meyer 2014).
Baseline FEV1: For the purpose of this study, the FEV1 value that is the mean of the best FEV1 
obtained with the provided study spirometer at the Screening Visit and the best FEV1 obtained at 
the Baseline (randomization) Visit is referred to as “baseline FEV1”. 
CLAD (BOS and RAS phenotypes): Following the ISHLT 2019 recommendations (Verleden et 
al., 2019) for the definition of lung allograft disease following lung transplantation, sufficient 
diagnostic proof using – amongst others – spirometry, body plethysmography, and/or CT scans 
should be available to confirm the diagnosis of CLAD and differentiate subtypes (see also Table 
1 and Table 2). 
For the purpose of this protocol, patients with RAS phenotypes are to be excluded applying the 
definitions in the consensus report issued by the ISHLT 2019 (Glanville et al., 2019). In particular, 
persisting parenchymal opacities on historical High Resolution CT scan or Chest X-Ray should be 
considered as an important diagnostic feature of CLAD - RAS phenotype. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 14 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
Table 1. CLAD Staging of Lung Allograft Disease Following Lung Transplantation 
CLAD Stage (2019) 
Spirometric criteria 
BOS Grade (2002) 
CLAD 0 
FEV1 > 90% of personal best 
0 
CLAD 0 
FEV1 81-90% of personal best 
0-p
CLAD 1 
FEV1 66-80% of personal best 
1 
CLAD 2 
FEV1 51-65% of personal best 
2 
CLAD 3 
FEV1 35-50% of personal best 
3 
CLAD 4 
FEV1 < 35% of personal best 
3 
Table 2. Basic Phenotypes of Chronic Lung Allograft Dysfunction 
Obstruction 
(FEV1/FVC < 0.7) 
Restriction 
(TLC decline ≥ 10% 
from baseline) 
CT opacities 
BOS 
YES 
NO 
NO 
RAS 
NO 
YES 
YES 
Mixed 
YES 
YES 
YES 
Undefined 
YES 
YES 
NO 
YES 
YES 
NO 
For example, the diagnosis and staging according to these recent recommendations would read 
“CLAD Stage 2, BOS phenotype” for a diagnosis which would have been entitled “BOS Grade 2” 
following previous recommendations (Glanville 2019). 

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  1 5  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
5  P R O T O C O L  S Y N O P SI S  
Pr ot oc ol  Title:  
A P hase III, Pr os pecti ve, 
M ultice nter, Ra n d o mize d, C o ntr olle d 
Cli nical Trial t o De m o nstrate  t he Efficac y a n d Safet y of Li p os o mal 
C ycl os p ori ne A ( L -Cs A) I n halati o n S ol uti o n Deli vere d via t he 
 
 pl us Sta n dar d of Care vers us 
Sta n dar d  of Care  Al o ne i n t he  Treat me nt  of  C hr o nic  L u n g  All o graft 
D ysf u ncti o n / Br o nc hi olitis O blitera ns S y n dr o me i n Patie nts p ost 
Si n gle L u n g Tra ns pla ntati o n  
S p o ns or:  
Za m b o n  S p A  
Via  Lill o  del  D uca,  1 0 
Bress o ( MI) 2 0 0 9 1  
Ital y 
Pr ot oc ol  N u m ber:  
B T – L -Cs A – 3 0 1 – S L T  ( B O S T O N-1)  
I N D N u m ber:  
7 8, 8 5 4  
E U D R A C T  N u m ber:  
2 0 1 8 -0 0 3 2 0 4 -3 9  
N C T  N u m ber:  
N C T 0 3 6 5 7 3 4 2  
I n vesti g ati o n al 
Me dici n al  Pr o d uct:  
Li p os o mal  C ycl os p ori ne  A  ( L-Cs A)  I n halati o n S ol uti o n  
Pr ot oc ol  P h ase:  
P hase  III 
Pr ot oc ol  D ate:  
Versi o n  5. 0;  2  Fe br uar y  2 0 2 3  
Pr ot oc ol  A me n d me nt:  
4  
Cli nic al Tri al 
Ce nters/ C o u ntries:  
A p pr o xi matel y  4 3  ce nters W orl d wi de.  
Pl a n ne d  Cli nic al  Tri al 
Peri o d:  
D urati o n of t hera p y:  
 4 8 wee ks  
T otal cli nical trial d urati o n per patie nt:  
u p  t o 5 6  wee ks  
Pl a n ne d  N u m ber  of 
P atie nts:  
T he cli nical trial pla ns t o st o p ra n d o mizati o n u p o n ac hie ve me nt of  
a t otal of a p pr o xi matel y 2 2 0 patie nts 
wit h cli nicall y defi ne d 
br o nc hi olitis o blitera ns s y n dr o me ( B O S) c o nsi deri n g t he prese nt 
( B O S T O N-1)  a n d t he B T  –  L -Cs A  –  3 0 2  –  D L T  ( B O S T O N-2)  
st u dies c o m bi ne d. 
Patie nts  will  be ra n d o mize d  1: 1  as f oll o ws: 
Tre at me nt  Ar m  A  (i nvesti g ati o n al tre at me nt ar m):  
L -Cs A  i n halati o n t hera p y ( 5 m g bi d)  pl us  Sta n dar d  of  Care  ( S o C).
Tre at me nt  Ar m  B  (c o ntr ol tre at me nt ar m):  
S o C  al o ne. 
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  1 6  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
O bjecti ve:  
T he o bjecti ve of t he trial is t o assess t he efficac y a n d safet y of L - 
Cs A pl us S o C i n t he treat me nt of B O S i n si n gle l u n g tra ns pla nt 
( S L T) reci pie nts. 
Cli nic al  Tri al  Desi g n:  
T his  is a P hase  III, pr os pecti ve,  m ultice nter,  ra n d o mize d, c o ntr olle d 
cli nical tr ial of L-Cs A f or t he treat me nt of br o nc hi olitis o blitera ns 
s y n dr o me i n a d ults dia g n ose d wit h B O S f oll o wi n g si n gle l u n g 
tra ns pla nt. 
Patie nts 
will recei ve 
eit her 
L -Cs A ( 5 m g) 
via t he  
 
 t wice dail y  pl us  S o C 
treat me nt or S o C al o ne, f or a peri o d of 4 8 wee ks.  
All patie nts will be eli gi ble t o c o nti n ue i n a n o pe n -la bel e xte nsi o n 
trial of L-Cs A f oll o wi n g c o m pleti o n of B O S T O N -1.  
Str atific ati o n  
T o ass ure bala nce bet wee n treat me nt ar ms wit h re gar d t o s o me ke y 
varia bles 
a n d 
p ote ntial 
c o nf o u n ders, stratificati o n 
pri or t o 
ra n d o mizati o n will be perf or me d f or t he f oll o wi n g varia bles: 
•
Scree ni n g F E V 1  ≥8 1 % of pers o nal best F E V 1  val ue p ost - 
tra ns pla nt versus Scree ni n g F E V 1  bet wee n 8 0 -5 1 % of
pers o nal best F E V 1  val ue p ost -tra ns pla nt
•
U n derl yi n g i n dicati o n f or l u n g tra ns pla nt: C O P D vers us all
ot her u n derl yi n g diseases
•
Re gi o n:  N ort h  A merica  vers us  all ot her  c o u ntries t o get her
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 17 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
Eligibility 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:
a) Screening FEV1 between 85-51% of personal best
FEV1 value post-transplant
OR 
b) 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
a) within 12 months prior to the screening visit
OR 
b)
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

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 18 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
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.

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 19 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
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 (including CPAP) 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.

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  2 0  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
1 7.
Ps yc hiatric dis or ders or altere d 
me ntal stat us precl u di n g
u n dersta n di n g 
of t he i nf or me d 
c o nse nt 
pr ocess 
a n d/ or
c o m pleti o n of t he necessar y pr oce d ures.
1 8.
A n y c o -e xisti n g me dical c o n diti o n t hat i n t he I n vesti gat or’s
j u d g me nt will s u bsta ntiall y i ncrease t he ris k ass ociate d  wit h t he
patie nt’s  partici pati o n  i n t he cli nical  trial.
I n vesti g ati o n al 
Me dic al  Pr o d uct:  
T he L -Cs A l y o p hilizate is s u p plie d i n  
 c o ntai ni n g 5 m g of 
pr o d uct. T he l y o p hilizate is rec o nstit ute d wit h 1. 2 m L 0. 2 5 % Na Cl 
t o o btai n a rea d y t o use dis persi o n f or i n halati o n usi n g t he 
 
 
M o de of 
A d mi nistr ati o n/  
D osi n g  Sc he d ule:  
T he  i n vesti gati o nal me dici nal  pr o d uct  (I M P) will be  a d mi nistere d  b y 
t wice 
. At e ver y visit,  
 
 
. T he patie nt m ust re mai n in t he cli nic f or at least 2 
h o urs 
f or 
o bser vati o n 
after 
t he 
first 
i n halati o n.  
 
 s yste m Pr o vi des t he i n vesti gat ors wit h 
f urt her i nf or mati o n o n t he i n halti o ns perf or me d b y t he patie nt. 
Ne b ulizati o n ti me per i n halati o n d ose is a p pr o xi matel y 
 
mi n utes. I n halati o n will be perf or me d t wice dail y, a p pr o xi matel y 1 2 
h o urs  a part  t hr o u g h a m o ut h piece  b y  sl o w a n d dee p  res pirati o n usi n g 
t he L-Cs A  
. A hi g h efficie nc y partic ulate air filter is use d t o 
e ns ure a bse nce of e n vir o n me ntal c o nta mi nati o n.  
C CI
C CI
C CI
C CI
C CI
C CI
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 21 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
Treatment Regimen: 
Basic Immunosuppression: 
Regardless of treatment allocation, all participants will continue to 
receive their Standard of Care (SoC) regimen for maintenance of the 
lung allograft. 
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. See Section 11.3 for additional 
information regarding use of concurrent medications or treatments 
prior to and during clinical trial participation. The regimen must be 
stable within 4 weeks prior to randomization with respect to the 
therapeutic agents. Patients will be randomized to one of the 
following treatment groups: 
Patients will be randomized to one of the following treatment 
groups: 
Group A (L-CsA treatment plus SoC Therapy): 
•
L-CsA 5 mg/1.25 mL twice daily for 48 weeks
Plus
•
Standard of Care Therapy
Group B (Standard of Care alone): 
•
Standard of Care Therapy

L- Cs A: 
Pr ot o c ol N u m b er: 
S p o ns or: 
Treat me nt of B O S after S L T 
B T – L- Cs A – 3 0 1 – S L T 
Z a m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Pa g e 2 2  of 1 0 6  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 3 0 1 – S L T 
Versi o n 5. 0 _ 2- Fe br u ar y- 2 0 2 3 
 
E n d p oi nts: 
Pri m ary E n d p oi nt: 
Mea n c ha n g e i n F E V
1 ( m L) fr o m baseli n e t o Wee k 4 8.   
 
 
 
 
 
 
 
    
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S afety: 
 A d verse e ve nts (i n cl u di n g i nfecti o ns a n d mali g na ncies) 
 Ac ute t olera bilit y of I M P  
 Cli nical la b orat or y p ar a meters 
 Re nal F u n cti o n 
 Vital si g ns 
 P h ysi cal e xa mi nati o ns 
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  2 3  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
Cli nic al  Tri al  Pl a n:  
A t otal of 1 1 visits ( Scree ni n g, V 1 t hr o u g h V 1 0) will be perf or me d 
d uri n g t he cli nical trial.  
After i nf or me d c o nse nt has bee n o btai ne d, a Scree ni n g Visit will be 
carrie d o ut i n or der t o c hec k ge neral eli gi bilit y f or partici pati o n.  
At t he Baseli ne Visit ( V 1, ra n d o mizati o n visit), i ncl usi o n a n d 
e xcl usi o n criteria fr o m scree ni n g visit 
will be verifie d  a n d 
pr oce d ures as per Sc he d ule of Acti vities will be perf or me d.  
D uri n g t he 4 8 -wee k treat me nt peri o d, visits are sc he d ule d e ver y 4 -8 
wee ks ( V 2 –  9).  
Visit 1 0 will be a f oll o w -u p visit u nless t he patie nt is e nr olle d i nt o 
t he e xte nsi o n st u d y, i n w hic h case visit 1 0 will n ot be c o m plete d. 
E ver y  eff ort  will be ma de  t o ha ve all pla n ne d a n d u nsc he d ule d  visits 
at t he st u d y site. Ma n dat or y o n site visits are Scree ni n g, Visit 1 a n d 
Visit 9.  
H o we ver, if o ne of t he visits fr o m Visit 2 t o Visit 8 ca n n ot be 
perf or me d at site d ue t o  C O VI D -1 9 re m ote  visits (e. g. b y tele p h o ne) 
are p ossi ble. 
Assess me nt  of 
Effic ac y:  
Assess me nts:  
S pir o metr y ( F E V 1, 
, a n d F V C) will be meas ured at all visits 
usi n g t he pr o vi de d st u d y o n -site s pir o meter 
 
 
 
) acc or di n g t o A T S/ E R S 2 0 0 5 g ui deli nes. 
S pir o metr y meas ure me nts o n site will be perf or me d b y a re gistere d 
res pirat or y t hera pist or certifie d p ul m o nar y f u ncti o n tec h nicia n w h o 
is bli n d t o t he patie nt’s treat me nt assi g n me nt. S pir o metr y data will 
be re vie we d b y a bli n de d ce ntral rea der, as descri be d i n t he 
 site ma n ual. 
P orta ble s pir o meters (
) will als o be i ntr o d uce d 
at scree ni n g f or all patie nts  ne wl y  e nr ole d  u n der  pr ot oc ol  versi o n  3. 0 
or  later. I n a d diti o n  t o t he S pir o metr y perf or me d  o n  t he 
 
all patie nts  will  perf or m  s pir o metr y usi n g  t he 
 at e ver y 
o n -site st u d y visit (i ncl u di n g Scree ni n g visit, Visit 1 a n d Visit 9) . If 
patie nts ca n n ot atte n d visits o n site d ue t o C O VI D -1 9, re m ote visits 
wit h g ui de d h o me s pir o metr y will be perf or me d ( F E V 1, 
, 
a n d F V C) usi n g t he 
. 
F or t he deter mi nati o n of eli gi bilit y at Scree ni n g, o nl y s pir o metr y 
data o btai ne d wi t h t he st u d y  
 s pir o meter will be use d. 
F or t he e val uati o n of B O S pr o gressi o n d uri n g t he cli nical trial 
peri o d, a decli ne of F E V 1  of ≥ 1 0 %  or  2 0 0 m L fr o m baseli ne a n d 
a bs ol ute  decrease  i n F E V 1/ F V C of  >  5 %  m ust  be  c o nfir me d  b y  
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  2 4  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
meas ure me nts ta ke n wit h  
 s pir o meter at least 2 wee ks 
a part. 
C ha n ges t o sta n dar d of care are all o we d at t he i n vesti gat or’s 
discreti o n 
(e. g., 
c ha n ges i n 
d oses 
of i m m u n os u p pressi o n, 
azit hr o m yci n,  
A T G,  
P h ot o p heresis, 
le u k otrie ne  
rece pt or 
a nta g o nists, c yt ostatics, irra diati o n t hera p y).  All c ha n ges t o S o C 
m ust be rec or de d i n t he electr o nic case re p ort f or m (e C R F).  
All me dicall y i n dicate d pr oce d ures perf or me d d uri n g t he c o urse of 
t he cli nical trial will be d oc u me nte d i n the e C R Fs.  
F or assess me nt of patie nt s ur vi val, o verall m ortalit y, B O S -relate d 
m ortalit y a n d n o n -B O S -relate d m ortalit y will be ta ke n i nt o acc o u nt 
at a n y ti me t hr o u g h o ut t he cli nical trial peri o d.  
C u m ulati ve 
d ose 
of i m m u n os u p pressa nts 
will 
be 
assesse d  
t hr o u g ho ut t he 
St u d y f or tacr oli m us, 
M M F/e q ui vale nt, 
a n d 
c ortic oster oi ds. 
Q ualit y of Life will be assesse d at Visits 1, 4, 6, a n d 9/ E n d of 
Treat me nt ( E o T) w he n patie nts ha ve t o c o m plete t he E Q -5 D -5 L 
Q uesti o n naire. A bs ol ute a n d relati ve c ha n ge fr o m baseli ne will b e 
calc ulate d. 
H os pitalizati o n will be assesse d f or o verall n u m ber of da ys, da ys o n 
re g ular war d, da ys i n I C U, a n d da ys i n I C U o n ve ntilati o n. 
Assess me nt  of  S afet y:  
Safet y Assess me nts at e ver y visit i ncl u de: p h ysical e xa mi nati o n, 
vital si g ns, a d verse e ve nt re p orti n g, a n d cli nical la b orat or y tests 
perf or me d i n t he l ocal la bs at eac h cli nical trial site.  
Ac ute t olera bilit y of I M P will be assesse d b y meas uri n g s pir o metr y  
bef ore a n d 
 
. 
C CI
C CI

L-CsA: 
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 25 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
 
 
 
 
 
Data Monitoring 
Committee: 
An independent Data Monitoring Committee (DMC) will be 
established to monitor the safety of Investigational Medicinal 
Product (IMP) throughout the clinical trial. The DMC will monitor 
safety by evaluating the safety analyses generated by the ublinded 
statistician during the course of the clinical trial. Details of the safety 
analyses will be included in the DMC’s Charter. 
The DMC will evaluate treatment groups for possible trends in 
adverse events, determine whether the basic protocol assumptions 
remain valid, evaluate whether the overall integrity, scientific merit 
and conduct of the clinical trial remain acceptable, and make 
recommendations to the Sponsor. 
The DMC will also perform comparisons between the rate of 
observed COVID-19 cases, rate of patients withdrawal, and rate of 
missing data among trial participants in both treatment arms. 
Adjudication 
Committee: 
An independent, blinded Adjudication Committee (AC) will be 
established to assess all events that meet the progression of BOS 
criteria in every patient. Details of the event review will be included 
in the AC’s Charter. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 26 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
Sample size 
The original sample size of 110 patients (55 in each treatment 
group) was based on the assumption of a treatment group 
difference for FEV1 change from baseline of 200 mL, a standard 
deviation of 350 mL at the end of treatment Week 48, and a drop- 
out rate of approximately 10%. Based on these assumptions, the 
planned sample size would have had a power of approximately 
80% using an independent samples t-test with a one-sided type I 
error level of =0.025. However, due to serious enrolment 
problems experienced in this study, randomization will be 
stopped when a total of approximately 220 patients with clinically 
defined bronchiolitis obliterans syndrome (BOS) considering the 
present (BOSTON-1) and the BT – L-CsA – 302 – DLT 
(BOSTON-2) studies combined is reached in order to obtain an 
adequately sized safety database for L-CsA inhalation, and it is 
anticipated that much fewer than 110 patients (i.e., approximately 
50-60 patients) will be enrolled in the present study.

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  2 7  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
St atistic al 
C o nsi der ati o ns:  
D ue t o seri o us e nr ol me nt pr o ble ms (see Sa m ple size), it is e x pecte d 
t o cl ose t his st u d y wit h fe wer t ha n 1 1 0 patie nts ori gi nall y pla n ne d 
a n d c o nse q ue ntl y t he st u d y will be u n der p o were d f or t he ass u me d 
effect.. T heref ore, all pla n ne d a nal yses will be perf or me d a n d t he 
i m pact of t he re d uce d sa m ple will be c o nsi dere d.. F or t he sa me 
reas o n, t he pre-pla n ne d bli n de d i nteri m a nal ysis f or sa m ple size re - 
esti mati o n will n ot be perf o r me d. T he Statistical A nal ysis Pla n 
( S A P) will pr o vi de a detaile d descri pti o n of t he statistical a nal yses. 
F E V 1  data c ollecte d fr o m t he 
 s pir o meter 
will be 
c o nsi dere d pri mar y, w hile t he data c ollecte d wit h t he  
 h o me 
s pir o meter will be use d for s u p p orti ve a nal yses.  
T he pri mar y esti ma n d t o be assesse d will be t he bet wee n -treat me nt- 
gr o u p differe nce  i n mea n a bs ol ute c ha n ge i n F E V 1  bet wee n baseli ne 
a n d t he e n d of Wee k 4 8, assesse d i n t he patie nt p o p ulati o n defi ne d 
b y t he i ncl usi o n a n d e xcl usi o n c riteria, re gar dless of w het her or n ot 
starti n g a d diti o nal  i m m u n os u p pressi ve me dicati o n  or  st o p pi n g of  t he 
i n vesti gati o nal treat me nt ha d occ urre d ( Treat me nt P olic y Strate g y, 
efficac y). Testi n g will be perf or me d o n t he f ull a nal ysis set ( F A S) 
w hic h will i ncl u de all ra n d o mize d patie nts w h o ha ve at least o ne 
p ost -baseli ne assess me nt of t he pri mar y o utc o me meas ure.  
All a vaila ble  F E V 1  meas ure me nts  will  be  e ntere d  i nt o a li near mi xe d 
m o del ( L M M), 
wit h c ha n ge i n F E V 1  bet wee n baseli ne a n d 
s u bse q ue nt visits as t he de pe n de nt varia ble, ra n d o mize d treat me nt, 
ti me, re gi o n ( N ort h A merica vers us all ot her c o u ntries t o get her),  
a n d u n derl yi n g i n dicati o n f or tra ns pla nt ( C O P D vers us all ot hers) as 
t he i n de pe n de nt fact ors, a n d wit h baseli ne F E V1  a n d az it hr o m yci n 
use at ra n d o mizati o n as c o variates. M ore o ver, t he treat me nt b y ti me 
i nteracti o n a n d t he baseli ne F E V1  b y ti me i nteracti o n 
will be 
i ncl u de d i nt o t he m o del. D ue t o t he re d uce d sa m ple size, t he 
c o variates will be selecte d ta ki n g i nt o acc o u nt m o del c o n ver ge nce  
Se veral se nsiti vit y a nal yses were pla n ne d i n t he ori gi nal pr ot oc ol. 
D ue t o t he re d uce d sa m ple size, t he val ue of t hese se nsiti vit y 
a nal yses is re d uce d a n d s o me of t he m mi g ht n ot be a p plica ble.  
Se nsiti vit y a nal yses will be perf or me d i n t he per -pr ot oc ol a nal ysis 
set as well as usi n g a n alter nati ve esti ma n d acc or di n g t o w hic h 
o utc o me  meas ure me nts  will  o nl y  be  use d  f or t he peri o d  d uri n g  w hic h 
patie nts were  o n  ra n d o mize d treat me nt (i. e., pri or  t o t he i nitiati o n of 
a d diti o nal i m m u n os u p pressi ve t hera p y or L -Cs A disc o nti n uati o n; 
W hile -o n -Treat me nt 
strate g y, 
efficac y). 
M ore o ver, 
se nsiti vit y 
a nal yses  will  als o  be  perf or me d  t o assess  t he vali dit y  of  t he Missi n g- 
at-Ra n d o m ass u m pti o n f or t he L M M.  
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  2 8  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
T he o ver -all t y pe I err or rate of t he cli nical trial will be  = 0. 0 2 5 
o ne -si de d, c orres p o n di n g t o  = 0. 0 5 t w o -si de d. T he a-pri ori 
or deri n g of h y p ot heses f or pri mar y 
 e n d p oints, w hic h 
was  ori gi nall y pla n ne d t o kee p  t he st u d y-wise t y pe I err or  rate u n der 
c o ntr ol, will be mai ntai ne d o nl y f or t he ti me t o pr o gressi o n of B O S, 
b ut t he hierarc h y will be c o nsi dere d o nl y wit hi n t he B T –  L -Cs A –  
3 0 2 –  D L T st u d y.  
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 29 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
6 INTRODUCTION 
6.1 Bronchiolitis Obliterans and Bronchiolitis Obliterans Syndrome 
Lung transplantation is the ultimate treatment option for patients with advanced lung disease or 
irreversible pulmonary failure. Although refinements and advancements in surgical techniques, 
lung preservation, immunosuppressive regimen, management of ischemia/reperfusion injury and 
infections, as well as post-transplant patient care have resulted in improved outcomes, acute and 
chronic pulmonary allograft rejection continues to be the major obstacle for satisfactory long-term 
results. Acute rejection after lung transplantation exceeds the incidence and severity compared 
with other solid organ transplantations. Chronic rejection, commonly denoted bronchiolitis 
obliterans (BO), obliterative bronchiolitis (OB), or bronchiolitis obliterans syndrome (BOS), is the 
leading cause of death beyond the first-year after lung transplantation. Whereas the development 
of BOS is rare within the first year after lung transplantation, annual increments of approximately 
10% are recorded in subsequent years, resulting in a cumulative incidence range of 40-50% within 
the first five years and 70-80% within 10 years of transplantation (Figure 1; [ISHLT Registry 
2017]). 
Figure 1: Freedom from bronchiolitis obliterans syndrome by diagnosis [ISHLT Registry 
2017] 
Adult Lung Transplants 
Freedom from Bronchiolitis Obliterans Syndrome 
by Diagnosis Conditional on Survival to 14 days 
(Transplants: January 1994 – June 2015) 
100 
A1ATD (N=1,051) 
CF (N=3,027) 
COPD (N=7,131) 
IIP (N=6,684) 
75 
ILD-not IIP (N=1,079) 
Retransplant (N=778) 
50 
25 
0 
No pair-wise comparisons were significant 
at p < 0.05 except all comparisons with 
Retransplant and CF vs. COPD 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Years 
10 
11 
12 
13 
14 
15 
16 
2017 
JHLT. 2017 Oct; 36(10): 1037-1079 
Freedom from Bronchiolitis 
Obliterans Syndrome (%) 

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  3 0  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
T he mai n hist ol o gic hall mar k of B O is scarri n g wit h fi br osis of t he air wa y. H o we ver, t his pr ocess 
is patc h y, ma ki n g t he se nsiti vit y of tra ns br o nc hial bi o ps y f or detecti o n of B O hi g hl y de pe n de nt o n 
a de q uac y  of sa m pli n g  a n d s kill of hist ol o gic  i nter pretati o n. T her ef ore,  t he cli nical ma nifestati o n 
of B O, t he br o nc hi olitis o blitera ns s y n dr o me ( B O S), is defi ne d as irre versi ble air wa y o bstr ucti o n, 
dia g n ose d b y p ul m o nar y f u ncti o n, i n t he a bse nce of ot her ca uses. T his dia g n osis d oes n ot re q uire 
hist ol o gic  c o nfir mati o n  b ut  is c o nsi dere d  a relia ble s urr o gate p h ysi ol o gic  mar ke r of t he  prese nce 
of B O.  
I n its m ost  c o m m o n pre se ntati o n, B O  is characterize d  b y t he  pat h o p h ysi ol o gical  feat ures of 
res pirat or y o bstr ucti o n. T he maj or fi n di n gs o n s pir o metr y are a re d uce d f orce d e x pirat or y v ol u me 
i n 1 sec o n d  ( F E V1), a n or m al, or sli g htl y  de crease d f orce d vital  ca pacit y  ( F V C), a n d a re d uce d 
rati o of F E V 1  t o F V C,  wit h  p o or  resp o nse  t o i n hale d br o nc h o dilat ors.  L u n g  v ol u mes  i n dicate air 
tra p pi n g, wit h a n or mal t otal l u n g ca pacit y a n d hi g h resi d ual v ol u me. H o we ver, a s u bset of  patie nts 
prese nt  wit h  a restricti ve patter n c haracterize d b y a  l o w F V C  a n d a n or mal  F E V 1/ F V C rati o, or a 
m i xe d patter n  of o bstr ucti o n  an d  restricti o n  [Bar ker  2 0 1 4 ]. B O S is ofte n a  dia g n osis  of e xcl usi o n 
a n d ot her  ca uses of all o graft  d ysf u nc ti o n, i ncl u di n g restricti ve all o graft  s y n dr o me ( R A S), ac ute 
rejecti o n, a n d ac ute i nfecti o n, nee d t o be e xcl u de d bef ore t he dia g n osis of B O S is ma de ( Gla n ville 
2 0 1 9 ). 
T he 2 0 0 2 B O S gra di n g s yste m f or Gra des 0 t hr o u g h 3, ( Ta ble 3 ), w hic h is base d s olel y o n F E V1  
an d/ or  
), is a use f ul s urr o gate mar ker  f or B O:  it is eas y t o 
meas ure  b y sta n dar dize d  s pir o metr y a n d is re pr o d uci ble; it bec o mes  a b n or mal  pri or  to  hist ol o gic 
c o nfir mati o n [C hac o n 2 0 0 0 ]; a n d it dis pla ys hi g h se nsiti vit y a n d s pecificit y w he n assesse d a gai nst 
bi o ps y-  a n d a ut o ps y-c o nfir me d  B O  [He n g  1 9 9 8 ]. I n t he f oll o wi n g Ta bles,  “ baseli ne” is defi ne d 
as t he patie nt’s pers o nal best F E V 1  f oll o wi n g tra ns pla nt. 
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  3 1  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
T a ble  3.  Br o nc hi olitis  o bliter a ns  s y n dr o me ( B O S) cl assific ati o n 
Ori gi n al  cl assific ati o n 
( 1 9 9 3) 
2 0 0 2  Cl assific ati o n  
2 0 1 9  I S H L T Cl assific ati o n  
B O S  0 
F E V 1  > 9 0 % of baseli ne a n d 
 > 7 5 % of baseli n e  
B O S  0 
F E V 1  8 0 % or m ore 
of baseli n e  
B O S  0 -p 
F E V 1  8 1 %  t o 9 0 %  of  
baseli n e  a n d/ or 
 ≤ 7 5 %  of  baseli ne  
C L A D  0  
F E V 1  >  8 0 %  of  
baseli ne  
B O S  1 
F E V 1  6 6 %  t o 8 0 %  
of  baseli ne  
B O S  1 
F E V 1  6 6 %  t o 8 0 %  of  
baseli ne  
C L A D  1  
F E V 1  6 6 -8 0 %  of 
baseli ne  
B O S  2 
F E V 1  5 1 %  t o 6 5 %  
of  baseli ne  
B O S  2 
F E V 1  5 1 %  t o 6 5 %  of  
baseli ne  
C L A D  2  
F E V 1  5 1 -6 5 %  of  
baseli ne  
B O S  3 
F E V 1  5 0 % or  less 
of baseli n e  
B O S  3 
F E V 1  5 0 % or less  of 
baseli ne  
C L A D  3  
F E V 1  3 5 -5 0 %  of  
baseli ne  
C L A D  4 
F E V 1  <  3 5 %  of  
baseli ne  
B O S: br o nc hi olitis o blitera ns s y n dr o me; 
; F E V1: f orce d e x pirat or y v ol u me i n 1 
sec o n d [Este n ne 2 0 0 2 ]. C L A D:  c hr o nic l u n g all o graft d ysf u ncti o n.  
T a ble  4.  B asic  P he n ot y pes  of  C hr o nic  L u n g  All o gr aft  D ysf u ncti o n  
O bstr ucti o n 
F E V 1/ F V C <  0. 7)  
Restricti o n  
( T L C decli ne   1 0 % 
fr o m b aseli ne) 
C T  o p acities  
B O S  
Yes  
N o  
N o  
R A S  
N o  
Yes  
Yes  
Mi xe d  
Yes  
Yes  
Yes  
U n defi ne d  
Yes  
Yes  
N o  
Yes  
Yes  
N o  
B O S re prese nts t he maj or deter mi na nt of l o n g -ter m graft a n d patie nt s ur vi val. T o re d uce t he rate 
of rejecti o n (ac ute as well as c hr o nic f or ms), i m m u n os u p pressi ve re gi me ns are e m pl o ye d. 
Alt h o u g h t he i m m u n os u p pressi ve pr ot oc ols var y fr o m ce nter t o ce nter, c o n ve nti o nal mai nte na nce 
t hera p y c o nsists pri nci pall y of tri ple dr u g t hera p y c o m prisi n g a calci ne uri n i n hi bit or (c ycl os p ori ne 
A [ Cs A] or tacr oli m us [ T A C]), a n a nti pr oliferati ve a ge nt ( m yc o p he n olate 
m ofetil [ M M F], 
azat hi o pri ne [ A Z A], sir oli m us, or e ver oli m us) , a n d c ortic oster oi ds. Hist oricall y, Cs A a n d A Z A 
were use d al o n g wit h pre d nis o ne, b ut a d diti o nal a ge nts ha ve bec o me a vaila ble, i ncl u di n g 
tacr oli m us, m yc o p he n olate,  a n d Ma m malia n  Tar get  of  Ra pa m yci n  ( m T O R) i n hi bit ors li ke 
C CI
C CI
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 32 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
sirolimus and everolimus. Often when BOS is diagnosed in a lung transplant recipient, 
immunosuppression is augmented but no augmentation therapy has been demonstrated to impact 
BO reliably. Additional systemic immunosuppression comes with the added burden of additional 
end-organ toxicity and tolerability issues. Development of BOS is the major confounding factor 
of long-term successful outcome. BOS is reported as the main cause of death beyond the first post- 
transplant year over the last three decades (Figure 2; [ISHLT Registry 2017]). 
Figure 2: Relative incidence of leading causes of death [ISHLT Registry 2017] 
Bronchiolitis obliterans as a disease has been recognized for many decades. However, the need 
for better treatment options for BOS increased dramatically in the 1990s when lung transplantation 
became a more acceptable treatment for lung failure, but was also limited by BO as a late-term 
sequelae. A better understanding of the pathology of the disease as well as the limitations of high- 
dose systemic immunosuppression, due to their toxic effects, has led to the idea of administering 
higher doses of drug via alternative routes. BO is uniquely suited to this potential approach as a T- 
cell mediated disease of the airways of the lungs. 
The first studies of an inhaled immunosuppressive for BOS associated with lung transplantation 
were done using cyclosporine in a formulation that contained propylene glycol, CsA-propylene 
Adult Lung Transplants 
Relative Incidence of Leading Causes of Death 
(Deaths: January 1990 – June 2016) 
50 
OB/BOS 
Malignancy (non-Lymphoma/PTLD) 
Cardiovascular 
Graft Failure 
Infection (non-CMV) 
40 
30 
20 
10 
0 
0-30 Days 
(N=3,574)
31 Days - 1 Year 
>1 Year - 3 
>3 Years - 5 
>5 Years - 10 
(N=6,367) 
Years (N=6,194) Years (N=3,656) Years (N=4,578) 
>10 Years
(N=1,837)
2017 
JHLT. 2017 Oct; 36(10): 1037-1079 
% of Deaths 

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  3 3  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
gl yc ol  ( Cs A- P G). I n t hese st u dies, Cs A- P G  s h o we d p o or t olera bilit y  d ue  t o t he h y per os m olalit y 
of t he P G f or m ulati o n a n d its pr o pe nsit y t o ca use air wa y i nfla m mati o n. H o we ver, efficac y res ults 
fr o m cli nical trials e val uati n g pre ve nti o n of B O S were pr o misi n g [Iac o n o 1 9 9 6; Iac o n o 2 0 0 6]. 
Wit h  t he g oal  of i ncreasi n g  t olera bilit y as well  as i m pr o vi n g air wa y de p ositi o n,  a lip os o mal 
f or m ulati o n of Cs A ( L- Cs A) was de vel o pe d. L- Cs A als o was f or m ulate d s pecificall y f or use wit h 
t he 
 f or o pti mal aer os ol d y na mics. 
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  3 4  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
7  B A C K G R O U N D  I N F O R M A TI O N 
7. 1  I n v e sti g ati o n al M e di ci n al  P r o d u ct  
T he I n vesti gati o nal 
Me dici nal Pr o d uct is a dr u g/ de vice c o m bi nati o n c o nsisti n g of li p os o mal 
c ycl os p ori ne A ( L -Cs A) a n d t he 
. 
7. 1. 1  
D r u g  c o m p o n e nt  
L -Cs A c o nsists of t he acti ve s u bsta nce Cs A a n d e xci pie nts as descri be d i n t he I n vesti gat or
Br oc h ure (I B). L -Cs A is a l y o p hilisate f or rec o nstit uti o n wit h 0. 2 5 % sali ne. T he f or m ulati o n is
de vel o pe d  f or i n halati o n use  a n d is t heref ore a dj uste d  t o a p h ysi ol o gical  t olera ble val ue  of  
.
T he li p os o me size i n t he rec o nstit ute d f or m ulati o n is i n t he ra n ge of 4 0 -1 0 0 n m wit h a 
p ol y dis persit y i n de x of n ot m ore t ha n 0. 5 0, w hic h i n dicates t he wi dt h of t he size distri b uti o n. PI 
val ues a b o ve 0. 5 i n dicate a br oa d distri b u ti o n. 
T he d ose of 5 m g L -Cs A is rec o nstit ute d i n a t otal v ol u me of 1. 2 5 m L.  T he e ntire v ol u me of t he 
rec o nstit ute d s ol uti o n is use d per aer os ol a d mi nistrati o n. 
A d diti o nal  i nf or mati o n ca n be  f o u n d i n t he I B. 
7. 1. 2  
D e vi c e  c o m p o n e nt  
 
 
 
T he 
 t o be use d i n t his cli nical trial is a c ust o mize d versi o n of t he 
 
 
 f or a n o pti mize d deli ver y of t he i n vesti gati o nal dr u g f or t he desi g nate d patie nt gr o u p. T he 
c o nfi g urati o n of t he o pti mize d 
 has a hi g h deli vere d d ose, s h ort ne b ulizati o n ti me  
a n d i n hi bits c o nta mi nati o n of t he e n vir o n me nt b y usi n g a n e x halati o n filter. T he de vice is C E - 
mar ke d i n E ur o pe. C o m para ble de vices are als o a vaila ble o n t he U S mar ket. T he 
 
was use d i n t he n o ncli nical a n d  cli nical trials of L -Cs A. 
 
 
 T he  us ual 
ne b ulizati o n ti me is 
 f or t he 5 m g d ose. 
A d diti o nal  i nf or mati o n ca n be  f o u n d i n t he I B. 
7. 1. 3  
N o n cli ni c al  D at a  
F or s yste mic a d mi nistrati o n of Cs A, t he n o ncli nical p har mac ol o gic, p har mac o ki netic, a n d t o xicit y 
pr ofiles of s yste mic Cs A are well esta blis he d [ U K S m P C Cicl os p ori n A  
)].  
F or aer os olize d a d mi nistrati o n of L -Cs A, a d diti o nal n o ncli nical st u dies ha ve b ee n c o n d ucte d wit h 
L -Cs A.  I m p orta ntl y, L -Cs A  i n hi bite d T -cell pr oliferati o n  i n sti m ulate d h u ma n  peri p heral  bl o o d
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  3 5  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
m o n o n uclear  cells. Acr oss  3 n o ncli nical  t o xic ol o g y st u dies i n rats, aer os olize d  L -Cs A  gi ve n  as 
4 -da y, 6 -wee k, a n d 2 6 -wee k re peate d a p plicati o ns of u p t o 2. 6 m g/ k g/ da y, n o d ose -li miti n g
t o xicit y  occ urre d.   T he   n o -o bser ve d -a d verse -effect -le vel  ( N O A E L)  is  c o nsi dere d   t o  be
2. 0 m g/ k g/ da y via i n halati o n f or c hr o nic a p plicati o n base d o n t he ma xi m u m d osa ge ac hie ve d i n
t he 2 6-wee k i n halati o n st u d y i n rats.
N o ncli nical a n d cli nical data t o date wit h L -Cs A s h o w ne gli gi ble i ncrease i n ser u m le vels of 
calci ne uri n i n hi bit ors a n d d o n ot s h o w a n i ncrease d ris k of ne p hr ot o xicit y, res pirat or y i nfecti o ns, 
or mali g na ncies.  
A d diti o nal  i nf or mati o n ca n be  f o u n d i n t he I B. 
7. 1. 4  
Cli ni c al  E x p eri e n c e  
L -Cs A  has  bee n  e val uate d i n 3  cli nical  trials i n a d ult  patie nts  w h o  recei ve d a si n gle-l u n g or  d o u ble - 
l u n g tra ns pla ntati o n: ( 1) a P hase 1 b st u d y of t he de p ositi o n a n d p har mac o ki netics ( P K) of
aer os olize d L -Cs A i n patie nts wit h l u n g tra ns pla ntati o n ( G 0 3 5. 0 1 1); ( 2) a P hase 3 st u d y of t he
efficac y,  safet y, a n d P K  of  t he a d diti o n  of  aer os olize d  L -Cs A  to  S O C  s yste mic i m m u n os u p pressi o n
t hera p y vs aer os olize d place b o pl us S O C t hera p y i n t he pre ve nti o n of B O S f oll o wi n g l u n g
tra ns pla ntati o n ( 1 2 0 1 1. 2 0 1; st u d y 
was ter mi nate d earl y f or b usi ness reas o ns); a n d ( 3) a n
i n vesti gat or-i nitiate d st u d y of t he efficac y, safet y, a n d P K of t he a d diti o n of aer os olize d L-Cs A t o
S O C s yste mic i m m u n os u p pressi o n t hera p y vs S O C t hera p y al o ne i n t he treat me nt of B O S
f oll o wi n g l u n g tra ns pla ntati o n ( AI 0 0 1). C ollecti vel y, t hese st u dies pr o vi de d safet y, efficac y, a n d
P K  data  t o s u p p ort f urt her e val uati o n  i n 2 P hase III  st u dies of  t he efficac y a n d safet y of  t he a d diti o n
of aer os olize d L -Cs A t o S O C s yste mic i m m u n os u p pressi o n t hera p y vs S O C t hera p y al o ne f or t he
treat me nt of B O S f oll o wi n g si n gle l u n g tra ns pla ntati o n ( B T –  L -Cs A –  3 0 1 –  S L T ) or d o u ble l u n g
tra ns pla ntati o n ( B T –  L -Cs A –  3 0 2 –  D L T).  I n partic ular:
•
T he P hase 1 b  l u n g de p ositi o n  st u d y ( G 0 3 5. 0 1 1) s h o we d t hat i n halati o n of  1 0 m g a n d  2 0 m g
L -Cs A via t he 
 w o ul d res ult i n s ufficie nt peri p heral l u n g de p ositi o n of L-Cs A
( ≥1 5 m g L -Cs A/ wee k).  Aer os ol  a p plicati o n  of  1 0 m g  L -Cs A  was  ass ociate d  wit h  a n acce pta ble
i n halati o n ti me of a p pr o xi matel y 9 mi n utes.
•
I n t he P hase 3 st u d y i n vesti gati n g pre ve nti o n of B O S ( 1 2 0 1 1. 2 0 1), t he pri mar y e n d p oi nt f or
pre ve nti o n of B O S ( B O S -free s ur vi val) was n ot met, alt h o u g h efficac y res ults ma y ha ve bee n
c o nf o u n de d b y earl y ter mi nati o n of t he trial d ue t o b usi ness reas o ns.
•
I n t he i n vesti gat or-i nitiate d st u d y i n vesti gati n g treat me nt of B O S ( AI 0 0 1), t he res p o n der
a nal ysis of B O S pr o gressi o n -free s ur vi val base d o n Ka pla n-Meier esti mates re veale d a
treat me nt s uccess rate of 8 1. 8 % i n t he L-Cs A + S O C gr o u p ( 9 of 1 1 patie nts) a n d 5 0 % i n t he
c o ntr ol  gr o u p  ( 5 of 1 0 patie nts).  F E V 1  sl o pe a nal yses o ver  ti me res ulte d i n m o nt hl y  decre me nts
of -0. 0 0 8 L i n t he L -Cs A + S O C gr o u p a n d -0. 0 4 5 L i n t he c o ntr ol gr o u p. T his differe nce
tra nslate d i nt o a n a n n ual preser vati o n of F E V1  of m ore t ha n 4 0 0 m L i n t he L -Cs A + S O C
gr o u p, c o nsiste nt wit h a mea ni n gf ul sl o wi n g of t he pr o gressi o n of t he disease. T he be neficial
effect  of  L -Cs A  was  als o reflecte d i n c o nsiste ntl y  p ositi ve  tre n ds fa v ori n g t he L -Cs A + S O C
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  3 6  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
gr o u p  i n ot her l u n g f u ncti o n para meters, i ncl u di n g 
, F V C, a n d F E V1  %  pre dicte d. Fi ve 
years  after t he start of  St u d y  AI 0 0 1  (as of Se pte m ber 2 0 1 7),  5 of  1 1 patie nts  treate d wit h 
L -Cs A + S O C were ali ve, c o m pare d wit h 0 of 1 0 c o ntr ol patie nts w h o recei ve d S O C al o ne.
Wit h  res pect t o safet y, i n hale d L- Cs A  w as ge nerall y  we ll t olerate d acr oss all cli nical trials. T he 
o verall a nal ysis of A d verse E ve nts ( Aes), Seri o us A d verse E ve nts ( S A Es), a n d deat hs s h o we d t hat 
t hese were m ostl y ass ociate d wit h p ul m o nar y a n d i m m u n ol o gical e ve nts, w hic h are e x pecte d i n a 
p o p ulati o n  of l u n g  tra ns pla nt a n d im m u n os u p presse d  pat ie nts a n d di d  n ot  d iffer fr o m t he c o ntr ol 
ar ms. Neit her la b orat or y val ues n or vital si g ns assess me nts s h o we d a n y cli nicall y rele va nt c ha n ges 
o ver ti me. 
N o ncli nical a n d cli nical data t o date wit h L- Cs A d o n ot s h o w a n i ncrease d risk of ne p hr ot o xicit y, 
res pirat or y i nfecti o ns, or mali g na ncies. 
A d diti o nal i nf or mati o n ca n be f o u n d i n t he I B. 
7. 1. 5  
S u m m ar y of  K n o w n a n d P ot e nti al Ri s k s a n d B e n efits 
Details a b o ut s pecific ris ks f or patie nts partici pati n g in t his cli nical trial ma y be f o u n d in t he I B, 
i ncl u di n g a ta b ular s u m mar y of all ad verse reacti o ns re p orte d t o date f or L- Cs A. 
Patie nts in cli nical trials g e nerally ca n n ot ex pect to recei ve d irect b e nefit fr om treat me nt d ur i n g 
partici pati o n, as cli nical trials are d esi g ne d t o pr o vi de inf or mati o n a b o ut t he safet y a n d 
effecti ve ness of a n i n vesti gati o nal me dici ne. 
B O S is a k n o w n life-li miti n g c o m plicati o n of l u n g tra ns pla ntati o n wit h o ut a n y mea ni n gf ul 
t herap y. T his trial is the first to e val uate t he safet y a n d efficac y of L- Cs A f or t he treat me nt of 
B O S in patie nts w it h B O S f oll o wi n g si n gle lu n g tra ns pla ntati o n. 
C O VI D- 1 9 s pecific c o nsi derati o ns: acc or di n g t o t he G ui da nce fr o m t he I nter nati o nal S ociet y of 
Heart a n d L u n g Tra ns pla ntati o n re gar di n g t he S A R S C o V- 2 pa n de mic [I S H L T, 2 0 2 0] “at t his 
ti me, it is u n k n o w n if specific p a tie nt p o p u l ati o ns ar e at hi g her risk of S A R S- C o V- 2 i nfecti o n. 
P u blis he d c ase series a n d pers o n al re p orts th us far d o n ot su g gest t h at tr a ns pl a nt reci pie nts in 
p artic ul ar h av e a hi g her risk of a c q uirin g t he vir us”. 
T he me dical val ue of t his trial re mai ns u nc ha n ge d. 
F urt her m ore, t he m e dical s ur veilla nce of tra ns pla nte d patie nts is alrea d y base d o n s pecific 
preca uti o ns ty pical to all p atie nts ta kin g i m m u n os u p pressi ve age nts. 
7. 1. 6  
J u stifi c ati o n of  D o s e R e gi m e n 
Alt h o u g h m ultifact orial i n eti ol o g y, m ost e vi de nce s u g gests t hat B O is a h ost- de pe n de nt , i m m u ne 
me di ated air wa y i nj ury t o br o nc hi olar cells . It has been p ost ul ate d t hat t he m ost i m p orta nt ca use 
of c hr o nic rejecti o n of t he lu n g all o graft a n d B O S is T-l y m p h oc yte acti vatio n b y maj or 
hist oc o m pati bilit y all oa nti ge ns- or all oi m m u ne- de pe n de nt mec ha nis ms [ Hall ora n 1 9 9 7 ; S o u ba ni  
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  3 7  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
& U berti 2 0 0 7 ]. C ycl os p ori ne A was selecte d as t he acti ve s u bsta nce f or t he de vel o p me nt of a 
li p os o mal f or m ulati o n beca use of its 
well c haracterize d 
m o de of acti o n a n d pr o ve n 
i m m u n os u p pressi ve p ote nc y. 
T he  li p os o mal f or m ulati o n of c ycl os p ori ne A ( L -Cs A)  was de vel o pe d  wit h t he i nte nt of i m pr o vi n g 
l ocal t olera bilit y, as s h o w n i n st u dies 1 2 0 1 1. 2 0 1 a n d AI 0 0 1. Beca use l u n g f u ncti o n is si g nifica ntl y 
c o m pr o mise d i n patie nts wit h B O S, a n i n halati o n f or m ulati o n t hat is t olera ble a n d facilitates 
patie nt  use  is i m p orta nt f or treat me nt c o m plia nce a n d  assess me nt of  safet y a n d efficac y  para meters 
of t he I M P. T he rati o nale f or t he selecti o n of t wice -dail y 5 m g a n d 1 0 m g d oses of aer os olize d L - 
Cs A, i n S L T a n d D L T patie nts, res pecti vel y, is base d o n:  
•
C orrelati o n of dr u g a m o u nt de p ositi o n a n d sta bilizati o n of l u n g f u ncti o n [ C orc ora n
2 0 0 4 ] wit h Cs A-P G
•
Cli nical trial de p ositi o n data fr o m C orc ora n [ 2 0 0 6 ] i n S L T a n d D L T patie nts ( Cs A- 
P G)
•
Cli nical  trial de p ositi o n  data  fr o m Be hr  [2 0 0 9 ] i n S L T  a n d D L T  patie nts  ( L-Cs A)
D uri n g t he cli nical de vel o p me nt of c ycl os p ori ne i n its pr o p yle ne gl yc ol f or m ulati o n, [ C orc ora n 
2 0 0 4] rec or de d l u n g f u ncti o n i n c orrelati o n wit h differe nt a m o u nts of Cs A -P G de p osite d i n t he 
tra ns pla nte d l u n g. A t hres h ol d of ≥ 5 m g Cs A-P G peri p heral d ose per  i n halati o n was deter mi ne d 
t o be re q uire d t o res ult i n a sta bilizati o n of l u n g f u ncti o n o n t he basis of F E V1  meas ure me nts. 
Patie nts i n t his cli nical trial i n hale d Cs A -P G t hree ti mes per wee k. He nce, t he mi ni mal effecti ve 
peri p heral dr u g d ose was calc ulate d  t o be 1 5 m g/ wee k. 
T he sa me gr o u p [ C orc ora n 2 0 0 6] i n vesti gate d t he patter n of dr u g de p ositi o n i n S L T a n d D L T 
patie nts a n d disc o vere d t hat s u bsta ntial a m o u nts of dr u g were f o u n d o nl y i n t he tra ns pla nte d parts 
of t he l u n g. T he nati ve l u n g of S L T patie nts wa s al m ost free of dr u g d ue t o its li mite d ve ntilati o n 
ca pacit y. T he sa me res ult was ac hie ve d w he n Be hr [ 2 0 0 9] re peate d t he i n vesti gati o n of dr u g 
de p ositi o n i n S L T a n d D L T patie nts wit h t he L -Cs A f or m ulati o n. A gai n, it was s h o w n t hat maj or 
de p ositi o n of t he dr u g t o o k place o nl y i n t he ve ntilate d parts of t he l u n g all o graft, i.e., al m ost n o 
dr u g arri ve d i n t he nati ve l u n g via i n halati o n.  
T he c o m bi nati o n of t he cli nical data cite d a b o ve o n dr u g de p ositi o n be ha vi or a n d t he 
p har mac o ki netic data fr o m Be hr [ 2 0 0 9] s h o wi n g t hat a p pr o xi matel y  
 of t he i n hale d dr u g 
reac hes t he peri p her y of t he l u n g le d t o t he calc ulati o n f or a d osi n g re gi me n of L-Cs A.  It is 
esti mate d t hat a d ose of L -Cs A 5 m g BI D will res ult i n 2 m g de p osite d i n t he peri p heral air wa ys 
per da y, a n d 1 4 m g per wee k.  
7. 1. 7  
St at e m e nt  of  C o m pli a n c e  
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol a p pr o ve d b y t he a p pr o priate 
I nstit uti o nal Re vie w  B oar ds  (I R B) a n d Et hics  C o m mittees  ( E C), acc or di n g  t o I nter nati o nal 
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 38 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
Council of Harmonisation (ICH) and Good Clinical Practice (GCP) standards, and in accordance 
with the ethical principles that have their origin in the Declaration of Helsinki. 
7.1.8 
Population 
Recipients of a primary single pulmonary allograft, ≥ 18 years of age, with clinically defined BOS 
with screening FEV1 above 51% of personal best FEV1 value post-transplant during the screening 
period. The study investigator should confirm the diagnosis of BOS prior to referring the subject 
for the study. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 39 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
8 TRIAL OBJECTIVES AND PURPOSE 
8.1 Trial Objectives 
The objective of the trial is 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 single lung 
transplant recipients. 
8.2 Purpose of the Trial 
Currently, there is no approved medicinal product for the prevention or treatment of BOS after 
lung transplantation. All attempts for therapeutic intervention to alter the incidence or the 
progression of BOS are empirical and investigational and are usually based on center-specific 
evidence. This circumstance explains the diversity and disharmony of therapeutic concepts in the 
lung transplant community. There are SoC practices established to manage BOS that develops 
after lung transplantation, but no therapeutic regimens have conclusively demonstrated evidence 
of significant benefit in the prevention or treatment of BOS. Adequately designed and executed, 
randomized, controlled trials to assess efficacy and safety are needed to identify optimal therapies 
for established BOS. 
The hypothesis that local delivery of CsA by aerosol inhalation will achieve higher intrapulmonary 
concentration than by systemic administration alone, and will result in decreased allograft rejection 
with limited toxicity compared to similar systemic doses due to minimal absorption of drug into 
the blood circulation has been substantiated by the studies described in Section 7.1.4. 
In particular, the investigator-initiated trial AI001 provided evidence of L-CsA’s potential to delay 
progression of BOS when administered as add-on inhalation therapy as compared to SoC for 
systemic BOS therapy. In combination with the acceptable safety profile of L-CsA, observed in 
clinical trial 12011.201 when patients were treated for up to two years, L-CsA has the potential to 
provide superior efficacy over current best practice BOS therapy. The purpose of this trial is to 
confirm the efficacy and safety of L-CsA in a distinct lung transplant population, i.e., in single 
lung transplant recipients. 

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  4 0  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
9  T RI A L  D E SI G N  
9. 1  E n d p oi nts  
9. 1. 1  
P ri m a r y  E n d p oi nt  
Mea n  c ha n ge i n F E V 1  ( m L) fr o m baseli ne  t o Wee k  4 8.  
 
 
 
 
 
 
 
 
 
Safet y:  
•
A d verse  e ve nts (i ncl u di n g i nfecti o ns a n d mali g na ncies)
•
Ac ute  t olera bilit y of  I M P
•
Cli nical  la b orat or y para meters
•
Re nal  F u ncti o n
•
Vital  si g ns
•
P h ysical  e xa mi nati o ns
C CI
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 41 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
9.2 Trial Design 
This is a Phase III, prospective, multicenter, randomized, controlled clinical trial in the treatment 
of BOS in adult recipients of a unilateral pulmonary allograft. Approximately 50-60 patients are 
planned for enrollment. The clinical trial will be conducted in approximately 43 centers worldwide. 
Patients will be randomly allocated to receive either L-CsA plus SoC or SoC alone for the 
treatment of BOS. Patients will be monitored at every 4-8 weeks over 48 weeks for efficacy 
parameters and for all safety evaluations. 
The rationale for not using a placebo control is driven by concerns that a sucrose-containing 
formulation could increase a potential risk of pulmonary infection without the benefit of L-CsA. 
Sucrose is a lyoprotectant in the manufacturing process. After carefully weighing alternative 
options for lyoprotection, no sugar-free alternatives that qualify as real placebo (i.e., 
undistinguishable by means of appearance, taste or smell) could be identified. Therefore, a 
randomized controlled trial versus SoC is the only suitable alternative. 
An open-label clinical trial generally bears the potential regarding biased patient treatment and 
care, and thus trial outcome. However, for this trial the risk of bias is considered low because of 
the following reasons: 
•
Currently, the general strategy to treat BOS is augmentation of immunosuppressive therapy
to the highest tolerable level unless limited by systemic toxicity. Since application of L-CsA
via inhalation has not shown to lead to an additional systemic drug burden, dose reductions or
adaptations of other components of the immunosuppressive cocktail will not be required and
are not desired.
•
Furthermore, the selected primary endpoint FEV1 is an objective parameter and its
measurement will be performed according to recommended guidelines of ATS/ERS which
have to be respected by each participating center. Following this methodology, a subjective
and intentional manipulation of outcome is highly unlikely even if health care professional
and patient are aware of the treatment allocation.
•
The pulmonary function technicians, respiratory therapists, or physiotherapists who perform
spirometry at each site will be blinded to each patient’s treatment assignment.
•
Finally, the correctness and validity of individual FEV1 curves and their resulting value has to
be approved in a central and blinded reading by a pulmonary expert who is independent and
not involved in patients’ care or treatment.
The implementation of these measures shall guarantee that the reported data of the primary 
outcome will be free of bias induced by the open-label character of the clinical trial. 
A similar Phase III clinical trial, BT–L-CsA–302–DLT (BOSTON-2) will be conducted in the 
same investigational centers in patients who have undergone double-lung transplantations. 
Patients who complete either BOSTON-1 or BOSTON-2, will be eligible to participate in a follow- 
on study, BT–L-CsA–303–FU (BOSTON-3). 

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  4 2  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
9. 3  St r atifi c ati o n a n d R a n d o mi z ati o n  
At t he baseli ne visit (see Secti o n 1 4. 2. 2 ), after all i ncl usi o n a n d e xcl usi o n criteria ha ve bee n f ull y 
e val uate d, eli gi ble patie nts will be assi g ne d t o t he t w o treat me nt gr o u ps at a rati o  of 1: 1 b y mea ns 
of bl oc k ra n d o mizati o n. Ra n d o mizati o n will be perf or me d b y a statisticia n ot her wise n ot i n v ol ve d 
wit h t he trial,  usi n g vali date d ra n d o m n u m ber  ge nerat or s oft ware. T he  ra n d o mizati o n c o de of eac h 
patie nt will be pr o vi de d t o t he I n vesti gat or after c o m plia nce wit h all eli gi bilit y criteria has bee n 
c o nfir me d, t hr o u g h t he electr o nic Case Re p ort F or m (e C R F) i nt o w hic h t he ge nerate d ra n d o m  
c o de list will be u pl oa de d. Eac h patie nt will be assi g ne d a n u m ber as part of t he ra n d o mizati o n 
pr ocess. T he n u m ber assi g ne d t o a patie nt will bec o me t hat patie nt’s u ni q ue treat me nt n u m ber 
t hr o u g h o ut t he cli nical trial a n d ca n n ot be re-assi g ne d t o a n ot her patie nt.  
F oll o wi n g u nilateral l u n g tra ns pla ntati o n, it is well k n o w n t hat t he resi di n g nati ve l u n g of patie nts  
s ufferi n g fr o m c hr o nic o bstr ucti ve p ul m o nar y disease ( C O P D) pr o gressi vel y i nflates a n d, i n its 
e m p h yse mat o us state, will ne gati vel y i m pact t he F E V 1  sl o pes o ver ti me. T he ra n d o mizati o n will 
t heref ore be stratifie d b y Scree ni n g F E V1  ≥ 8 1 % of pers o nal best F E V 1  val ue p ost -tra ns pla nt 
vers us Scree ni n g F E V 1  bet wee n 8 0 -5 1 % of pers o nal best F E V 1  val ue p ost -tra ns pla nt, b y t he 
prese nce or a bse nce of C O P D, a n d b y re gi o n ( N ort h A merica vers us all ot her c o u ntries t o get her). 
T he bl oc k size will be wit h hel d fr o m t he i n ve sti gat ors i n or der t o re d uce t he pre dicta bilit y of t he 
treat me nt assi g n me nt a n d is t heref ore n ot me nti o ne d i n t his pr ot oc ol. 
9. 3. 1  
Bli n di n g  
T he p ul m o nar y f u ncti o n tec h nicia ns, res pirat or y t hera pists, or p h ysi ot hera pists w h o c o n d uct 
s pir o metr y o n  site will  be  bli n de d  t o treat me nt assi g n me nt. Patie nts  a n d ot her  u n bli n de d  pers o n nel 
will be as ke d t o n ot s hare treat me nt assi g n me nt i nf or mati o n wit h t he p ul m o nar y f u ncti o n 
tec h nicia ns, res pirat or y t hera pists, a n d p h ysi ot hera pists. F or details of t he bli n di n g of t he Da ta 
M o nit ori n g C o m mittee me m bers, see Secti o n  1 3. 2 . F or  details of t he bli n di n g of t he A dj u dicati o n 
C o m mittee me m bers, see Secti o n 1 3. 3 . Cli nical trial m o nit ors, treati n g p h ysicia ns, st u d y n urses, 
st u d y c o or di nat ors, a n d e nr olle d patie nts will n ot be bli n ded t o treat me nt assi g n me nt.  
9. 4  I n v e sti g ati o n al M e di ci n al P r o d u ct: T r e at m e nt, D o s a g e a n d 
A d mi ni st r ati o n  
9. 4. 1  
F o r m ul ati o n of  L- C s A 
T he c o m p ositi o n of t he L- Cs A f or m ulati o n is s h o w n i n Ta ble 5 . It is a l y o p hilisate i nte n de d 
f or rec o nstit uti o n wit h 0. 2 5 % sali ne. T he f or m ulati o n is de vel o pe d f or i n halati o n use a n d 
a dj uste d t o p h ysi ol o gical t olera ble val ues of  
 
 
). 
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  4 3  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
T a ble  5.  Q u alit ati ve  C o m p ositi o n  of  t he I M P 
I n gre die nt 
F u ncti o n  
Q u alit y  
C ycl os p ori ne  A  
Acti ve  i n gre die nt 
P h  E ur 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1:  E ur o pea n  P har mac o peia  
2:  U nite d  States  P har mac o peia  
T he particle size of t he li p os o mes is i n t he ra n ge of 4 0 -1 0 0 n m wit h a p ol y dis persit y i n de x of n ot 
m ore t ha n 0. 5 0, w hic h i n dicates t he wi dt h of t he size distri b uti o n. Val ues of p ol y dis persit y i n de x 
a b o ve 0. 5 i n dicate a br oa d distri b uti o n. F or c oll oi dal dis perse s yste ms a PI of 0. 2 0 t o 0. 5 0 is 
a p pr o priate. 
T he  I M P L -Cs A  a n d 0. 2 5 %  sali ne f or rec o nstit uti o n will  be  s u p plie d b y:  
Za m b o n  S p A  
Via  Lill o  del  D uca,  1 0 
Bress o ( MI) 2 0 0 9 1 
Ital y 
9. 4. 2  
T r e at m e nt  a n d  D os a g e  
B asic  I m m u n os u p pressi o n: 
Re gar dless of treat me nt all ocati o n, all partici pa nts will recei ve Sta n dar d of Care ( S o C).  Eli gi ble 
patie nts s h o ul d be o n a mai nte na nce re gi me n of i m m u n os u p pressi ve a ge nts i ncl u di n g tacr oli m us,  
a sec o n d a ge nt s uc h as b ut n ot li mite d t o M M F or azat hi o pri ne,  a n d a  s yste mic c ortic oster oi d s uc h 
as pre d nis o ne as t hir d a ge nt.  T he re gi me n m ust be sta ble wit hi n  4 wee ks pri or t o ra n d o mizati o n 
wit h  res pect t o t he t hera pe utic a ge nts.  Patie nts  recei vi n g azit hr o m yci n  f or pr o p h yla xis  or  treat me nt 
of B O S, m ust be o n a sta b le re gi me n f or at least 4-wee ks pri or t o ra n d o mizati o n a n d will c o nti n ue 
t o recei ve azit hr o m yci n d uri n g t he trial as dee me d a p pr o priate b y t he i n vesti gat or. 
After  scree ni n g, patie nts c o m pl yi n g  wit h  all i ncl usi o n a n d e xcl usi o n  criteria  (see Secti o ns  1 0. 1  a n d 
1 0. 2 ) will be ra n d o mize d 1: 1 t o o ne of t he f oll o wi n g treat me nts: 
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  4 4  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
Gr o u p  A  ( L-Cs A  tre at me nt pl us  St a n d ar d  of  C are):  
•
L -Cs A 5 m g/ 1. 2 5 m L t wice dail y f or 4 8 wee ks
Pl us
•
Sta n dar d  of  Care  (as directe d  b y  treati n g p h ysicia n)
Gr o u p  B  ( St a n d ar d of  C are  al o ne):  
•
Sta n dar d  of  Care  (as directe d  b y  treati n g p h ysicia n)
9. 4. 3  
A d mi ni st r ati o n  of  L -Cs A  
Patie nts ra n d o mize d t o L -Cs A treat me nt will recei ve L -Cs A i n halati o n t hera p y i n a d diti o n t o S o C 
as o utli ne d bel o w. 
Pri or use i n cli nical trial 1 2 0 1 1. 2 0 1 a n d cli nical trial AI 0 0 1 create d n o e vi de nce s u g gesti n g L - 
Cs A was i nt olera ble t o patie nts. H o we ver, p atie nts wit h B O S t y picall y ha ve i nfla me d air wa ys 
w hic h c o ul d i ncrease t he li keli h o o d of br o nc h os pas m. T h us, t o 
mi ni mize ris k t o patie nts 
ra n d o mize d t o L-Cs A, patie nts will recei ve trai ni n g o n t he use of t he de vice a n d t he first d ose of  
L -Cs A 
. I n
a d diti o n, d uri n g all s u bse q ue nt sc he d ule d visits t he L -Cs A i n halati o n will be self -a d mi nistere d b y
t he patie nt a n d u n der t he s u per visi o n of trai ne d pers o n nel.
Eac h patie nt will i dea ll y recei ve t w o L-Cs A a d mi nistrati o ns per da y, 
 
. T he i n halati o ns are sc he d ule d t o be ta ke n a p pr o xi matel y 
 
. I nstr ucti o ns f or a d mi nistrati o n s h o ul d be f oll o we d as descri be d 
i n t he I nstr ucti o ns F or Use. 
If patie nts de vel o p d ys p nea or si g ns of dr u g i nt olera nce at a n y p oi nt d uri n g t he c o urse of t he trial, 
t he site i n vesti gat or s h o ul d ta ke a p pr o priate acti o ns, i m me diatel y. If cli nicall y i n dicate d, L-Cs A 
will be hel d a n d rec halle n ge d a n d/ or disc o nti n ue d.  Patie nts will be e nc o ura ge d t o c o m plete all 
re mai ni n g st u d y visits t hr o u g h t he e n d of t he trial. 
Patie nts w h o de m o nstrate si g ns of ac ute i nfecti o n or ac ute rejecti o n s h o ul d be e val uate d b y t he 
treati n g p h ysicia n a n d treate d a p pr o priatel y.  L -Cs A s h o ul d be c o nti n ue d if t olerate d d uri n g t his 
peri o d.  If L-Cs A is hel d, it s h o ul d be trac ke d i n t he e C R Fs.  T he reas o ns f or disc o nti n uati o n or 
d osa ge a dj ust me nts ha ve t o be d oc u me nte d acc or di n gl y wit h s pecificati o n of t he date a n d reas o n 
o n t he res pecti ve case re p ort f or m.  
F or t h ose patie nts o n i n halati o n t hera p y, reas o ns f or te m p orar y i nterr u pti o n ma y i ncl u de t he 
f oll o wi n g: 
o
Si g nifica nt  ac ute  res pirat or y i nfecti o n re q uiri n g a nti micr o bial  t hera p y u ntil  a cli nical
res p o nse is d oc u me nte d
o
Res pirat or y  fail ure fr o m a n y ca use  u ntil  t he e ve nt  has  res ol ve d
o
Mec ha nical  ve ntilati o n
C CI
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  4 5  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
o
If a si g nifica nt decli ne i n F E V1  (
 s h o ul d occ ur ass ociate d wit h breat hless ness or
ot her res pirat or y s y m pt o ms.
Patie nts te m p oraril y i nterr u pti n g L -Cs A i n halati o n will be as ke d t o ret ur n f or cli nical trial visits 
acc or di n g t o t he visit sc he d ule defi ne d i n t he pr ot oc ol b ut s hall n ot recei ve I M P. If t here is f ull 
cli nical res ol uti o n of t he reas o ns f or te m p orar y i nterr u pti o n, t he I n vesti gat or ma y atte m pt t o re - 
i ntr o d uce t he I M P at a later ti me. If t he patie nt a grees, s he/ he will res u me all ma n dat or y 
e val uati o ns acc or di n g t o t he pr ot oc ol u ntil e n d of treat me nt ( Wee k 4 8).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  4 6  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
9. 5  I n v e sti g ati o n al M e di ci n al  P r o d u ct P a c k a gi n g,  L a b eli n g  a n d  St o r a g e  
9. 5. 1  
P a c k a gi n g  a n d  L a b eli n g  of  L -Cs A  
Pac ka gi n g  
T he i n vesti gati o nal me dici nal pr o d uct will be pr o vi de d as 5 m g L -Cs A l y o p hilisate 
 
 
 
 
La beli n g: 
 L-Cs A  ( U. S. Versi o n. La belli n g will 
meet a p plica ble 
re g ulat or y re q uire me nts.) 
•
Pr ot oc ol N o.:  B T  –  L -Cs A  –  3 0 1  –  S L T
•
5  m g  L -Cs A,  p o w der  f or ne b ulizati o n  s ol uti o n.
•
F or  i n halati o n use.
•
Batc h  N o.:
•
E x pir y  Date:  m m/ y y y y
•
Za m b o n  S p A
La beli n g: Sali ne 0. 2 5 % S ol uti o n ( U. S. Versi o n. La belli n g will 
meet a p plica ble re g ulat or y 
re q uire me nts.) 
•
Pr ot oc ol  N o.:  B T  –  L -Cs A  –  3 0 1  –  S L T
•
Na Cl  0. 2 5 %,  s ol ve nt f or L -Cs A
•
L O T  N o.:
•
E X P:  m m/ y y y y
•
Za m b o n  S p A
La beli n g: O uter Pac ka gi n g C o ntai ni n g 
 Sali ne 
0. 2 5 %  ( U. S. Versi o n. La belli n g will meet a p plica ble re g ulat or y re q uire me nts.) 
•
Pr ot oc ol  N o.:  B T –  L -Cs A  –  3 0 1  –  S L T
•
F O R  SI N G L E  L U N G  T R A N S P L A N T  P A TI E N T S  O N L Y
•
 L-Cs A 5  m g p o w der  f or ne b ulizati o n  s ol uti o n a n d 
 0. 2 5 %  Na Cl
S ol uti o n - 1. 2 m L
•
F or  i n halati o n use
•
L O T  N o:
•
B o x  N o.:
•
E x pir y  Date:  m m/ y y y y
•
, acc or di n g  t o t he i nstr ucti o ns fr o m
y o ur researc h tea m.
•
D o  n ot  st ore a b o ve 7 7  ° F ( 2 5 ° C), d o  n ot  freeze. Pr otect  fr o m li g ht.
C CI
C CI
C CI
C CI
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  4 7  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
•
Kee p  o ut  of  reac h of  c hil dre n.
•
F O R  C LI NI C A L  T RI A L  U S E  O N L Y
•
Ret ur n  all u n use d  me dicati o n  t o t he i n vesti gat or.
•
S p o ns or:  Za m b o n S. p. A., Via Lill o del D uca 1 0, 2 0 0 9 1 Bress o ( MI), Ital y,
P h o ne: + 3 9 0 2 6 6 5 2 4 1
•
I n vesti gat or na me :
•
Site  N o.:
•
Patie nt  N o.:
•
Visit  N o.:
9. 5. 2  
St or a g e  
T he u n o pe ne d I M P m ust be ke pt i n a sec ure l ocati o n caref ull y st ore d n ot a b o ve 7 7 ° F ( 2 5 ° C) 
pr otecte d fr o m li g ht.  
9. 5. 3  
 
 
 
 
 
 
 
 
 
9. 6  St o p pi n g  r ul e s  a n d  Di s c o nti n u ati o n  C rit eri a  
9. 6. 1  
P ati e nt  L e v el  
Re g ular  ter mi nati o n of  cli nical  trial partici pati o n:  
T he i n vesti gati o nal treat me nt will be ter mi nate d after 4 8 wee ks ( E n d of Treat me nt [ E o T]). T he 
treat me nt peri o d will be f oll o we d b y a f oll o w-u p of 4 wee ks’ d urati o n ( E n d of St u d y [ E o S]). 
Patie nts  w h o  e nr oll i n  Cli nical  Trial B T  –  L -Cs A  –  3 0 3  –  F U ( B O S T O N -3)  will  f ore g o t he 4 -wee k 
f oll o w-u p peri o d of B O S T O N -1 a n d will e nr oll directl y i nt o B O S T O N -3 at t he Wee k 4 8 Visit.  
F or t hese patie nts, t he E O T visit will be t he E O S visit.  
C CI
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 48 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
Any patients with ongoing SAEs will be followed-up until recovery or stabilization of the SAE. 
If a patient has enrolled in BOSTON-3, pharmacovigilance will be continuously assessed in the 
scope of the follow-up clinical trial. 
Premature termination of clinical trial participation: 
•
Patients may discontinue participation in the clinical trial at any time by revoking their
informed consent.
•
The Investigator may withdraw a patient at any time if it is in the best interest of the patient
based upon clinical assessments.
•
Patient is lost to follow-up
•
Re-transplantation. 
Patients who are eligible for and/or listed for re-transplantation will
continue to participate in the trial until they receive re-transplantation surgery.
•
Pregnancy (the patient will be followed via a pregnancy registry)
•
Zambon SpA may choose to terminate the study at a site or as a whole for reasons such as,
but not limited to, medical futility, safety concerns, or poor study site performance.
Patients stopping to take study treatment but not revoking their consent will be encouraged to 
continue the visits planned until the scheduled end and perform all the important safety and 
efficacy assessments for the full duration of the study. 
If the patient to return for clinical follow-up, the patient will be contacted by telephone or a letter 
will be sent requesting a mandatory clinic visit and the reason for non-compliance will be 
documented. 
9.6.2 
Center Level 
Regular termination of clinical trial centers: 
All centers will be closed after the pre-defined number of patients have been randomized 
(approximately 220 in the BOSTON 1 and BOSTON 2 studies combined) and all the patients 
enrolled have completed clinical trial participation. 
Premature termination of a clinical trial center: 
The sponsor may close a center for the following reasons: 
•
In case of repeated and continuous violations of GCP regulations
•
Inaccurate or incomplete data collection
•
Falsification of records
•
Failure to adhere to the protocol
•
Organizational or structural changes in the center which challenge the requirements or
qualification for clinical trial participation (e.g., change of investigator, shift of center
activities etc.)

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  4 9  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
I n case a ce nter is cl ose d f or a n y of t he reas o ns a b o ve, eff orts will be ma de t o e ns ure t he safet y  
a n d data relia bilit y of o n g oi n g patie nts u ntil cli nical trial c o m pleti o n.  
9. 6. 3  
St u d y  L e v el  
Re g ular  ter mi nati o n of  t he cli nical trial: 
T he cli nical trial will be c o nsi dere d c o m plete after t he pre -defi ne d n u m ber of patie nts ha ve bee n 
ra n d o mize d (a p pr o xi matel y 2 2 0 i n t he B O S T O N 1  a n d B O S T O N 2 st u dies c o m bi ne d), a n d all t he 
patie nts ha ve c o m plete d c li nical trial partici pati o n (last patie nt last visit). 
Pre mat ure  ter mi nati o n of  t he cli nical trial: 
•
Seri o us Safet y c o ncer ns t hat i n dicate a p ote ntial healt h hazar d ca use d b y treat me nt wit h t he
I M P or S o C (ter mi nati o n d ue t o safet y iss ues)
Za m b o n S p A ma y c h o ose t o ter mi nate  t he st u d y as a w h ole f or reas o ns s uc h as, b ut n ot li mite d t o, 
me dical f utilit y or safet y c o ncer ns.  I n t his case, a d verse e ve nt data will be re p orte d t o F D A/ C As 
acc or di n g t o a p plica ble re g ulat or y re q uire me nts. T he I n vesti gat or m ust n otif y his I R B/ E C of 
cli nical trial cl os ure.  
9. 7  I n v e sti g ati o n al M e di ci n al  P r o d u ct:  S u p pl y  a n d  A c c o u nt a bilit y  
Eac h  I n vesti gat or is res p o nsi ble f or e ns uri n g  t hat deli veries  of  I M P vials  a n d b o xes,  
 
a n d ot her cli nical trial materials fr o m Za m b o n S p A are c orrectl y recei ve d a n d rec or de d, t hat t hese 
are ha n dle d  a n d st ore d safel y a n d pr o perl y,  a n d t hat t he y are  use d  i n acc or da nce  wit h  t his pr ot oc ol. 
 
 
U n use d  a n d use d  L -Cs A  
, a n d 
 
m ust be ret ur ne d t o Za m b o n S p A or destr o ye d o n -site after dr u g acc o u nta bilit y is perf or me d or at 
least at ter mi nati o n of t he cli nical trial w he n o verall dr u g acc o u nta bilit y has bee n c o m plete d. A 
list of L-Cs A, 
, a n d ot her materials recei ve d, use d, ret ur ne d, or destr o ye d m ust be 
pre pare d, c o m plete d a n d si g ne d b y t he I n vesti gat or; a n y discre pa ncies m ust be acc o u nte d f or.  
C O VI D -1 9 s pecific c o nsi derati o n: I n case t he pla n ne d o n -site visit ca n n ot be perf or me d, t he 
Pri nci pal I n vesti g at or ( PI) or t he S u b -I n vesti gat or a n d/ or a n a p pr o priatel y q ualifie d site st u d y 
tea m me m ber ca n arra n ge f or t he deli ver y of t he I M P directl y t o patie nt h o me, if all o we d b y 
l ocal re g ulati o n a n d t he site I R Bs/ E Cs. 
C CI
C CI
C CI
C CI
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 50 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
10 SELECTION AND WITHDRAWAL OF PATIENTS 
10.1 Patient Inclusion Criteria 
1. Adult patients of  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:
a) Screening FEV1 between 85-51% of personal best FEV1 value post-transplant
OR
b) 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
a) within 12 months prior to the screening visit
OR
b) 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).
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.

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 51 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
10.2 Patient 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
Definitions),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 (including CPAP) 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.

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  5 2  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
1 0. 3  P ati e nt  Wit h d r a w al  Crit eri a  
I n t he e ve nt of patie nt wit h dra wal, t he I n vesti gat or m ust c o m plete t he a p pr opriate e n d of st u d y 
f or m i n t he e C R F as s o o n as p ossi ble after wit h dra wal, stati n g t he reas o n a n d date of wit h dra wal. 
A n a ut o mate d e -mail alert will be ge nerate d b y t he e C R F s yste m a n d will be se nt t o t he Cli nical 
Researc h Or ga nizati o n ( C R O).  
1 0. 3. 1  P r o c e d u r e s  f o r P ati e nt  Wit h d r a w al  a n d  T y p e  a n d  Ti mi n g  of  D at a  C oll e cti o n  
T he  patie nt  is free t o wit h dra w fr o m  t he cli nical  trial f or a n y reas o n a n d at a n y ti me wit h o ut gi vi n g 
a reas o n f or d oi n g s o a n d wit h o ut pe nalt y or prej u dice. T he I n vesti gat or is als o free t o ter mi nate a 
patie nt’s i n v ol ve me nt i n t he cli nical trial at a n y ti me if t he patie nt’s cli nical c o n diti o n warra nts it 
a n d if it is i n t he best i ntere st of t he patie nt base d u p o n cli nical assess me nts. 
If t he s u bject deci des t o wit h dra w t he c o nse nt or t he I n vesti gat or deci de t o wit h dra w n a patie nt 
fr o m t he st u d y, he/s he s h o ul d perf or m: 
• E n d of Treat me nt Visit” ( Visit 9) P RI O R t o disc o nti n uati o n, w he ne ver p ossi ble (t he
reas o n f or pre mat ure wit h dra wal s h o ul d al wa ys be d oc u me nte d)
• A fi nal  cli nical  trial visit  ( Visit 1 0)  at least 1  m o nt h  after Visit  9,  if p ossi ble
If a s u bject per ma ne ntl y disc o nti n ues st u d y treat me nt or t he I n vesti gat or deci des t o wit h dra w a 
s u bject fr o m st u d y treat me nt, t his s u bject s h o ul d be f oll o we d f or a d diti o nal o utc o me i nf or mati o n 
pr o vi de d t hat he/s he mai ntai ns his/ her c o nse nt t o st u d y partici pati o n. I n ot her w or ds, s u bjects 
s h o ul d be e nc o ura ge d t o c o nti n ue t he partici pati o n i n t he cli nical trial u ntil t he sc he d ule d e n d, 
re gar dless of  t he treat me nt ar m. S u bjects  s h o ul d perf or m  all st u d y visits  re q uire d b y  St u d y  Pr ot oc ol 
perf or mi n g all i m p orta nt  safet y a n d efficac y assess me nts f or t he f ull d urati o n of t he St u d y 
It is als o p ossi ble t hat t he C o m pete nt A ut h orit y(ies), I R Bs/ E Cs or t he s p o ns or re q uest ter mi nati o n 
of t he c o m plete cli nical trial, if t here are c o ncer ns a b o ut c o n d uct or safet y.  
Reas o ns f or wit h dra wal are o utli ne d i n detail i n Secti o n 9. 6. 1 . 
T he reas o ns f or wit h dra wal m ust be rec or de d i n t he e C R F.  
1 0. 3. 1. 1  A d diti o n al i nf or m ati o n f o r t h e I n v e sti g at o r i n c a s e of d e ci si o n t o wit h d r a w a p ati e nt 
f r o m I M P 
T o  s u p p ort t he I n vesti gat or i n his/ her decisi o n t o wit h dra w a patie nt  fr o m I M P, it is rec o m me n de d 
t o use  t he ma xi m u m  i nte nsit y of  a n y I M P-relate d a d verse e ve nts (see  Secti o n  1 3. 1. 1. 3 ) as t he basis 
f or e val uati o n. If t he patie nt re p orts a n y se vere a d verse e ve nts t hat are deter mi ne d t o be relate d t o 
L -Cs A, t he I n vesti gat or s h o ul d c o nsi der wit h dra wi n g t he patie nt fr o m I M P.
S pir o metr y usi n g t he  
 s pir o met er will be perf or me d 
 
 
Patie nts  ma y  be  e val uate d i n t he cli nic o n  Da y  2  f or f urt her o bser vati o n  wit h  a d mi nistrati o n  of  L - 
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  5 3  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
Cs A if warra nte d i n t he I n vesti gat or’s o pi ni o n base d u p o n Da y -1 L -Cs A a d mi nistrati o n. A 
re d ucti o n i n t he F E V1  of 
 ass ociate d wit h cli nical s y m pt o ms of breat hless ness or ot her 
res pirat or y s y m pt o ms will be c o nsi dere d i nt olera bilit y of t he I M P a n d gr o u n ds f or disc o nti n uati o n 
of i n halati o n.  
1 0. 3. 2  R e pl a c e m e nt  of  Wit h d r a w n  P ati e nts  
Patie nts wit h dra w n bef ore ra n d o mizati o n (e. g., scree ni n g fail ures) will be re place d u ntil t he pre - 
defi ne d n u m ber of ra n d o mize d patie nts has bee n reac he d. If a s u bject fails t he scree ni n g pr ocess 
d ue t o n ot meeti n g i ncl usi o n/e xcl usi o n criteria, a re -scree ni n g is all o we d. Ra n d o mize d patie nts 
will n o t be re place d. T he eli gi bilit y of pre mat urel y wit h dra w n patie nts f or t he differe nt a nal ysis 
p o p ulati o ns will be deter mi ne d i n a bli n d data re vie w meeti n g wit h c o nsi derati o n of t he defi niti o n 
of t hese a nal ysis p o p ulati o ns pr o vi de d i n Secti o n 1 5. 1 . 
1 0. 3. 3  F oll o w -u p  of  Wit h d r a w n  P ati e nts  
Patie nts st o p pi n g t o ta ke st u d y treat me nt b ut n ot re v o ki n g t heir c o nse nt will be e nc o ura ge d t o 
c o nti n ue t he visits pla n ne d u ntil t he sc he d ule d e n d a n d perf or m all t he i m p orta nt safet y a n d 
efficac y assess me nt f or t he f ull d urati o n of t he st u d y.  
All  patie nts  wit h dra w n fr o m t he cli nical trial pre mat urel y will  be f oll o we d f or A Es a n d S A Es f or  
a f urt her 4 wee ks. A n y patie nt wit h o n g oi n g S A Es will be f oll o we d u ntil rec o ver y or sta bilizati o n 
of t he S A E.  
T he 4 -wee k safet y f oll o w -u p will be o bs olete if a patie nt c o m pletes partici pati o n i n t he cli nical 
trial a n d c o nse nts t o partici pate i n Cli nical Trial B T –  L -Cs A –  3 0 3 –  F U ( B O S T O N -3). I n t his 
case, safet y will be c o nti n u o usl y assesse d i n t he sc o pe of t he f oll o w -u p cli nical trial.  
1 0. 3. 4  C o m pl eti o n  of  Cli ni c al  T ri al  a n d  L o s t t o F oll o w -u p  
Patie nts will be c o nsi dere d t o ha ve c o m plete d t he cli nical trial if t he y were f oll o we d -u p t hr o u g h 
Visit 9 ( Wee k 4 8).  
A patie nt will be c o nsi dere d l ost -t o-f oll o w-u p o nl y if n o c o ntact has bee n esta blis he d b y t he ti me 
t he cli nical trial is c o m plete d s uc h t hat t here is i ns ufficie nt i nf or mati o n t o deter mi ne t he patie nt’s 
stat us at Visit 9  ( Wee k 4 8).  T he  I n vesti gat or s h o ul d d oc u me nt  atte m pts  t o re-esta blis h c o ntact wit h 
a n y missi n g patie nt t hr o u g h o ut t he cli nical trial peri o d. If c o ntact wit h a missi n g patie nt is re - 
esta blis he d, I M P i n halati o n a n d f oll o w -u p s h o ul d res u me acc or di n g t o t he pr ot oc ol.  
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  5 4  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
1 1  T R E A T M E N T O F  P A TI E N T S 
1 1. 1  St a n d a r d of  C a r e Al o n e 
Patie nts ra n d o mize d to t he c o ntr ol ar m will recei ve o nl y t he Sta n dar d of Car e re gi me n as 
prescri be d b y t he treatin g p h ysicia n a n d as de scri be d in Secti o n 9. 4. 2 . 
A n y c ha n ges i n Sta n dar d of Care treat me nt will be d oc u me nte d i n t he e C R F. 
1 1. 2  L- C s A pl u s  St a n d a r d of  C a r e 
Patie nts ra n d o mize d t o t he L- Cs A ar m will recei ve L- Cs A 5 m g t wice dail y i n a d diti o n t o S o C as 
prescri be d b y t he treati n g p h ysicia n a n d as descri be d i n Secti o n 9. 4. 2. L- Cs A will be a d mi nistere d 
as 5 m g/ 1. 2 5 m L i n halati o n via t he 
 f or 4 8 wee ks. 
A n y c ha n ges i n Sta n dar d of Care treat me nt will be d oc u me nte d i n t he e C R F. 
1 1. 3  C o n c u r r e nt T r e at m e nt o r  M e di c ati o n  
All partici pa nts ra n d o mize d, w het her e nr olle d i n t he L- Cs A ar m pl us S o C ar m or Sta n dar d of Care 
ar m of t his pr ot oc ol, will recei ve sta n dar d of care t hera pies f or t he mai nte na nce of t heir all o graft. 
S o C  i ncl u des mai nte na nce  i m m u n os u p pressi ve me dicati o n,  pr o p h yla xis  a gai nst c o m m o n 
o p p ort u nistic i nfecti o ns, a n d all ot her necessar y me dicati o ns a n d t hera pies f or t he o pti mal care of 
t he patie nt.  T his  als o i ncl u de vacci nati o n  agai nst  C o V- S A R S  2. C ha n ges  t o i m m u n os u p pressi o n 
a n d use  of  azit hr o m yci n  are als o c o nsi dere d  S o C.  All  c ha n ges i n t he c o nc urre nt  treat me nt or 
me dicati o n will be a d mi nistere d acc or di n g t o site’s sta n dar d of care. 
1 1. 3. 1  I m m u n o s u p p r e s si v e M e di c ati o n 
Mai nte na nce I m m u n os u p pressi ve T hera p y  
Mai nt e na nce  i m m u n os u p pressi ve t hera p y  i ncl u di n g tacr oli m us, a sec o n d a ge nt s uc h as b ut  n ot 
li mite d t o M M F  or azat hi o pri ne,  a n d a s yste mic c ortic oster oi d s uc h as pre d nis o ne  as t hir d a ge nt. 
will be a d mi nistere d acc or di n g t o i nstit uti o nal sta n dar ds. D osa ges, dates of start a n d st o p or c ha n ge 
i n d osa ge will be rec or de d o n t he res pecti ve e C R F. 
S yste mic  tacr oli m us d oses  s h o ul d n ot  nee d  t o be  a dj uste d  base d  o n pri or  e x perie nce  usi n g 
aer os olize d  c ycl os p ori ne  A.  H o we ver,  syste mic  tacr oli m us d os es s h o ul d be  a dj uste d  base d  u p o n 
re nal f u ncti o n. S h o ul d  ele vati o ns o f creati ni ne  occ ur  d uri n g  t he co urse  of t he  trial b y  3 0 % fr o m 
baseli ne  at ra n d o mizati o n, tacr oli m us le vels gi ve n  s yste micall y s h o ul d be  re d uce d b y 
a p pr o xi matel y 3 0 %  fr o m baseli ne  an d  le vels s h o ul d be  f oll o we d a n d  creati ni ne m o nit ore d 
acc or di n g t o sta n dar d pr ot oc ols at t he discreti o n of t he I n vesti gat or. 
I n t he e ve nt of re nal  i ns ufficie nc y (creati ni ne  > 2. 5 m g/ d L),  t he d ose  of oral  tacr oli m us ma y  be 
re d uce d b y 3 0 % a n d  t he creati ni ne  s h o ul d be  f oll o we d b y s u bse q ue nt  m o nt hl y  bl o o d  a nal yses. 
Alter nati vel y, a s witc h fr o m Calci ne uri n I n hi bit or ( C NI) t o m T O R i n hi bit ors s h o ul d be c o nsi dere d 
a n d will be all o we d. 
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  5 5  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
A u g me ntati o n  or  C ha n ge  of  I m m u n os u p pressi o n 
A u g me ntati o n or c ha n ge of i m m u n os u p pressi o n/i m m u n o m o d ulati o n f oll o wi n g ra n d o mizati o n of 
t he patie nt i nt o t he cli nical trial m ust be rec or de d o n t he c o nc o mita nt me dicati o n pa ge i n t he 
e C R Fs. 
1 1. 3. 2  P r o p h yl a xi s  a n d  T h e r a p y  of  I nf e cti o ns 
All patie nts will recei ve sta n dar d i nfecti o us disease pr o p h yla xis a n d t hera p y c o nsisti n g of 
a p pr o priatel y tar gete d a nti bi otics, a nti virals a n d/ or  a ntif u n gals acc or di n g t o i nstit uti o nal sta n dar ds. 
Dates of  start a n d st o p or c ha n ge i n d osa ge will be rec or de d o n t he res pecti ve e C R F.  
1 1. 3. 3  A zit h r o m y ci n  
Patie nts  recei vi n g azit hr o m yci n pri or  t o ra n d o mizati o n (f or pr o p h yla xis  or treat me nt of B O S)  m ust 
be o n a sta ble re gi me n f or at least 4 wee ks pri or t o ra n d o mizati o n. T hese patie nts ca n c o nti n ue t o 
recei ve azit hr o m yci n d uri n g t he cli nical trial as dee me d a p pr o priate b y t he i n vesti gat or. 
1 1. 3. 4  Ot h e r  M e di c ati o n  
All c o nc urre nt treat me nt or me dicati o ns gi ve n wit hi n 3 0 da ys pri or t o Ra n d o mizati o n a n d u ntil 
Visit 1 0/ E o S, will be rec or de d i n t he e C R F.  
T he use of a n y i n hale d f or m ulati o n of C ycl os p ori ne A ot her t ha n t he I M P is strictl y pr o hi bite d 
d uri n g  t he c o m plete cli nical trial peri o d. T o pical f or m ulati o ns  (e. g., e ye dr o ps)  c o ntai ni n g Cs A are 
all o we d. Patie nts s h o ul d n ot recei ve s yste mic C ycl os p ori ne A at a n y ti me d uri n g Scree ni n g a n d 
Ra n d o mizati o n. If me dicall y i n dicate d after Ra n d o mizati o n, t he treati n g p h ysicia n ca n e xc ha n ge 
Tacr oli m us f or s yste mic C ycl os p ori ne A.  
All i n hale d me dicati o ns, e xce pt i n vesti gati o nal i n hale d me dicati o ns, are per missi ble d uri n g t he 
trial a n d s h o ul d be a d mi nistere d i n t he f oll o wi n g or der: i n hale d br o nc h o dilat ors, i n hale d 
c ortic oster oi ds, i n hale d a ntif u n gals/a nti bi otics, a n d t he n i n hale d L -Cs A. S pir o metr y m ust be 
perf or me d wit h o ut t he use of br o nc h o dilat ors (see Secti o n 1 2. 1. 1 ) a n d prefera bl y bef ore b ut at 
least 2 h o urs after t he last a d mi nistrati o n of i n hale d a ntif u n gals/a nti bi otics. 
T o sta n dar dize s pir o metr y acr oss t he t w o treat me nt ar ms, patie nts s h o ul d n ot use s h ort -acti n g 
br o nc h o dilat ors (e. g., al b uter ol) wit hi n 2 h o urs pri or t o s pir o metr y.  Patie nts o n sc he d ule d L o n g - 
Acti n g Beta A g o nists ( L A B As) or L o n g -Acti n g M uscari nic A nta g o nists ( L A M As) s h o ul d i deall y 
ha ve s pir o metr y d o ne at t he sa me ti me of da y f oll o wi n g t heir sc he d ule d d ose.  Patie nts ha ve t o 
n ote t heir use a n d ti mi n g of br o nc h o dilat ors caref ull y.  
1 1. 3. 5  
 
 
 
 
 
 
 
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  5 6  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  5 7  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
1 2  A S S E S S M E N T O F  E F FI C A C Y 
1 2. 1  M et h o d s a n d Ti mi n g of  Effi c a c y A s s e s s m e nt s a n d A n al y s e s 
1 2. 1. 1  S pi r o m et r y 
1 2. 1. 1. 1  
 
F or o n-site s pir o metr y eac h cli nical trial site will be pr o vi de d wit h a 
 
, w hic h will sta y o n site. 
Cli nical trial pers o n nel at eac h site will be trai ne d a n d certifie d o n t he use of pr ot oc ol s pecific 
s oft ware i nstalle d o n t he 
 S pir o metr y will be meas ure d acc or di n g t o A merica n 
T h oracic S ociet y ( A T S)/ E ur o pea n Res pirat or y S ociet y ( E R S) s pir o metr y g ui deli nes at eac h visit 
[Miller 2 0 0 5a ; Miller 2 0 0 5 b ; Wa n ger 2 0 0 5 ; Pelle gri n o 2 0 0 5 ]. T hree acce pta ble ma ne u vers will be 
o btai ne d a n d t he lar gest val ue f or F V C  a n d F E V1 will be  rec or de d. T he 
 fr o m t he ma ne u ver 
wit h t he lar gest s u m of F E V1 + F V C will be rec or de d. F E V 1, F V C, a n d 
 will be rec or de d 
i n a bs ol ute ter ms. Ce ntralize d o verrea d will be a p plie d t o all ma ne u vers o btai ne d. 
It is well k n o w n t hat s pir o metr y relies o n t he c o o perati o n bet wee n t he patie nt a n d e xa mi ner a n d 
t hat t he res ults o btai ne d will de pe n d o n tec h nical as well as pers o nal fact ors. T heref ore, all eff orts 
will be u n derta ke n t o ha ve a partic ular patie nt assesse d b y t he sa me e xa mi ner. T o re d uce t he 
varia bilit y of t he res ults, t he met h o d s h o ul d be sta n dar dize d as far as p ossi ble. 
Wit hi n -ma ne u ver  acce pta bilit y  criteria: 
I n di vi d ual s pir o gra ms are  acce pta ble  if: 
•
T he y  are  free fr o m artefacts
o
C o u g h  d uri n g  t he first sec o nd  of  e x halati o n
o
Gl ottis  cl os ure t hat i nfl ue nces t he meas ure me nt
o
Earl y  ter mi nati o n or  c ut-off
o
Eff ort  t hat is n ot  ma xi mal  t hr o u g h o ut
o
Lea k
o
O bstr ucte d  m o ut h piece
•
T he y  ha ve  g o o d  starts
o
E xtra p olate d  v ol u me  <  5 %  of  F V C  or  0. 1 5  L  w hic he ver is  greater
•
T he y  s h o w satisfact or y e x halati o n
o
D urati o n of  6 sec o n ds or a platea u i n t he v ol u me -ti me c ur ve or if t he patie nt ca n n ot or
s h o ul d n ot c o nti n ue t o e x hale
Bet wee n -ma ne u ver  re peata bilit y criteria: 
After  t hree acce pta ble  s pir o gra ms ha ve  bee n  o btai ne d,  a p pl y t he f oll o wi n g test: 
•
T he  t w o lar gest val ues  of  F V C  m ust  be wit hi n  0. 1 5 0  L  of  eac h ot her
C CI
C CI
C CI
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  5 8  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
•
T he t w o lar gest val ues of F E V 1  m ust be wit hi n 0. 1 5 0 L of eac h ot her
If b ot h of t hese criteria are met, t he test sessi o n ma y be c o ncl u de d. 
If b ot h  of  t hese criteria  are n ot  met,  c o nti n ue  testi n g u ntil:  
•
B ot h of t he criteria are met wit h a nal ysis of a d diti o nal acce pta ble s pir o gra ms
or
•
A t otal of ei g ht tests ha ve bee n perf or me d ( o pti o nal)
or
•
T he  patie nt  ca n n ot  or  s h o ul d n ot  c o nti n ue
Sa ve, as a mi ni m u m, t hree acce pta ble a n d re peata ble ma ne u vers. 
1 2. 1. 1. 2  
 
Eac h  site will recei ve p orta ble s pir o meters 
 
 f or patie nts t o be use d at all o n-site a n d re m ote visits. Cli nical trial pers o n nel 
will be trai ne d i n t he use of t he 
, patie nts will be trai ne d b y t he cli nical trial 
pers o n nel i n t he use of t he de vice at scree ni n g. Refres her trai ni n g f or patie nts will be pr o vi de d at 
all s u bse q ue nt cli nic visits (a n d d uri n g re m ote visits, if re q uire d). T he patie nt will recei ve writte n 
i nstr ucti o ns o n h o w t o use t he  
 t o perf or m s pir o metr y c orrectl y. 
S pir o metr y o n t he  
 s h o ul d be perf or me d usi n g t he sa me wit hi n a n d bet wee n ma ne u ver 
criteria t hat w o ul d be a p plie d d uri n g o n-site s pir o metr y testi n g as descri be d a b o ve. T he lar gest 
val ue f or F V C a n d F E V 1 will be rec or de d. T he 
 fr o m t he ma ne u ver wit h t he lar gest s u m 
of F E V 1 + F V C will be rec or de d. F E V 1, F V C, a n d 
 will be rec or de d i n a bs ol ute ter ms. As a 
mi ni m u m, t hree acce pta ble a n d re peata ble ma n oe u vres will be rec or de d. 
T o assist t he cli nical trial pers o n nel a n d patie nt t o ac hie ve t he s pir o metr y wit hi n (acce pta bilit y) 
a n d bet wee n (re peata bilit y) ma n oe u vre criteria descri be d a b o ve ( Miller 2 0 0 5a ; Miller 2 0 0 5 b ; 
Wa n ger 2 0 0 5 ; Pelle gri n o 2 0 0 5), t he 
 will be pr o gra m me d t o gi ve fee d bac k. F or 
e xa m ple, if a n i n di vi d ual s pir o gra m di d n ot meet t he start of test criteria, t he de vice will i n dicate 
t o t he patie nt t here was a sl o w start of test. 
S pir o metr y data st ore d o n t he  
 de vice will be tra ns mitte d t o a ce ntral data base, via a G S M 
cra dle fr o m t he patie nts h o me a n d be s u bject t o ce ntralize d o verrea d. 
1 2. 1. 1. 3  Ge ner al c o nsi der ati o ns 
F or t he deter mi nati o n of eli gi bilit y at Scree ni n g, o nl y s pir o metr y data o btai ne d wit h t he 
 s pir o meter will be use d. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  5 9  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
T o sta n dar dize s pir o metr y acr oss t he t w o treat me nt ar ms, patie nts s h o ul d n ot use a s h ort-acti n g 
br o nc h o dilat or (e. g., al b uter ol) 2 h o urs pri or t o s pir o metr y. If patie nts are o n sc he d ule d L A B As 
or L A M As t he n t he ti me fr o m last d ose t o s pir o metr y s h o ul d be c o nsiste nt t hr o u g h o ut t he st u d y. 
S pir o metr y s h o ul d i deall y be perf or me d bef ore, or a mi ni m u m of 2 h o urs f oll o wi n g t he last 
i n halati o n of i n hale d a ntif u n gals/a nti bi otics. 
All i n hale d me dicati o ns, e xce pt i n vesti gati o nal i n hale d me dicati o ns, are per missi ble d uri n g t he 
trial a n d s h o ul d be a d mi nistere d i n t he f oll o wi n g or der: i n hale d br o nc h o dilat ors, i n hale d 
c ortic oster oi ds, i n hale d a ntif u n gals/a nti bi otics, a n d t he n i n hale d L- Cs A. 
S pir o metr y m ust al wa ys be  perf or me d bef ore L- Cs A i n halati o n. 
1 2. 1. 1. 4  O nsite visits 
O n -site s pir o metr y s h o ul d be perf or me d b y bli n de d pers o n nel. 
At e ver y visit, s pir o metr y will be meas ure d usi n g t he 
 a n d t he  
 s pir o meters. 
I nstr ucti o ns f or Use (i ncl u di n g a d diti o nal i nf or mati o n o n acc urac y c hec ks, clea ni n g of t he de vice 
a n d f urt her s u p p ort) f or b ot h de vices are a vaila ble i n t he St u d y Ma n ual. At least t hree acce pta ble 
a n d re peata ble ma ne u vers o n eac h de vice s h o ul d be o btai ne d at eac h visit. 
At Visit 1, t he s pir o metr y at 
 will o nl y be perf or me d usi n g t he 
 
S ufficie nt rest bet wee n b ot h s pir o metr y sessi o ns s h o ul d be gra nte d t o t he s u bject at t he 
I n vesti gat or’s discreti o n. F or t he  
 s pir o metr y sessi o n, pr oce d ures i de ntical t o t h ose t o be 
use d at h o me will be f oll o we d. 
1 2. 1. 1. 5  Re m ote visits 
If patie nts ca n n ot atte n d cli nic visits d ue t o C O VI D- 1 9, re m ote visits usi n g g ui de d h o me 
s pir o metr y ma y be perf or me d ( F E V 1,  
, a n d F V C) o n t he  
 de vice. F or re m ote visits, 
t he cli nical trial pers o n nel 
will tele p h o ne t he patie nt a n d g ui de t he m t hr o u g h perf or mi n g 
s pir o metr y o n t he  
 de vice (f or f urt her assess me nts d uri n g re m ote visits, see Secti o n 1 4. 2. 8 ). 
H o me s pir o metr y s h o ul d be sc he d ule d ar o u n d t he sa me ti me as t he us ual cli nic visits, w he ne ver 
p ossi ble, t o mi ni mize t he effects of circa dia n variati o n of l u n g f u ncti o n meas ure me nts. 
I n case meas ure me nts are n ot satisfact or y after ce ntral o verrea d, h o me s pir o metr y ma y be  re peate d 
as cl ose t o t he i nitiall y sc he d ule d re m ote visit as p ossi ble. 
1 2. 1. 2  P r o g r e s si o n of  B O S 
D ue t o t he patc h y distri b uti o n of affecte d areas i n t he p ul m o nar y all o graft, c hr o nic rejecti o n a n d 
B O S are n ot u nif or ml y detecta ble b y bi o ps y. T his met h o d has t ur ne d o ut t o be t o o u ns pecific a n d 
har mf ul f or r o uti ne dia g n ostic use. T heref ore, n o n-i n vasi ve s pir o metr y has bee n r o uti nel y 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  6 0  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
esta blis he d usi n g sta n dar dize d airfl o w meas ure me nts w hic h n o wa da ys is use d t o deter mi ne F E V 1 as 
a s urr o gate mar ker f or t he dia g n osis of B O S, its classificati o n a n d its c o ntr ol of pr o gressi o n. 
Pr o gressi o n of B O S d uri n g t he treat me nt peri o d is defi ne d as a decli ne of F E V 1 of ≥ 1 0 % or  ≥ 2 0 0 
m L fr o m Baseli ne F E V 1 a n d a bs ol ute decrease i n F E V 1/ F V C of > 5 % t hat is c o nfir me d b y 
meas ure me nts t hat are ta ke n wit h  
 s pir o meter at least 2 wee ks a part O R w orse ni n g i n 
B O S Se verit y gra de O R Re-tra ns pla ntati o n, O R Deat h fr o m res pirat or y fail ure. 
1 2. 1. 3  A u g m e nt ati o n or  C h a n g e of  I m m u n o s u p p r e s si o n 
A u g me ntati o n or c ha n ge of i m m u n os u p pressi o n/ i m m u n o m o d ulati o n m ust be rec or de d i n t he 
e C R Fs. 
1 2. 1. 4  R e -t r a n s pl a nt ati o n 
Re -tra ns pla ntati o n is defi ne d as t he date t hat a patie nt u n der g oes l u n g re-tra ns pla ntati o n s ur ger y. T he 
reas o n f or re-tra ns pla ntati o n will be rec or de d. At t he ti me of re-tra ns pla ntati o n, t he patie nt will be 
wit h dra w n fr o m t he st u d y. 
1 2. 1. 5  D e at h 
If a patie nt dies d uri n g t he cli nical trial, t he me dical m o nit or s h o ul d be c o ntacte d as s o o n as is 
feasi ble. T he ca use of deat h a n d a cli nical s u m mar y will be re q ueste d. 
1 2. 1. 6  A c ut e R ej e cti o n a n d it s S e v e rit y 
A patie nt wit h s y m pt o ms of a c o nc o mita nt me dical c o n diti o n s h o ul d be e val uate d as cli nicall y 
i n dicate d. If a patie nt is dia g n ose d wit h ac ute rejecti o n, t he dia g n osis s h o ul d be  rec or de d acc or di n g 
t o t he f oll o wi n g classificati o n sc he me. A n y me dicati o ns use d t o treat ac ute rejecti o n s h o ul d be 
rec or de d o n t he c o nc o mita nt me dicati o n e C R F. T he gra de of ac ute rejecti o n, air wa y i nfla m mati o n, 
c hr o nic air wa y rejecti o n a n d c hr o nic vasc ular rejecti o n will be e val uate d b y t he I n vesti gat or 
acc or di n g t o t he re vise d w or ki n g f or m ulati o n f or classificati o n a n d gra di n g of p ul m o nar y all o graft 
rejecti o n [Ste wart 2 0 0 7 ] (Ta ble 6 ): 
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 61 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
Table 6. Revised Working Formulation for Classification and Grading of Pulmonary 
Allograft Rejection 
A: Acute rejection 
Grade 0 
None 
Grade 1 
Minimal 
Grade 2 
Mild 
Grade 3 
Moderate 
Grade 4 
Severe 
B: Airway inflammation 
Grade 0 
None 
Grade 1R 
Low grade 
Grade 2R 
High grade 
Grade X 
Ungradable 
C: Chronic airway rejection – obliterative bronchiolitis 
0 
Absent 
1 
Present 
D: Chronic vascular rejection – accelerated graft vascular sclerosis 
“R” denotes revised grade to avoid confusion with 1996 scheme. 
12.1.7 Antibody-Mediated Rejection 
While less common in patients more than one-year post-transplant, if the treating physician 
makes the diagnosis of antibody-mediated rejection (AMR), this should be recorded in the eCRF. 
The diagnostic criteria and a working consensus definition established by the ISHLT with the 
aim of determining criteria for pulmonary AMR and establishing a definition should be used to 
support the diagnosis Levine 2016. See Appendix III for further information on Antibody- 
Mediated Rejection. 
12.1.8 Quality of Life Questionnaire (EQ-5D-5L) 
The EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical appraisal. Patients will be asked 
to manually complete the EQ-5D-5L at Visits 1, 4, 6, and 9/EoT and results will be entered into 
the eCRFs by site staff. 
12.1.9 Hospitalizations 
Hospitalizations for any reason other than a scheduled procedure should be regarded as serious 
adverse event and should be recorded in the eCRFs with admission date, discharge date, reason 
for admission, and additional diagnoses. If a patient requires mechanical ventilation for any 
reason other than a planned surgical procedure, dates of mechanical ventilation, and reason for 
mechanical ventilation should be recorded separately. A Hospitalization Discharge Summary 
may be requested by the Medical Monitor and shared with the DMC and/or AC. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 62 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
13 ASSESSMENT OF SAFETY 
13.1 Safety Parameters 
Safety Assessments at every visit include physical examination, vital signs, adverse event 
reporting, and clinical laboratory parameters (performed at the local labs in each study site). 
Acute tolerability of IMP during initial dosing will be assessed by spirometry before and after 
inhalation. 
COVID-19 specific consideration: In case the planned on-site visit cannot be performed, the PI or 
the Sub-Investigator and/or an appropriately qualified site study team member must call the patient 
to assess any potential adverse events (AEs) and to confirm the patient’s status and wellbeing (see 
also Section 14.2.8). 
13.1.1 Adverse Events (AEs) 
13.1.1.1 Definitions 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient after administration of a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product (ICH Guidelines for Good Clinical 
Practice, E6(R2), 9 November 2016). 
This includes worsening of a pre-existing condition or increase in frequency of a pre-existing 
condition. An adverse event is considered serious if it meets any of the serious criteria listed below. 
To ensure no confusion or misunderstanding of the difference between the terms “serious” and 
“severe”, which are not synonymous, the following clarification is provided: 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious”, which is based 
on patient/event outcome or action criteria usually associated with events that pose a threat to a 
patient’s life or functioning. Seriousness (not severity) serves a guide for defining regulatory 
reporting obligations. 
The official definition also extends to AEs occurring during the off-treatment follow-up period. 
Each patient will be closely observed and questioned for AEs throughout the clinical trial period 
with non-leading questions (e.g., how do you feel?). The patients will be instructed to report to the 
clinical trial staff immediately any symptoms and/or signs which occur between the scheduled 
observation times. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 63 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
All AEs reported by the patient or observed by the Investigator or hospital personnel will be 
documented in the respective eCRF. The following information regarding each adverse event will 
be obtained: date and time of onset and resolution (duration), serious or non-serious (as defined 
below), severity, treatment required, outcome, relationship to certain medication, and if the AE 
caused withdrawal from the clinical trial. 
In addition to the Investigator's own description of the AE, each AE event will be coded by data 
management according to the MedDRA code list. The verbatim term will be recorded in the eCRF. 
Abnormal laboratory test results will be reported as AEs if they are indicative of a clinical 
condition that meets the criteria for an AE. 
Adverse Drug Reaction (ADR) 
Adverse drug reactions (ADRs) are all noxious and unintended responses to a medicinal product 
related to any dose that a causal relationship between the medicinal product and an adverse event 
is at least a reasonable possibility, i.e., the relationship cannot be ruled out. An unexpected ADR 
is any adverse reaction not identified in nature, frequency, or intensity in the current Investigator’s 
Brochure. 
Serious Adverse Event (SAE) 
Each adverse event is to be classified by the Investigator as SERIOUS or NON-SERIOUS. 
The International Conference on Harmonisation (ICH) of Technical Requirements for Registration 
of Pharmaceuticals for Human Use defines a serious adverse event as any adverse event occurring 
at any dose that results in any of the following outcomes: 
•
Death
•
A life-threatening event (immediate risk of death at the time of the event)
•
Inpatient hospitalization or prolongation of existing hospitalization
•
A persistent or significant disability/incapacity
•
A congenital anomaly/birth defect
•
Other important medical event (Medical and scientific judgment should be exercised in
deciding whether expedited reporting is appropriate in other situations, such as important
medical events that may not be immediately life-threatening or result in death or
hospitalization but may jeopardize the patient or may require intervention to prevent one of
the other outcomes listed in the definition above. These should also usually be considered
serious.)
13.1.1.2 Relationship to Clinical Trial Treatment Assignment 
All adverse events will be evaluated by the Investigator for potential relationship to the clinical 
trial treatment assignment (L-CsA plus SoC or SoC alone) in the following categories: 

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  6 4  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
•
U nrel ate d : A n A E f or w hic h t here is n o e vi de nce of a n y ca usal relati o ns hi p wit h t he cli nical
trial treat me nt assi g n me nt
•
P ossi ble : A n A E t hat mi g ht be d ue t o t he use of t he cli nical trial treat me nt assi g n me nt. A n
alter nati ve e x pla nati o n, e. g.,  c o nc o mita nt dr u g(s), c o nc o mita nt disease(s), is i nc o ncl usi ve.
T he relati o ns hi p i n ti me is reas o na ble; t heref ore, t he ca usal relati o ns hi p ca n n ot be e xcl u de d.
•
Defi nite : A n a d verse e ve nt t hat f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n
of t he cli nical trial treat me nt assi g n me nt; t hat f oll o ws a k n o w n or e x pecte d res p o nse patter n
t o t he s us pecte d cli nical trial treat me nt assi g n me nt.
1 3. 1. 1. 3  M a xi m u m  I nt e nsit y 
All  a d verse  e ve nts will  be  gra de d  acc or di n g  t o t he f oll o wi n g: 
•
Mil d : E ve nt  re q uiri n g n o  s pecial treat me nt a n d ge nerall y  d oes  n ot  i nterfere wit h  us ual
acti vities.
•
M o der ate : E ve nt t hat i m pairs us ual acti vities b ut ma y be a meli orate d b y si m ple t hera pe utic
ma ne u vers.
•
Se vere *:  E ve nt  w hic h  i m pairs us ual  acti vities  a n d re q uires i nter ve nti o n.
* T here is a disti ncti o n bet wee n a se vere a d verse e ve nt a n d a seri o us a d verse e ve nt; a se vere
reacti o n is n ot a seri o us a d verse e ve nt u nless it meets o ne of t he criteria f or seri o us e ve nts (see
Secti o n 1 3. 1. 1. 1 ).
1 3. 1. 1. 4  S e ri o us  A d v e rs e  E v e nt  ( S A E) R e p orti n g  
A n y  seri o us a d verse  e ve nts occ urri n g  
•
bet wee n t he first cli nical trial pr oce d ure after o btai ni n g i nf or me d c o nse nt a n d wit hi n 4 wee ks
after t he c o m pleti o n of t he E o T visit, w het her or n ot c o nsi dere d relate d t o t he cli nical trial
treat me nt assi g n me nt
or
•
at a n y ti me after  c o m pleti o n of  t he last f oll o w-u p  a n d c o mi n g  t o t he atte nti o n  of  t he
I n vesti gat or, if it is j u d ge d as relate d t o t he patie nt’s partici pati o n i n t he cli nical trial
m ust  be  re p orte d  t o 
 I M M E DI A T E L Y, b ut  wit hi n  2 4  h o urs  u p o n  k n o wle d ge , as  f oll o ws: 
•
D oc u me nt  t he e ve nt i n t he e C R F wit hi n  2 4  h o urs  of  disc o ver y
•
S u b mit  t he S A E  re p ort b y  Fa x  or  e-mail  t o a list of  pre defi ne d  reci pie nts.
•
F oll o w -u p  t he S A E  u ntil  t he o utc o me  is deter mi ne d,  pr o vi di n g  peri o dic  u p dates  i n t he e C R F
•
Pr o vi de  a n y a d diti o nal  i nf or mati o n if re q ueste d
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  6 5  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
 
 
 
 
 
 
 
 
 
C o ntacts  of  
 are  as f oll o ws: 
1 3. 1. 1. 4. 1  Ti m eli n es f o r S us p ect e d U n e x p ect e d S e ri o us A d v e rs e R e acti o n ( S U S A R) r e p o rti n g t o 
C o m p et e nt A ut h o riti es a n d I R Bs / E Cs  
All s us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) will be re p orte d b y t he S p o ns or t o 
t he C o m pete nt A ut h orities a n d t o t he I R Bs/ E Cs c o ncer ne d as s o o n as p ossi ble, b ut wit hi n a 
ma xi m u m of 1 5 da ys (fatal or life -t hreate ni n g S U S A Rs wit hi n a ma xi m u m of 7 da ys) of first 
k n o wle d ge.  
Rele va nt f oll o w -u p i nf or mati o n of fatal or life -t hreate ni n g S U S A Rs will be c o m m u nicate d 
s u bse q ue ntl y wit hi n a n a d diti o nal ei g ht da ys.  
1 3. 1. 1. 4. 2  Ot h e r  E v e nts  t o b e  T r e at e d  as  S e ri o us  A d v e rs e  E v e nts  
E x p os ure  t o dr u g  d uri n g  pre g na nc y/lactati o n : 
I n pri nci ple, pre g na nc y a n d t he lactati o n peri o d are e xcl usi o n criteria. I n t he e ve nt of a pre g na nc y 
occ urri n g d uri n g t he c o urse of t h e cli nical trial, t he patie nt m ust be wit h dra w n fr o m all I M P 
treat me nt i m me diatel y a n d per ma ne ntl y. T he S p o ns or m ust be n otifie d wit h o ut dela y a n d t he 
patie nt f oll o we d d uri n g t he e ntire c o urse of t he pre g na nc y a n d p ost part u m peri o d. Pre natal a n d 
ne o natal o utc o mes m ust be rec or de d e ve n if t he y are c o m pletel y n or mal a n d wit h o ut A Es. T he 
S A E re p orti n g pr oce d ure s h o ul d be f oll o we d, e ve n t h o u g h pre g na nc y is n ot c o nsi dere d a n S A E. 
N o “seri o us criteri o n” s h o ul d be c hec ke d. T he S A E re p ort f or m is s olel y use d t o e ns ure e x pe dite d 
re p orti n g. 
If a n y cli nical trial patie nt bec o mes pre g na nt d uri n g t he cli nical trial peri o d, t he I n vesti gat or m ust 
c o ntact Za m b o n S p Aas t he S p o ns or of t he cli nical trial or its desi g nee t o disc uss t he ma na ge me nt 
of t he patie nt.  
1 3. 1. 1. 4. 3  I n v esti g ati o n al M e di ci n al  P r o d uct  O v er d osi n g  
A n o ver d ose is a deli berate or i na d verte nt a d mi nistrati o n of a treat me nt at a d ose hi g her t ha n 
s pecifie d i n t he pr ot oc ol. F or t he p ur p oses of t his cli nical trial, a n y d ose of aer os olize d I M P 
a d mi nistere d t o a patie nt t hat e xcee ds t he d ose f oresee n i n t he p r ot oc ol b y m ore t ha n 5 0 % o ver 4 
wee ks s h o ul d be re p orte d as a n o ver d ose.  
P P D
P P D
P P D
P P D

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  6 6  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
T he I n vesti gat or/ S p o ns or res p o nsi bilities i n re gar d t o re p orti n g S A Es are i n acc or da nce wit h t he 
U S F o o d a n d Dr u g A d mi nistrati o n a n d ot her C o m pete nt A ut h orities c o ncer ne d.  
1 3. 1. 1. 4. 4  E v e nts  n ot  R e g a r d e d  as  A d v e rs e  E v e nts / S eri o us  A d v e rs e  E v e nts  
T he f oll o wi n g  e ve nts will  be  n ot  re gar de d as A Es/ S A Es:  
•
Pre -sc he d ule d ( bef ore a n y trial-relate d acti vities c o m me nce d) h os pitalizati o ns/s ur geries/
i nter ve nti o ns
•
Trial  e n d p oi nt -relate d w orse ni n g;  t his will  be  assesse d  i n t he e n d p oi nt  a nal ysis.
1 3. 1. 1. 4. 5  D u r ati o n  of  F oll o w -u p  aft e r  A d v e rs e  E v e nts  
All a d verse e ve nts s h o ul d be f oll o we d u ntil t he y are res ol ve d or u ntil a sta ble cli nical e n d p oi nt is 
reac he d. T he occ urre nce of A Es a n d S A Es will be m o nit ore d u ntil 4 wee ks after t he E o T visit. 
A n y patie nt wit h o n g oi n g S A Es will be f oll o we d u ntil rec o ver y or sta bilizati o n of t he S A E.  
C O VI D -1 9 s pecific c o nsi derati o ns: All c o nfir me d cases of C O VI D -1 9, occ urri n g after t he patie nt 
has  pr o vi de d  i nf or me d c o nse nt a n d u ntil 4  wee ks after  t he E o T  visit,  m ust be  re p orte d as S A E,  a n d 
re p orte d t o 
 wit hi n 2 4 h o urs u p o n k n o wle d ge. 
T he seri o us ness criteri o n f or C O VI D -1 9 h os pitalize d patie nts s h o ul d be “ h os pitalizati o n”; if t he 
patie nt was n ot a d mitte d t o a h os pital or t he e ve nt is n ot res ulti n g i n pr ol o n ge d h os pitalizati o n, t he 
seri o us ness citeri o n “ me dicall y si g nifica nt” s h o ul d be use d.  
I n all cases, details of t he patie nt's s y m pt o ms, treat me nt a n d a n y cli nicall y rele va nt i nf or mati o n, 
s h o ul d be e ntere d i n t he S A E f or ms, as a p pr o priate. 
1 3. 1. 2  A c ut e  T ol e r a bilit y  of  L -Cs A  
Ac ute t olera bilit y of L -Cs A d uri n g i nitial d osi n g will be deter mi ne d b y meas uri n g s pir o metr y  
. F E V 1  will  be meas ure d  pri or t o  d osi n g  wit h  L -Cs A.  A  decli ne  of  
 ass ociate d  wit h  s y m pt o ms c o ul d warra nt  I M P disc o nti n uati o n . 
1 3. 1. 3  I nf e cti o ns 
Ac ute  i nfecti o ns will  be  e val uate d  acc or di n g t o t he f oll o wi n g criteria: 
•
Bacterial i nfecti o n:  bacterial i nfecti o ns will be dia g n ose d b y c o n ve nti o nal la b orat or y c ult ure
met h o ds i n c o m bi nati o n wit h cli nical s y m pt o ms [ B o n villai n 2 0 0 7 ]. P ne u m o nia re q uires
prese nce of ne w w orse ni n g i nfiltrates b y c hest ra di o gra p h y a n d gr o wt h of or ga nis ms i n
Br o nc h oal ve olar La va ge ( B A L) or s p ut u m sa m ples wit h a nti -micr o bial treat me nt.
•
F u n gal i nfecti o n:  t he re vise d c o nse ns us defi niti o ns of t he E ur o pea n Or ga nizati o n f or Researc h
a n d Treat me nt  of  Ca ncer  / M yc osis  St u d y  Gr o u p  will  be  use d  f or t he dia g n osis  of  f u n gal
C CI
C CI
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 67 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
infections [De Pauw 2008]. Fungal infections will be classified as proven, probable or possible 
according to host, clinical and microbiological criteria. 
•
Viral infection: the diagnosis of viral infection requires a 4-fold increase in serial serum 
samples and/or one of the following: a newly positive IgM antibody titer associated with 
clinical signs/symptoms requiring antiviral therapy; sero-conversion; virus isolation; or 
histopathologic evidence of viral infection [Bonvillain 2007]. The diagnosis of viral 
pneumonia requires impairment of either pulmonary mechanisms or gas exchange, or 
reduction in gas transfer in the appropriate clinical context.
Occurrence of acute infections will be monitored permanently throughout the complete clinical 
trial period. Sputum and BAL samples will be collected, if indicated, and monitored for the 
presence of bacterial, viral and fungal pathogens. 
An infection is defined as any acute infection requiring antimicrobial therapy. All acute infections 
will be reported as AEs. Information captured on the AE CRF will include: date of onset, pathogen 
identified, resolution, and action taken. 
In the case of an acute infection episode fulfilling the criteria of a serious adverse event, the 
reporting timelines as laid down in Section 13.1.1.4 have to be adhered to. 
The cumulative incidence of acute infections as well as the number of acute infections per patient 
will be summarized by treatment group. 
The samples should be evaluated by the local certified laboratory of each center. When needed 
due to unexpected circumstances and upon clinical judgment (e.g. patient travelling, acute event 
happening in a location distant to clinical center etc.), samples could also be analyzed by a 
different laboratory as per patient convenience and the related results will be provided to the 
Investigator. 
13.1.4 Malignancies 
All malignancies must be confirmed by histopathology. Malignancies will be documented on the 
AE CRF. 
13.1.5 Clinical Laboratory 
Laboratory assessments will be performed following the routine protocols at each visit by the local 
laboratory at each site. 
The following clinical laboratory parameters have to be documented: 
•
White Blood Cell (WBC) count with differential
•
Red Blood Cell (RBC) count
•
Platelet count
•
Alkaline phosphatase (AP)
•
Alanine Aminotransferase (ALT)

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 68 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
•
Aspartae Aminotransferase (AST)
•
Gamma Glutamyl Transferase (-GT)
•
Blood Urea Nitrogen (BUN)
•
Serum bilirubin
•
Serum creatinine
Laboratory assessments listed above will be performed at a certified local facility. 
13.1.5.1 Pregnancy Test 
Serum samples from women of childbearing potential will be collected for pregnancy tests at 
screening and with all scheduled blood draws. Positive results will be recorded in the eCRF and 
appropriate actions will be taken. At Visit 1, a serum or urine pregnancy test must be obtained 
within 7 days prior to randomization. A urine pregnancy test is allowed at this visit so that the 
result can be obtained rapidly in order to not delay randomization. 
13.1.5.2 Cyclosporine A and Tacrolimus Whole Blood Trough Levels 
A whole blood sample for the determination of cyclosporine A and/or tacrolimus trough level will 
be collected at each visit. In patients allocated to L-CsA inhalation, the sample should be collected 
within 60 minutes before inhalation. The mean cyclosporine A and/or tacrolimus trough level will 
be compared across treatment groups. Blood samples will be evaluated by the local laboratories. 
13.1.5.3 Donor Specific Antibody Test 
Serum samples for donor specific antibody testing will be collected at Screening, and at Visits 4, 6, 
and 9. If a DSA test performed within 4 weeks before screening is available, a further DSA test at 
screening visit will not be mandatory and the previous result will be reported in eCRF. 
13.1.5.4 Renal Function 
As lung transplant patients frequently present with symptoms of renal impairment special 
emphasis is paid for the key parameter of renal function, i.e., serum creatinine. The classification 
of renal dysfunction shall follow a unique terminology to describe the disorder (Table 7): 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 69 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
Table 7. Terminology of renal disorders 
Proposed Term 
Medical Condition 
Preferred Term 
Blood creatinine abnormal 
or 
Enhanced creatinine level 
or 
Increase of creatinine level 
Temporarily increased creatinine values 
due to medical or nutrition condition 
Blood creatinine increased 
Renal impairment 
Continuously increased creatinine values 
due to medical condition 
No treatment required 
Renal impairment 
Continuously increased creatinine values 
due to medical condition 
Treatment required and laboratory values 
clinically significant 
Acute renal dysfunction 
Creatinine value temporarily over 2.5 
mg/dL 
Possible actions: Fluid administration; 
adjustment of TAC/CsA or co-medication 
Renal impairment 
Severe renal dysfunction 
Creatinine value stable over 2.5 mg/dL 
Treatment required, but adjustment of 
TAC/CsA or co-medication not effective 
anymore; CNI toxicity 
Renal impairment 
Chronic severe renal dysfunction 
or 
Renal failure 
Creatinine value stable over 2.5 mg/dL 
Dialysis or renal transplantation required 
Renal impairment 
Renal Failure 
Terminology of renal disorders table is prepared in accordance with Dictionary MedDRA - 23.1 
13.1.6 Vital Signs 
Vital signs will be assessed at each visit. 
The following vital signs will be recorded: 
Systolic and diastolic blood pressure (sitting, after 5 minutes of rest), pulse rate (sitting, after 5 
minutes of rest), body temperature (the same method should be used for each patient and 
throughout the clinical trial), and respiratory rate. 
Abnormal values will be summarized by Common Toxicity Criteria (CTCAE) AE grade (version 
5.0) for each patient. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 70 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
13.1.7 Physical Examinations 
A physical examination will be carried out at the Screening Visit and at every subsequent visit. 
The following body systems will be examined: body weight, cardiovascular, respiratory, nervous, 
gastrointestinal, hepatic, renal, dermatological, musculoskeletal, extremities, eyes, ears, nose, 
throat, and lymphatic. Patient height will be measured at Screening Visit only. 
Abnormal findings will be summarized for each patient. 
13.2 Data Monitoring Committee (DMC) 
An independent Data Monitoring Committee (DMC) will be established to monitor the safety of 
IMP throughout the studies BT – L-CsA – 301 – SLT and BT – L-CsA – 302 – DLT. The DMC 
will monitor safety by evaluating the safety analysis generated by the unblinded independent 
statistician during the course of the clinical trial. Details of the safety analyses will be included in 
the DMC’s Charter. 
The DMC will evaluate treatment groups for possible trends in adverse events, determine whether 
the basic clinical trial assumptions remain valid, evaluate whether the overall integrity, scientific 
merit and conduct of the clinical trial remain acceptable, and make recommendations to the 
Sponsor. 
The DMC will peform a comparison between the rate of observed COVID-19 cases, rate of patients 
withdrawal, and rate of missing data among trial participants in both treatment arms. 
Members of the DMC will be unblinded to the treatment group label, i.e., the DMC will know 
which group is L-CsA + Standard of Care and which group is Standard of Care alone. The DMC 
will evaluate all safety and acute tolerability parameters, to be detailed in the DMC charter. 
Safety and acute tolerability parameters include adverse events, acute tolerability of L-CsA, acute 
infections, malignancies, clinical laboratory data (white blood cell count with differential, red 
blood cell count, platelet count, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, gamma glutamyl transferase, blood urea nitrogen, serum bilirubin, serum 
creatinine), vital signs, physical examinations and FEV1. The statistics provided will be merely 
descriptive. 
13.3 Adjudication Committee (AC) 
An independent, blinded Adjudication Committee (AC) will be established to assess all events 
that meet the progression of BOS criteria in every patient. Details of the event review will be 
included in the AC’s Charter. 

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  7 1  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
1 4  VI SI T  S C H E D U L E  
All cli nical trial visits, i n vesti gati o ns a n d acti vities are liste d i n t he Cli nical Trial Sc he d ule of 
Acti vities bel o w. F urt her details o n t he met h o d ol o g y of t hese i n vesti gati o n s a n d acti vities are 
descri be d i n detail i n Secti o n 1 2 a n d 1 3 . T he i n vesti gat or will a d here t o t he visit a n d pr oce d ure 
sc he d ule as cl osel y as p ossi ble. 
All patie nts assi g ne d t o a ra n d o mizati o n n u m ber will be f oll o we d acc or di n g t o t he pr ot oc ol u nless 
c o nse n t f or f oll o w-u p is wit h dra w n. T he S p o ns or m ust be n otifie d of all de viati o ns fr o m t he 
pr ot oc ol visit sc he d ule or e val uati o ns, a n d t hese visits/e val uati o ns, if a p plica ble, 
m ust be 
resc he d ule d or perf or me d at t he cl osest p ossi ble ti me t o t he ori gi nal sc he d ule. 
F or patie nts ra n d o mize d t o L -Cs A, pr o per patie nt u n dersta n di n g a n d c o m pete nc y of t he 
 
 use will be  e ns ure d i n a n i n di vi d ual trai ni n g b y  t he res p o nsi ble cli nic  pers o n nel. T he  patie nt 
will be a d mi nisteri n g t he dr u g i n de pe n de ntl y u n der s u per visi o n t o verif y patie nt c o m pete nc y wit h 
t he e q ui p me nt a n d dr u g t olera bilit y. 
After  ra n d o mizati o n, patie nts  will  visit  t he cli nic  e ver y 4 -8  wee ks  t hr o u g h o ut t he 4 8 -wee k  d urati o n 
of t he treat me nt peri o d.  
It is rec o m me n de d t hat t he I n vesti gat ors c o ntact t he patie nt a p pr o xi matel y 1 t o 2 wee ks pri or t o  
t he ne xt visit  t o re mi n d t he patie nt a b o ut t he ne xt sc he d ule d  visit. Patie nts will be i nstr ucte d  t o call 
cli nical trial pers o n nel t o re p ort a n y a b n or malities, i ncl u di n g a n y h os pitalizati o ns or d oct or visits 
d uri n g t he i nter val bet wee n visits a n d t o c o me t o t he cli nical trial site if me dical e val uati o n is 
nee de d a n d ur ge nc y of t he sit uati o n per mits. F or e mer ge nc y a n d ot her u nsc he d ule d visits t o a 
me dical facilit y  ot her t ha n t he cli nical trial site, me dical rec or ds of t he visit s h o ul d be o btai ne d b y 
t he I n vesti gat or. 
If a patie nt pre mat urel y disc o nti n ues cli nical trial partici pati o n f or a n y reas o n, a part deat h, re - 
tra ns pla ntati o n or wit h dra wal of c o nse nt, he/s he will be e nc o ura ge d t o c o m plete t he f oll o w-u p 
visits pla n ne d i n t he pr ot oc ol. All patie nts w h o pre mat urel y disc o nti n ue t he st u d y, i ncl u di n g t he 
o nes w h o u n der g o re -tra ns pla ntati o n or wit h dra ws c o nse nt f or f urt her partici pati o n i n t he cli nical 
trial, s h o ul d co m plete at least t he e val uati o n liste d u n der “ E n d of Treat me nt Visit” ( Visit 9) pri or  
t o disc o nti n uati o n, w he ne ver p ossi ble (t he reas o n f or pre mat ure wit h dra wal s h o ul d al wa ys be 
d oc u me nte d).  
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  7 2  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
Sc he d ule  of  Acti vities  
Cli nic al  Tri al  Peri o d  
Scree ni n g  
B aseli ne  
Tre at me nt  
Visit  N u m ber  
- 
V  1 
V  2 
V  3 
V  4 
V  5 
V  6 
Wee k  &  Wi n d o w  
W  -4  t o W
0 
W  0  D a y  1 
W  4  
 7  D a ys  
W  8  
 7  D a ys  
W  1 2  
 7  D a ys  
W  1 6  
 7  D a ys  
W  2 4  
 1 4  D a ys  
Hist orical S pir o metr y (fr o m patie nt’s me dical 
file) 
X  
I nf or me d C o nse nt 1 
X  
De m o gra p hics/ Me dical  Hist or y  
X  
X  
D o n or -s pecific A nti b o d y  Test  
X 9  
X 8  
X 8  
I ncl usi o n/ E xcl usi o n 
X  
X  
(c o nfir mati o n 
of  s cree ni n g) 
Ser u m/ Uri ne  Pr e g na nc y  Test 2 
X  
X 2  
X 8  
X 8  
X 8  
X 8  
X 8  
P h ysical  E xa mi nati o n 3 
X  
X  
X  
X  
X  
X  
X  
Vital  si g ns4 
X  
X  
X  
X  
X  
X  
X  
Cli nical  La b orat or y  Tests  
X  
X 1 0  
X 8  
X 8  
X 8  
X 8  
X 8  
S pir o metr y 5 
X  
X  
X  
X  
X  
X  
X  
Ra n d o mizati o n  
X  
L -Cs A  A d mi nistrati o n 6
T wice  dail y  a d mi nistrati o n of  5  m g  L -Cs A  
A d here nce  via  
 
Per ma ne ntl y  t hr o u g h o ut t he c o m plete cli nical  trial peri o d  (f or Israel: after E o T)  
Bl o o d  Sa m pli n g  ( C NI, m T or  i n hi bit ors)7 
X  
X  
X 8  
X 8  
X 8  
X 8  
X 8  
C o nc o mita nt  Me dicati o n  
X  
X  
X  
X  
X  
X  
X  
A d verse  E ve nts  
Per ma ne nt  assess me nt  t hr o u g h o ut t he c o m plete  cli nical  trial peri o d  
Ac ute  L -Cs A  T olera bilit y 6 
X  
Dr u g  Acc o u nta bilit y 6 
X  
X  
X  
X  
X  
E Q -5 D -5 L  
X  
X  
X  
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  7 3  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
Cli nic al  Tri al  Peri o d  
Tre at me nt  
F oll o w -U p  
Visit  N u m ber  
V  7 
V  8 
V  9  / E O T  
Re m ote  Visit  
V  2  –  V 8  
V  1 0  / E o S  
Wee k/ M o nt h  &  Wi n d o w  
W  3 2  
 1 4  D a ys  
W  4 0  
 1 4  D a ys  
W  4 8  
 1 4  D a ys  
W  5 2  
 7  D a ys  
D o n or -s pecific A nti b o d y  Test  
X 8  
Ser u m/ Uri ne  Pr e g na nc y  Test 2 
X 8  
X 8  
X 8  
X 8  
P h ysical  E xa mi nati o n 3 
X  
X  
X  
X  
Vital  Si g ns 4 
X  
X  
X  
X  
Cli nical  La b orat or y  Tests  
X 8  
X 8  
X 8  
X 8  
S pir o metr y 5 
X  
X  
X  
X  
X  
L -Cs A  A d mi nistrati o n 6
T wice  dail y  a d mi nistrati o n  of  5  m g  L -Cs A  
A d here nce  via  
 
Per ma ne ntl y  t hr o u g h o ut t he c o m plete cli nical trial peri o d  (f or Israel: after E o T)  
Bl o o d  Sa m pli n g  ( C NI, m T or  i n hi bit ors)7 
X 8  
X 8  
X 8  
X 8  
C o nc o mita nt  Me dicati o n  
X  
X  
X  
X  
X  
A d verse  E ve nts  
Per ma ne nt  assess me nt  t hr o u g h o ut t he c o m plete  cli nical  trial peri o d  
Ac ute  L -Cs A  T olera bilit y 6 
Dr u g  Acc o u nta bilit y 6 
X  
X  
X  
E Q -5 D -5 L  
X  
N O T E:  T he  Scree ni n g  p h as e  (ti m e bet w ee n  s cree ni n g a n d  r a n d o mi z ati o n visit)  l ast fr o m o ne  d a y  t o u p  t o 4  wee ks.  
1
2
3
4
5
6
7
8 
C o n d uct pri or t o a n y scree ni n g acti vities. 
N ot m ore t ha n 7 da ys pri or t o Ra n d o mizati o n. Uri ne pre g na nc y test is all o we d at Visit 1 o nl y. A ustria o nl y : Uri ne pre ga na nc y tests will be perf or me d e ver y 
m o nt h acc or di n g t o l ocal la w ( Visits 5 t hr o u g h 9). 
I ncl u di n g b o d y wei g ht, hei g ht ( Scree ni n g Visit o nl y), car di o vasc ular, res pirat or y, ner v o us, gastr oi ntesti nal, he patic, re nal, der mat ol o gical, m usc ul os keletal, 
e xtre mities, e yes, ears, n ose, t hr oat, a n d l y m p hatic. 
I ncl u di n g s yst olic a n d diast olic bl o o d press ure (sitti n g, after 5 mi n utes of rest), p ulse rate (sitti n g, after 5 mi n utes of rest), b o d y te m perat ure (t he sa me met h o d 
s h o ul d be use d f or eac h patie nt a n d t hr o u g h o ut t he cli nical trial), a n d res pirat or y rate. 
At all visits, s pir o metr y will be perf or me d o n t he  
 a n d o n t he  
 as per  Secti o n 1 2. 1. 1 . At t he Baseli ne Visit ( V 1), serial s pir o metr y is t o be 
perf or me d pri or t o Ra n d o mizati o n ( 
 a n d  
 
;  
 o nl y), a n d  
 
;  
 o nl y) after
c o m pleti o n of L- Cs A d ose ( or after Ra n d o mizati o n t o S o C). Re m ote visits will be perf or me d usi n g t he  
 de vice o nl y. Visit 1 0 s pir o metr y will be 
perf or me d i n t h ose patie nts n ot r olli n g o ver t o B ost o n 3 o n t he 
 o nl y. 
O nl y i n patie nts ra n d o mize d t o recei ve L- Cs A treat me nt. 
wit hi n 6 0 mi n utes pri or t o ne xt C NI a d mi nistrati o n. Bl o o d le vels of m T or i n hi bit ors will be ta ke n o nl y if a p plica ble, i.e., if patie nt is treate d wit h m T or 
i n hi bit ors. 
± 3 da ys of  t he Visit date.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 74 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
9  If a DSA test performed within 4 weeks before screening is available, a further DSA test at screening visit will not be mandatory. 
10  Laboratory tests at V1 are not mandatory in case laboratory tests at screening visit have been performed within 2 weeks from V1. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 75 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
SLT patient with 
confirmed BOS 
diagnosis 
14.1 Clinical Trial Flow Chart 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 76 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
14.2 Visits 
14.2.1 Screening 
Eligible patients who express interest in participating in the trial must sign an IRB/EC approved 
informed consent form (ICF) prior to initiation of any clinical trial activities. Patients who fulfill 
all of the inclusion criteria and none of the exclusion criteria may be enrolled into the clinical trial. 
Documentation of the patient’s consent and eligibility must be completed by the Investigator or 
his/her designee. All patients who fail the screening activities will be documented in the screening 
failure log. 
The following screening activities will be performed during the screening period (up to 4 weeks 
prior to Visit 1): 
•
Informed Consent: Obtain informed consent prior to performing any clinical trial activities.
•
Demographics: Year of birth, gender, ethnic group, date of body measurements, height and
weight.
•
Medical History: Details related to each patient’s lung transplant will be recorded and will
include: underlying condition (cause of lung failure), date, type of transplantation, donor
demographics, donor cause of death, donor/recipient Human Leukocyte Antigen (HLA)-
status, induction therapy, antiviral/antifungal/antibacterial therapy, cold ischemia time,
donor/recipient CMV-status, donor/recipient Epstein Barr Virus (EBV)-status, acute lung
injury. All other significant medical conditions (including GERD) and procedures (including
past surgeries) occurring before the ICF is signed will be recorded as medical history. Females
will be queried regarding their reproductive histories.
•
Confirmation of screening FEV1 above -51% of personal best FEV1 value post-
transplant.
•
Proof of diagnosis will be recorded.
•
Donor-specific antibody assay: Collect a blood sample for this assay at the Screening Visit.
If DSA test performed within 4 weeks before screening is available, a further DSA test at
screening visit will not be mandatory.
•
Inclusion/Exclusion Criteria: Evaluate eligibility for the clinical trial per the
inclusion/exclusion criteria.
•
Serum Pregnancy Test: Will be obtained in women of childbearing potential (see Appendix
II). A serum or urine pregnancy test must be obtained within 7 days prior to randomization.
•
Physical Examination: Body weight and height, cardiovascular, respiratory, nervous,
gastrointestinal, hepatic, renal, dermatological, musculoskeletal, extremities, eyes, ears, nose,
and throat, and lymphatic.
•
Vital Signs: Blood pressure, heart rate, body temperature, respiratory rate.
•
Clinical Laboratory Tests: All parameters listed in Section 13.1.5 of the protocol, to be
performed in the local laboratory at the site.

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  7 7  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
•
H a n d- H el d s pir o meter ( 
 Patie nts will be trai ne d b y site pers o n nel o n t he use of t his 
p orta ble s pir o meter.
•
 ( o n 
 a n d  
 F E V 1,  
, F V C, F E V 1/ F V C rati o. A 
s pir o metr y assess me nt will be  perf or me d o n t he  
 a n d o n t he  
 as per Secti o n  
1 2. 1. 1 .
•
D oc u me nt hist oric al s pir o metr y d at a fr o m pers o nal best p ost-tra ns pla nt pri or t o Scree ni n g, 
pl us
o
Date of pers o nal best F E V 1 p ost-tra ns pla nt a n d all l u n g f u ncti o n val ues a vaila ble
( F V C [a bs ol ute], F E V1 [a bs ol ute], 
 [a bs ol ute])
o
Dates of meeti n g B O S criteria a n d all l u n g f u ncti o n val ues a vaila ble ( F V C, F E V1, 
)
•
Bl o o d S a m pli n g: F or deter mi nati o n of ser u m le vels of calci ne uri n i n hi bit ors a n d m T or 
i n hi bit ors
•
D os a ges of m ai nte n a nce i m m u n os u p pressi o n: rec or d o n t he C o nc o mita nt Me dicati o n e C R F
•
C o nc o mit a nt Me di ati o ns/ T her a pies: Na me of dr u g, d osa ge, d urati o n
•
A d verse E ve nts
1 4. 2. 2  Vi sit  1  /  B a s eli n e  Visit  
B aseli ne  Pri or  t o St art  of Tre at me nt  
•
Verif y  I nf or me d C o nse nt  was  o btai ne d
•
Verif y  De m o gra p hics/ Me dical  Hist or y
•
Verif y  I ncl usi o n/ E xcl usi o n Criteria  were  met  at Scree ni n g  Visit
•
Re peat Ser u m ( or Uri ne) Pre g na nc y Test, if res ult was o btai ne d m ore t ha n 7 da ys pri or t o t he
visit
•
P h ysical  e xa mi nati o n
•
Vital  si g ns
•
Cli nical la b orat or y tests. N ot ma n dat or y i n case la b orat or y tests a t scree ni n g visit ha ve bee n
perf or me d wit hi n 2 wee ks fr o m Visit 1.
•
 ( 
 a n d  
 if nee de d, refres her trai ni n g f or  
 Patie nts will
be pr o vi de d wit h t he p orta ble s pir o meter at t he Visit 1 / Baseli ne Visit o nl y if t he patie nt wil l
be ra n d o mize d i n t he st u d y
•
Ra n d o mizati o n
•
Bl o o d  sa m pli n g f or ser u m le vels of  calci ne uri n i n hi bit ors a n d m T or  i n hi bit ors
•
C o nc o mita nt  me dicati o ns/t hera pies
•
A d verse  e ve nts
•
E Q -5 D -5 L  Q uesti o n naire
St art  of  Tre at me nt  
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  7 8  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
F oll o wi n g  acti vities  will  be  perf or me d  (i n p atie nts  r a n d o mize d  t o L -Cs A):  
•
Trai n  patie nt  o n  
 use,  dr u g  st ora ge, a n d i n halati o n tec h ni q ue
•
L -Cs A  A d mi nistrati o n:  o nl y  i n patie nts  ra n d o mize d t o recei ve L -Cs A  treat me nt. S u per vise
first i n halati o n.
•
Acti vate  
f u ncti o n i n t he cli nical  trial ce nter
•
E m p hasize  i m p orta nce of  a d here nce  t o I M P
•
E m p hasize i m p orta nce of a d here nce t o us ual me dicati o ns as ta ke n pri or t o partici pati n g i n t he
trial
•
 at 
 after
c o m pleti o n of I M P i n halati o n
•
Q ueries  a b o ut  ge neral  healt h  stat us
•
Verif y  patie nt  is fa miliar wit h  dr u g  a d mi nistrati o n  a n d use  of  ne b ulizer  de vice
Pri or  t o release fr o m cli nic, a de q uate  dr u g  a n d t he ne b ulizer  s yste m f or h o me  use  will  be  dis pe nse d 
t o eac h patie nt. 
F oll o wi n g  acti vities  will  be  perf or me d  (i n p atie nts  r a n d o mize d  t o St a n d ar d  of  C are  al o ne):  
•
Q ueries  a b o ut  ge neral  healt h  stat us
•
E m p hasize i m p orta nce of a d here nce t o us ual me dicati o ns as ta ke n pri or t o partici pati n g i n t he
trial
•
 (
 o nl y)  at 
 after
Ra n d o mizati o n
1 4. 2. 3  Visit  2  t h r o u g h Vi sit  9  /  E o T  
•
P h ysical  e xa mi nati o n
•
Vital  si g ns
•
Cli nical  la b orat or y tests
•
Ser u m pre g na nc y  test (f or A ustria o nl y: a d diti o nal m o nt hl y uri ne pre g na nc y tests bet wee n t he
trial Visits 5 t hr o u g h 9)
•
 (
 a n d 
 if nee de d,  refres her trai ni n g f or 
•
L -Cs A  A d mi nistrati o n
•
Bl o o d  sa m pli n g ser u m le vels of  calci ne uri n  i n hi bit ors a n d m T or  i n hi bit ors
•
C o nc o mita nt  me dicati o ns/t hera pies
•
A d verse  e ve nts
•
H os pitalizati o n
•
A d here nce  via  
•
Dr u g  Acc o u nta bilit y
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  7 9  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
1 4. 2. 4  Vi sit s  1,  4,  6,  a n d  9  /  E o T  
•
E ur o  Q ualit y  of  Life  Q uesti o n naire  ( E Q-5 D -5 L)
1 4. 2. 5  Vi sit  1 0  /  E n d  of  St u d y  ( E o S) 
O nl y  perf or me d:  
-
i n t h ose patie nts n ot r olli n g o ver t o B ost o n 3.
-
I n patie nts w h o deci de d t o wit h dra w t he c o nse nt d uri n g t he st u d y (if p ossi ble) [see secti o n 
1 0. 3. 1 ]
•
P h ysical  e xa mi nati o n
•
Vital  si g ns
•
Cli nical  la b orat or y tests
•
Ser u m  pre g na nc y  test
•
 (
•
Bl o o d  sa m pli n g f or ser u m le vels of  calci ne uri n i n hi bit ors a n d m T or  i n hi bit ors
•
C o nc o mita nt  me dicati o ns/t hera pies
•
A d verse  e ve nts
•
H os pitalizati o n
1 4. 2. 6  P e r m a n e ntl y  t h r o u g h o ut t h e c o m pl et e  cli ni c al  tri al p e ri o d  
•
A d verse  e ve nts
1 4. 2. 7  U n s c h e d ul e d  Vi sits  
W he ne ver me dicall y warra nte d, t he I n vesti gat or ma y as k t he patie nt t o a p pear or t he patie nt ma y 
elect t o a p pear at t he cli nic f or a n u nsc he d ule d visit. All me dical meas ures perf or me d as 
a p pr o priate s hall be d oc u me nte d i n t he Case Re p ort F or m f or u nsc he d ule d visits.  
1 4. 2. 8  R e m ot e  Vi sit s  ( V 2-V 8)  
I n case a patie nt visit t o t he site is n ot feasi ble d ue t o C O VI D-1 9, t he site will sc he d ule a re m ote 
visit wit h t he patie nt acc or di n g t o t he visit wi n d o ws as defi ne d i n t he Sc he d ule of Acti vities. T he 
sc he d ule d ti me a n d t he se q ue nce of pr oce d ures (i.e. s pir o metr y, I M P i n halati o n) s h o ul d be t he 
sa me as d uri n g o n-site visits. T he PI or S u b-I n vesti gat or a n d/ or a n a p pr o priatel y q ualifie d site 
st u d y tea m me m ber m ust call t he patie nt t o 
•
ca pt ure a n y p ote ntial a d verse e ve nts ( A Es) a n d t o c o nfir m t he patie nt’s  stat us a n d 
well bei n g.
•
ca pt ure a n y c ha n ges i n c o nc o mita nt me dicati o n
•
c hec k I M P s u p pl y wit h patie nt (if re q uire d re-s u p pl y nee ds t o be arra n ge d, see  Secti o n 9. 7 )
•
pr o vi de refres her trai ni n g f or 
 if nee de d (f or patie nts e nr ole d u n der pr ot oc ol  
versi o n 3. 0 or later)
C CI
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  8 0  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
•
g ui de t he patie nt t hr o u g h a s pir o metr y sessi o n usi n g t he 
 de vice (see Secti o n 
1 2. 1. 1 .). H o me s pir o metr y s h o ul d be sc he d ule d ar o u n d t he sa me ti me as t he us ual cli nic 
visits, w he ne ver p ossi ble, t o mi ni mize t he effects of circa dia n variati o n of l u n g f u ncti o n 
meas ure me nts (f or patie nts e nr ole d u n der pr ot oc ol versi o n 3. 0 or later).
•
re mi n d t he patie nt t o bri n g t heir 
 wit h t he m t o t heir ne xt cli nic visit s o t hat it ca n 
be c hec ke d a n d ret ur ne d t o t he m f or c o nti n ue d use.
•
re mi n d t he patie nt of I M P i n halati o n (t o be perf or me d after h o me s pir o metr y assess me nt 
has bee n c o m plete d, f or f urt her details see als o Secti o n 1 2. 1. 1. 4 )
T he PI or S u b -I n vesti gat or m ust c o nfir m if, i n t heir o pi ni o n, t he patie nt is sta ble a n d s uita ble f or 
pr ol o n ge d h o me -treat me nt, a n d t hat patie nt is i n a gree me nt t o c o nti n ui n g h o me-treat me nt u ntil 
t heir ne xt o n-site st u d y visit ca n occ ur. 
All  me dical  meas ures  perf or me d  as a p pr o priate  s hall be  d oc u me nte d  i n t he e C R F. 
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  8 1  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
1 5  S T A TI S TI C S 
T his  secti o n prese nts  an  o ver vie w  of t he pla n ne d  a nal yses.  Fi nal  a nal yses are n ot  li mite d t o t he 
s u m maries descri be d  herei n.  T he  Statistical  A nal ysis  Pla n  ( S A P) will  pr o vi de  a detaile d 
descri pti o n  of t he  pla n ne d  statistical a nal yses an d  data  s u m maries. If circ u msta nces arise d uri n g 
t he cli nical trial t hat ma ke t hese a nal yses i na p pr o priate or if i m pr o ve d met h o ds bec o me a vaila ble, 
t he S A P  ma y  be  re vise d. If discre pa ncies  e xist bet wee n  t he te xt of  t he statistical a nal ysis as 
pla n ne d i n t he pr ot oc ol a n d t he fi nal SA P,  t he fi nal S A P will defi ne t he pla n ne d a nal ysis of rec or d. 
Reas o ns f or s uc h discre pa ncies will be descri be d i n t he fi nal Cli nical St u d y Re p ort ( C S R). 
D ue t o seri o us e nr ol me nt pr o ble ms (see secti o n 1 5. 5 Sa m ple Size C o nsi derati o ns), it is e x pecte d t o 
cl ose t his st u d y wit h fe wer t ha n 1 1 0 patie nts ori gi nall y pla n ne d a n d c o nse q ue ntl y t he st u d y 
will be u n de r p o were d f or t he ass u me d effect. T heref ore, all pl a n ne d a nal yses will be pe rf or me d 
a n d t he im pact of t he re d uce d sa m ple w ill be c o nsi dere d. . For t he sa me reas o n, t he pr e- pla n ne d 
bli n de d i nteri m anal ysis for sa m ple size re-esti mati o n will n o t be p erf or me d. T he S tatistical 
A na l ysis P la n ( S A P) will pr o vi de a de tailed descri pti o n of t he statistical anal yses. 
T he pri ma r y o utc o me meas ure of t he trial is t he differe nce in mea n F E V 1 ( m L) c ha n ge fr o m 
baseli ne t o Wee k 4 8 bet wee n t he L- Cs A pl us S oC an d S o C al o ne gr o u ps. 
 
 
 
F or t he p ur p ose of t his stu d y, “ baseli ne F E V 1” is t he mea n of t he best F E V1 o btai ne d at t he 
Scree ni n g Visit a n d t he best F E V 1 o btai ne d at t he Baseli ne (ra n d o mizati o n) Visit.  
F or all s pir o meter- base d meas ure me nts see secti o n 1 5. 3. 
Data w ill b e liste d b y patie nt an d treat me nt gr o u p. 
1 5. 1  A n al y si s D at a S ets 
T he f oll o wi n g a nal ysis data sets will be a nal yze d: 
S afet y a n al ysis set ( S A F Set) 
T he  S A F  is defi ne d  as all ra n d o mize d patie nts  i n t he S o C  gr o u p a n d  all ra n d o mize d patie nts 
recei vi n g at least o ne d ose of I M P i n t he L- Cs A pl us S o C gr o u p. All data c ollecte d after baseli ne 
t o t he e n d of cli nical trial partici pati o n  wi ll be  i ncl u de d i n t he safet y s u m maries. Patie nts  will  be 
a nal yse d acc or di n g t o t he treat me nt t he y act uall y recei ve d. 
F ull a n al ysis set ( F A S) 
T he F A S is defi ne d as all ra n d o mize d patie nts f o r w h o m at least o ne p ost- baseli ne meas ure of t he 
pri ma r y o utc o me meas ure is a vaila ble. Pa tie nts w ho recei ve a u g me ntati on of S o C thera p y, are re- 
tra ns pla nted, or die bef ore t he first p ost- baseli ne assess me nt of t he pri ma r y o utc o me meas ure will 
be retai ne d in t he F A S. P atie nts will be a nal yse d acc or di n g to t he treat me nt gr o u p to w hic h t he y 
w ere ra n d o mize d. 
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 82 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
A Data Review Meeting (DRM) will be used to determine if patients should be excluded from the 
FAS in cases of significant, major protocol deviations that would interfere with the assessment of 
treatment efficacy (e. g., patients not suffering from the condition under investigation). 
Per Protocol Set (PPS) 
The PPS is defined as all patients included in the FAS 
•
who complete randomized treatment as scheduled or who are withdrawn prematurely due to
lack of efficacy or lack of tolerability of the clinical trial treatment, and
•
for whom no major protocol deviations interfering with the assessment of treatment efficacy
are observed.
Eligibility for the analysis data sets will be determined in DRMs held after closing the database 
before the final analysis. Protocol deviations will be classified as ‘major’ when a significant 
influence on the assessment of the primary outcome measure for treatment efficacy cannot be 
excluded. Comprehensive justification for the classification of a protocol deviation as ‘major’ will 
be given in the DRM minutes as well as in the integrated CSR. Any exclusion of patients from the 
FAS will require individual justification. 
The primary analysis of treatment efficacy will be performed in the FAS. An additional efficacy 
analysis in the PPS will be provided as a sensitivity analysis. Any data pertaining to safety and 
tolerability will be analyzed in the SAS. 
15.2 Statistical and Analytical Methods 
15.2.1 Descriptive Statistics 
The data recorded in the case report forms will be summarized as appropriate, per treatment group 
and for the total group, using the following descriptive measures: 
•
All continuous assessments will be summarized using descriptive statistics (i.e., n, mean,
standard deviation, median, Q1, Q3, minimum, and maximum).
•
All categorical assessments will be summarized by time point, as applicable, using frequency
counts and percentages.
•
Discrete ordinal or higher-level data will be summarized as continuous data, but a tabulation
of categories may be included additionally depending on the number of categories.
For all measures analyzed descriptively (i. e., measures to characterize the treatment groups and 
their baseline status, efficacy, and safety outcomes), tabulations comparing the treatment groups 
will be prepared. For outcomes measured more than once, the analyses will include tabulations of 
the measured values by visit as well as an analysis of change from baseline. Where provided, all 
confidence intervals will be two-sided 95% confidence intervals. 

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  8 3  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
1 5. 2. 2  C h a r a ct eri z ati o n  a n d  B a s eli n e  C o m p a r a bilit y  of  T r e at m e nt  G r o u p s  
T he n u m ber a n d perce nta ge of patie nts w h o c o m plete a n d disc o nti n ue t he st u d y treat me nt a n d t he 
n u m ber a n d perce nta ge of patie nts w h o c o m plete a n d disc o nti n u e t he cli nical trial as well as 
reas o ns f or earl y disc o nti n uati o n ( of b ot h st u d y treat me nts) will be prese nte d. 
Descri pti ve statistics will be prese nte d f or de m o gra p hic, a nt hr o p o metric, me dical hist or y, a n d 
a nti b o d y -res p o nse data. 
1 5. 2. 3  A n al y s e s  of  Effi c a c y  
1 5. 2. 3. 1  P ri m a r y  e n d p oi nt  
A n al ysis  p o p ul ati o n  a n d  esti m a n d  
F E V 1  data c ollecte d fr o m t he  o n site  
 s pir o meter will be c o nsi dere d pri mar y, w hile t he 
data c ollecte d wit h t he  
 h o me s pir o meter will be use d f or s u p p orti ve a nal yses.  
T he pri mar y efficac y para meter is t he differe nce i n mea n F E V 1  c ha n ge fr o m baseli ne t o Wee k 4 8 
bet wee n L -Cs A pl us S o C a n d S o C al o ne i n t he F A S p o p ulati o n. I nterc urre nt e v e nts will be 
i g n ore d, i n li ne wit h t he “treat me nt p olic y strate g y” (I C H E 9 a d de n d u m o n esti ma n ds a n d 
se nsiti vit y a nal ysis i n cli nical  trials t o t he g ui deli ne  o n  statistical pri nci ples  f or cli nical  trials). After 
i nterc urre nt e ve nts s uc h as st o p pi n g treat ment wit h L -Cs A, a u g me ntati o n of S o C t hera p y etc., 
F E V 1  meas ure me nts will still be c ollecte d a n d use d i n t he a nal ysis. I nterc urre nt e ve nts pre ve nti n g 
t he use of F E V1  meas ure me nts after t he e ve nt are deat h, re -tra ns pla ntati o n, a n d wit h dra wal of t he 
patie nt’s c o nse nt. It is a ntici pate d t hat t hese e ve nts will be rare i n t his patie nt p o p ulati o n. T he 
esti ma n d will be esti mate d as if t hese e ve nts ha d n ot ha p pe ne d, i.e., t he u n o bser ve d F E V 1  data of 
s uc h patie nts will be m o dele d u ntil t he sc he d ule d e n d of treat me nt at Wee k 4 8.  
W o r ki n g  h y p ot h esis  
T he alterati ve h y p ot hesis ( H 1) f or t his trial is t hat L-Cs A pl us S o C is s u peri or t o S o C al o ne i n 
preser vi n g F E V 1, i. e., u n der H1  it is e x pecte d t hat patie nts treate d wit h L-Cs A pl us S o C will 
e x hi bit a s maller mea n F E V 1  decli ne bet wee n baseli ne a n d t he e n d of Wee k 4 8 t ha n t h ose w h o 
recei ve S o C al o ne. 
T h e  a n al ysis  m o d el  
T he pri mar y efficac y a nal ysis will be carrie d o ut wit h a li near mi xe d m o del ( L M M) f or re peat e d 
meas ure me nts, usi n g all a vaila ble F E V 1  meas ure me nts. T he de pe n de nt varia bles are t he a bs ol ute 
c ha n ge fr o m baseli ne of F E V 1  meas ure me nts at visits 2 (i. e., t he first p ost -baseli ne visit) t o 9 
( Wee k 4 8). 
A fle xi ble a n d r o b ust m o del will be c h ose n f or t h e ra n d o m part of t he L M M acc or di n g t o a pre - 
s pecifie d ste p wise pr oce d ure as descri be d i n detail i n t he S A P. T he fi xe d part of t he L M M is 
s pecifie d as f oll o ws. Ti me  will  be  re prese nte d i n a fle xi ble a n d r o b ust wa y  usi n g  c u bic  s pli nes, as 
C CI
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  8 4  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
descri be d i n detail i n t he S A P. T he m o del pr o p ose d i n t he ori gi nal pr ot oc ol c o ntai ne d t he f oll o wi n g 
c o variates (a part fr o m t he i nterce pt): ti me s pli nes, treat me nt, t he i nteracti o ns of ti me s pli nes b y 
treat me nt, baseli ne F E V1, t he i nteracti o ns of ti me s pli nes wit h t he baseli ne F E V1, re gi o n ( N ort h 
A merica vers us all ot her c o u ntirs t o get her), u n derl yi n g i n dicati o n f or l u n g tra ns pla nt ( C O P D vs 
all ot her), a n d use of azit hr o m yci n at ra n d o mizati o n. D ue t o t he re d uce d sa m ple size (see secti o n 
1 5. 5  Sa m ple Size C o nsi derati o ns), t he c o variates will be selecte d ta ki n g i nt o acc o u nt m o del 
c o n ver ge nce. T he pri mar y efficac y esti ma n d will be esti mate d fr o m t he m o del as t he a dj uste d 
differe nce bet wee n gr o u ps i n mea n F E V 1 c ha n ge fr o m baseli ne after 4 8 wee ks. T he o ne-si de d p- 
val ue a n d t he t w o-si de d 9 5 % c o nfi de nce i nter val will be pr o vi de d. S u peri orit y of L- Cs A will be 
de m o nstrate d b y a statisticall y si g nifica nt res ult ( defi ne d as p < 0. 0 2 5, o ne-si de d) i n fa v or of t he L- 
Cs A pl us S o C treat me nt. 
S e nsiti vit y a n al ys es 
Se veral se nsiti vit y a nal yses were pla n ne d i n t he ori gi nal pr ot oc ol. D ue t o t he re d uce d sa m ple size, 
t he val ue of t hese se nsiti vit y a nal yses is re d uce d a n d s o me of t he m mi g ht n ot be a p plica ble. 
I nterc urre nt missi n g val ues a n d val ues missi n g d ue t o deat h, re-tra ns pla ntati o n, a n d wit h dra wal of 
c o nse nt are ass u me d t o be 
Missi n g At Ra n d o m ( M A R). Se nsiti vit y a nal yses t o t he 
M A R 
ass u m pti o n 
will be perf or me d usi n g differe nt a p pr oac hes, i ncl u di n g selecti o n 
m o delli n g, 
si m ulta ne o us m o delli n g of re peate d F E V 1 o utc o me a n d ti me t o dr o p o ut, a n d c o ntr olle d missi n g 
val ues i m p utati o n, a n d a n a nal ysis w here re-tra ns pla ntati o n a n d deat h are i ncl u de d i n t he defi niti o n 
of o utc o me varia ble a n d esti ma n d as w orst o utc o mes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  8 5  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 5. 2. 4  C u m ul ati v e  M ai nt e n a n c e  I m m u n os u p p r e ssi o n 
T he t otal i m m u n os u p pressi o n a d mi nistere d fr o m t he da y o f ra n d o mizati o n will be e val uate d. At 
eac h trial visit, t he d oses of calci ne uri n i n hi bit ors (e. g., tacr oli m us), a nti meta b olic a ge nts (e. g., 
m yc o p he n olate 
m ofetil), a n d c ortic oster oi ds 
will be rec or de d b y t he I n vesti gat or o n t he 
c o nc o mita nt 
me dicati o ns e C R F . T he c u m ulati ve d ose of 
mai nte na nce i m m u n os u p pressi ve 
treat me nt will be s u m marize d f or eac h gr o u p a n d c o m pare d descri pti vel y. 
1 5. 2. 5  A n al y si s  of  S af et y  
Safet y o utc o mes are liste d i n Secti o n 1 3. 1 . All safet y meas ures will be c o m pare d descri pti vel y 
bet wee n t he treat me nt gr o u ps i n acc or da nce wit h t he c o nce pt of descri pti ve data a nal ysis i n t he 
S A F  p o p ulati o n. Treat me nt  gr o u p  c o m paris o ns of safet y  o utc o mes will  be  base d  o n  statistical tests 
a n d c o nfi de nce i nter vals (if a p plica ble).  
1 5. 2. 5. 1  E xt e nt  of  E x p os ur e  
E x p os ure t o I M P will be c o nfir me d base d o n t he re p ort of I M P vials ret ur ne d a n d d osi n g 
rec or de d i n t he cli nical data base. 
1 5. 2. 5. 2  A d v e rs e  E v e nts  
A d verse e ve nts ( A Es) will be c o de d usi n g t he 
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A). E ve nts  will  be  i de ntifie d as treat me nt-e mer ge nt ( T E A E) a n d n o n -treat me nt-e mer ge nt 
( N o n-T E A E) o n t he basis of t he date of o nset relati ve t o t he date of ra n d o mizati o n.  
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 86 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
Summaries (number and percentage of events as well as of patients with any events of a particular 
type) of treatment-emergent AEs (by system organ class and preferred term) will be provided. 
Number (%) of patients experiencing TEAEs by severity, relationship to IMP, seriousness, and 
action taken with regard to IMP will be summarized. Number (%) of patients with TEAEs leading 
to discontinuation of clinical trial participation will also be summarized. 
15.2.5.3 Laboratory and Other Safety Evaluations 
For clinical safety laboratory test results and vital signs, the numeric values and corresponding 
changes from baseline will be summarized using descriptive statistics by parameter and time point. 
In addition to the tables showing the distribution parameters, laboratory measures will be presented 
in ‘shift tables’ that show the position of all patients relative to the applicable reference range at 
clinical trial entry, broken down by the position at clinical trial exit. Common Toxicity Criteria 
(CTC version 5.0) will be applied to abnormal laboratory test results and abnormal vital signs. 
Parameters reflecting acute tolerability of IMP (spirometry, cough, or dyspnea) will be 
summarized. 
15.3 Interim Analysis 
Due to serious enrolment problems (see section 15.5 Sample Size Consideration), the originally 
pre-planned blinded interim analysis for sample size re-estimation will not be performed. 
15.4 Missing Data 
See Sections 15.2.3.1 and 15.2.3.2. 
15.5 Sample Size Considerations 
The initial sample size was based on the following considerations. Assuming a treatment group 
difference for mean FEV1 change from baseline of 200 mL and a standard deviation of 350 mL at 
the end of treatment Week 48, an independent samples t-test with a one-sided type I error level of 
=0.025 will have at least 80% power to reject the null hypothesis when the sample size in each 
treatment group is at least 50 patients. To compensate for a loss of power due to premature 
withdrawals, a total of 110 patients will initially be randomized. 
However, due to serious enrolment problems with the present study, it was agreed with FDA to 
enrol approximately 220 patients with clinically defined bronchiolitis obliterans syndrome (BOS) 
considering the present (BOSTON-1) and the BT – L-CsA – 302 – DLT (BOSTON-2) studies 
combined, in order to obtain an adequately sized safety database for L-CsA inhalation. Therefore, 
randomization will be stopped when this target is reached and it is anticipated that much fewer 
than the 110 patients originally planned (i.e., approximately 50-60 patients) will be randomized in 
the present study. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 87 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
16 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents. Examples of these original documents and data records include 
but are not limited to: hospital records, clinical and office charts, laboratory notes, memoranda, 
patients’ diaries or questionnaires or evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilms or magnetic media, X- 
rays, patient files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
Case report forms, all copies of test results, and clinical trial-related regulatory documents [e.g., 
Informed 
Consents, 
Institutional 
Review 
Board 
(IRB)/Ethics 
Committee 
(EC) 
approvals/correspondence, etc.] must be available always for regulatory agency inspection and 
review by the Sponsor or its designee. During the periodic site monitoring visits, the source 
documents will be verified against data entered onto the eCRF to assure that all data is accurately 
and completely reflected on the patient’s eCRF. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 88 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
17 QUALITY CONTROL AND QUALITY ASSURANCE 
This clinical trial will be monitored by the Sponsor or its designee according to ICH GCP 
guidelines. A site visit will be held prior to initiation of patient enrollment. The protocol, CRFs, 
IMP supplies, and relevant procedures will be explained in detail at the Site Initiation Visit. 
Subsequent to patient enrollment, a site monitor from the Sponsor or its designee will review the 
eCRFs and source documents to ensure that the clinical trial is conducted according to the protocol 
and ICH GCP guidelines. 
To ensure compliance with ICH GCP guidelines and all applicable regulatory requirements, the 
Sponsor or its designee may conduct a quality assurance audit. Regulatory agencies may also 
conduct a regulatory inspection of this clinical trial. Such audits or inspections can occur at any 
time during or after completion of the clinical trial. If audits or inspections occur, the Investigator 
and the institution agree to allow the auditor/inspector direct access to all relevant documents and 
to allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 89 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
18 INSTITUTIONAL REVIEW BOARD (IRB)/ETHICS COMMITTEE (EC) 
The protocol and informed consent form(s) for this clinical trial must be approved by an 
appropriately constituted Institutional Review Board (IRB)/Ethics committee (EC) as defined by 
local requirements. A list of the IRB/EC voting members, their titles or occupation, and their 
institutional affiliations (if available and allowable under EU law) and/or the IRB/EC general 
assurance number, if applicable, must be submitted to the Sponsor or its designee to be archived 
in the Trial Master File. 
Any documents that the IRB/EC may need to fulfill its responsibilities, such as protocol 
amendments, and information concerning patient recruitment, payment or compensation 
procedures, or information from Zambon SpAwill be submitted to the IRB/EC. The IRB’s/EC’s 
written approval/favorable opinion of the protocol and the informed consent form/patient 
information leaflet will be in the possession of the Investigator before the clinical trial is initiated. 
The IRB’s/EC’s unconditional approval/favorable opinion statement will be transmitted by the 
Investigator to Zambon SpAor its designee prior to shipment of IMP supplies to the site. This 
approval/favorable opinion must refer to the clinical trial by exact protocol title and number, and 
should identify the documents reviewed and the date of review. 
Protocol modifications or changes may not be initiated without prior written IRB/EC 
approval/favorable opinion except when necessary to eliminate immediate hazards to the patients 
or when the change(s) involves only logistical or administrative aspects of the clinical trial. Such 
modifications will be submitted to the IRB/EC and written verification that the modification was 
submitted should be obtained. 
The IRB/EC must be informed by the Investigator of informed consent changes or revisions of 
other documents originally submitted for review; serious and/or unexpected adverse events 
occurring during the clinical trial; new information that may adversely affect the safety of the 
patients or the conduct of the clinical trial; an annual update and/or request for re-approval; and 
when the clinical trial has been completed. 
The Investigator will ensure that the conduct of the clinical trial conforms to the Declaration of 
Helsinki (current revision) and with applicable national laws and regulations for clinical research. 
Before starting this clinical trial, the protocol will be submitted to each center’s Institutional 
Review Board/Ethics Committee for evaluation at each site. As required, the clinical trial will not 
start before the IRB/EC has given approval/favorable opinion. 
Periodic status reports and adverse events must be submitted to the IRB/EC according to the 
IRB/EC reporting requirements. The IRB/EC must also be notified of completion of the clinical 
trial and a final report must be submitted to the IRB/EC in accordance with the IRB/EC reporting 
requirements. The Investigator must maintain an accurate and complete record of all 
communication, reports and submissions to the IRB/EC. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 90 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
19 PATIENT INFORMED CONSENT 
Patients will be required to sign a statement of informed consent that meets the requirements of 
the Code of Federal Regulation (US FDA Title 21 CFR 50), local regulations, ICH GCP guidelines 
(ICH E6R2), and the IRB/EC of the center. The medical record will include a statement that written 
informed consent was obtained before the patient was enrolled in the clinical trial and the date 
written consent was obtained. 
Members of the treating team will review the nature of the clinical trial, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits and alternative therapies including 
best supportive care. Patients must be informed that participation in the clinical trial is voluntary, 
he/she may withdraw from the clinical trial at any time and withdrawal from the trial will not affect 
his/her subsequent medical treatment or relationship with the treating physician. Financial costs 
that will or may be incurred as a result of participation in the trial, as well as the efforts to maintain 
patient confidentiality will also be discussed. 
This consent must be dated and retained by the Investigator/Designeeas part of the clinical trial 
records. A copy of the informed consent form must be given to the patient. If the patient signed 
the informed consent more than 30 days prior to the date of randomization, it should be 
documented that consent has not been rescinded. Alternatively, the site should follow the 
IRB/EC’s requirement for re-consenting a patient. 
If an Experimental Patient’s Bill of Rights is applicable at the Investigator’s site, that form must 
also be prepared and signed by each patient and retained as a part of the required clinical trial 
records. A copy of the Bill of Rights must be given to the patient or the patient’s legally authorized 
representative. 
A copy of the IRB/EC approved consent form must be submitted to Zambon SpAor its designee 
prior to shipment of IMP supplies to the Investigator. Each patient’s signed informed consent must 
be kept on file by the Investigator for regulatory authority and Sponsor inspection at any time. 
The HIPAA Privacy rule authorization or General Data Protection Regulation (GDRP) language 
must be included in the Informed Consent/authorization form (or a separate authorization 
document) and approved by the IRB/EC (or Privacy board) as applicable. 
The Declaration of Helsinki, as amended (version of Fortaleza, 2013), recommendations guiding 
doctors in clinical research must be signed by the Investigator and returned to the Sponsor or its 
designee. A copy must also be kept on file by the Investigator. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 91 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
20 NOTIFICATION TO AUTHORITIES 
The protocol and any applicable documentation (e.g., patient information, informed consent form) 
will be notified to the regulatory authorities in compliance with applicable US, Israeli, and 
European regulations. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 92 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
21 DATA HANDLING AND RECORD KEEPING 
21.1 Confidentiality 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number and initials only. All clinical trial records will be kept at each 
center in a secure location. Clinical information will not be released without written permission of 
the patient, except as necessary for monitoring or inspections by the authorities or a designee of 
the Sponsor as described in the informed consent form. The Investigator must also comply with 
all applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act of 
1996). 
The Investigator must assure that the privacy of the patients, including their personal identity and 
all personal medical information, will be maintained at all times. In CRFs and other documents 
patients will not be identified by their names, but by an identification code (e.g., by an arbitrary, 
unique patient number). 
The Investigator agrees that all information received from Zambon SpAincluding but not limited 
to this protocol, eCRF, and any other clinical trial information, remain the sole and exclusive 
property of Zambon SpA during the conduct of the clinical trial and thereafter. This information 
is not to be disclosed to any third party (except employees or agents directly involved in the 
conduct of the trial or as required by law) without prior written consent from Zambon SpA The 
Investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the investigative site to any third party or otherwise into the public domain. 
21.2 Completion of Electronic Case Report Forms 
An eCRF will be used in this clinical trial. Staff authorized to enter or modify data on the eCRF 
will be assigned an appropriate user role: 
•
study coordinators or nurses may enter, modify, or delete data and may enter, modify, or delete
responses to queries;
•
investigators may perform the same activities as study coordinators. Moreover, they may
authorize data by entering an electronic signature.
Any data entries, modifications, and deletions will be recorded in an automated audit trail together 
with a time stamp and the identification code of the person performing the entry / modification / 
deletion. 
To access the eCRF authorized users will receive a unique user name and password that will also 
be required for data authorization (investigators only). These credentials are strictly personal and 
confidential and must not be shared with anyone. 

L-CsA: 
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 93 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
 
 
 
Investigators will be provided with detailed eCRF Completion Guidelines that will identify the 
required data points to be collected, how to document them and when these data should be 
documented. Appropriate training in electronic data capture and support will be provided. 
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs to record 
(according to the eCRF Completion Guidelines) all observations and other data pertinent to the 
clinical trial obtained during scheduled, remote or unscheduled visits. All eCRFs should be fully 
completed to ensure accurate data interpretation. 
All eCRF entries should be made within a maximum of two weeks of a visit by a designated and 
trained member of the site staff. The Investigator must ensure the accuracy, completeness legibility 
and timeliness of data reported in the eCRF and all required reports. Any change or correction to 
an eCRF must be documented as instructed and explained (if necessary) in the clinic notes, this 
applies to both written and electronic changes. The patient’s medical source documents must 
support any changes made. 
Data reported in the eCRF that are derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 
The investigator must review and electronically sign the completed eCRF casebook to verify its 
accuracy. 
The main objective is to obtain those data required by the protocol in a complete, accurate, legible, 
and timely fashion. These data in the eCRF should be consistent with the relevant source 
documents. 
The eCRFs and the corresponding electronic database shall be processed, evaluated, and stored in 
anonymous form in accordance with the personal data-protection regulations. 
These data recorded in the course of this clinical trial may periodically be remotely reviewed and 
compared to the electronic database. The computerized handling of these data after receipt of the 
eCRFs may generate additional requests via electronic queries to which the Investigator is obliged 
to respond by confirming or modifying these data questioned. These requests with their responses 
will be available in the audit trial of the eCRFs held by the Investigator and Sponsor. 
The eCRFs are regulatory documents and must be suitable for electronic submission to authorities. 
The Investigator must keep a separate patient identification list showing code numbers, names, 
and dates of birth to allow unambiguous identification of each patient included in the clinical trial. 
A note will be made in the hospital medical records that the patient is participating in a clinical 
trial. The eCRF will be completed appropriately. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 94 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
21.3 Source Data and Patient Files 
The Investigator has to keep a paper or electronic patient file for every patient participating in the 
clinical trial. In this patient file, the available demographic and medical information of a patient 
has to be documented, in particular the following: name, date of birth, sex, height, weight, patient 
history, concomitant diseases and concomitant medication (including changes during the clinical 
trial), statement of entry into the clinical trial, trial identification, patient number, the date of 
informed consent, all visit dates, pre-defined performed examinations and clinical findings, 
observed AEs (if applicable) and reason for withdrawal from clinical trial treatment or from the 
trial (if applicable). It should be possible to verify the inclusion and exclusion criteria for the 
clinical trial from the available data in this file. It must be possible to identify each patient by using 
this patient file. 
Additionally, any other documents with source data, especially original printouts of data that were 
generated by technical equipment have to be filed. This may include laboratory value listings, ECG 
recordings, X-rays, CT scans, etc. (if applicable). All these documents have to bear at least the 
patient identification and the printing date printed by the recording device to indicate to which 
patient and to which procedure the document belongs. The medical evaluation of such records 
should be documented as necessary and signed/dated by the Investigator. 
Printouts of computerized patient files must be signed and dated by the Investigator, and kept as a 
source document. 
21.4 Investigator File and Archiving 
The Sponsor will provide, and the investigator will maintain an Investigator Site File (ISF) 
containing all essential documents for the clinical trial. The ISF will contain each patient’s eCRF 
pdf after the database has been locked. The investigator should maintain a record of the 
location(s) of their respective essential documents including source documents. The storage 
system used during the trial and for archiving (irrespective of the type of media used) should 
provide for document identification, version history, search and retrieval. 
Essential documents are subject to audit and inspection at all times and will be archived according 
to applicable regulatory requirements. 
21.5 Monitoring, Quality Assurance, and Inspection by Authorities 
This clinical trial is to be conducted in accordance with ICH GCPE6 (R2) and applicable US, 
Israeli and European regulations. Monitoring and auditing of the trial will be the responsibility of 
the Sponsor or a designee authorized by the Sponsor. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 95 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
To ensure compliance with ICH GCP (E6R2)guidelines and all applicable regulatory 
requirements, the Sponsor or its designee may conduct quality assurance audits. Regulatory 
agencies may also conduct a regulatory inspection of this clinical trial. Such audits or inspections 
can occur at any time during or after completion of the clinical trial. If audits or inspections occur, 
the Investigator and the institution agree to allow the auditor/inspector direct access to all relevant 
documents and to allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any relevant issues and to implement corrective and preventive actions for 
such findings. 
21.6 Data Management and Data Control 
The Sponsor will be responsible for the processing and quality control of the data. Data 
management and filing will be carried out as described in the contracted CRO's SOPs for clinical 
trials. 
Prior and concurrent medications within 30 days of randomization will be listed. Prior/concurrent 
medications will be coded using the World Health Organization (WHO-DD) classification system 
and grouped by drug class and preferred term. AEs and medical history terms will be coded using 
MedDRA. 
The eCRF data and patient data listings will be archived by the Sponsor for the lifetime of the 
product. No clinical trial document or image should be destroyed without prior written agreement 
between the Sponsor and the Investigator. Should the Investigator wish to assign the clinical trial 
records to another party or move them to another location, advance written notice should be given 
to the Sponsor. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 96 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
22 FINANCING AND INSURANCE 
A separate financial agreement (Clinical Investigators' Agreement) will be made between each 
Investigator and the Sponsor before the IMP is delivered. The Sponsor will ensure financing of 
the complete clinical trial. 
The clinical trial is covered under a Sponsor group combined liability insurance policy. The 
certificate of insurance and an information leaflet containing essential information about the 
insurance coverage will be provided upon request. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 97 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
23 PUBLICATIONS 
After conclusion of the clinical trial, an integrated clinical and statistical study report will be 
prepared by the Sponsor or designee. The first publication of the clinical trial will comprise of data 
from the entire clinical trial population enrolled at all sites. Any publications of the results, either 
in part or in total (abstracts in journals or newspapers, oral presentations, etc.) by Investigators or 
their representatives will require pre-submission review by the Sponsor. The Sponsor is entitled to 
delay publication in order to obtain patent protection. For more details regarding publications, refer 
to the clinical trial agreement/Investigator trial agreement. 
The results of the clinical trial will be published and/or presented in scientific meetings in a timely 
manner. Any formal publication of clinical trial results will be a collaborative effort between the 
Sponsor and the Investigator(s). All manuscripts and abstracts will be reviewed and approved in 
writing by the Sponsor prior to submission. 
Policies regarding the publication of the clinical trial results are defined in the Clinical 
Investigator's Agreement. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 98 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
24 REFERENCES 
Barker AF, Bergeron, A Rom WN et al. Obliterative bronchiolitis. N Engl J Med 2014;370:1820- 
1828. 
Behr J, Zimmermann G, Baumgartner R et al. Lung deposition of a liposomal cyclosporine A 
inhalation solution in patients after lung transplantation. J Aerosol Med Pulm Drug Deliv 
2009;22(2):121-130. 
Bonvillain RW, Valentine VG, Lombard G et al. Post-operative infections in cystic fibrosis and 
non-cystic fibrosis patients after lung transplantation. J Heart Lung Transplant 2007; 26:890-897. 
Chacon RA, Corris PA, Dark JH et al. Tests of airway function in detecting and monitoring 
treatment of obliterative bronchiolitis after lung transplantation. J Heart Lung Transplant 
2000;19:263-269. 
Corcoran TE, Smaldone GC, Dauber JH et al. Preservation of post-transplant lung function with 
aerosol cyclosporin. Eur Respir J 2004;23(3):378-383. 
Corcoran TE. Inhaled delivery of aerosolized cyclosporine. Advances Drug Delivery Reviews 
2006;58:1119-1127. 
De Pauw B, Walsh TJ, Donnelly JP et al. Revised definitions of invasive fungal disease from the 
European Organization for Research and Treatment of Cancer/Invasive Fungal Infections 
Cooperative Group and the National institute of Allergy and Infectious Disease Mycoses Study 
Group. Clin Infect Dis 2008;46:1813-1821. 
Estenne M, Maurer JR, Boehler A et al. Bronchiolitis obliterans syndrome 2001: an update of the 
diagnostic criteria. J Heart Lung Transplant 2002;21(3):297-310. 
Glanville AR, Verleden GM, Todd JL et al. Chronic lung allograft dysfunction: Definition and 
update of restricitive allograft syndrome.A consensus report from the Pulmonary Council of the 
ISHLT, J Heart Lung Transplant 2019;5:483-492. 
Halloran PF. Immunosuppressive agents in clinical trials in transplantation. Am J Med Sci 
1997;313(5):283-288. 
Heng D, Sharples LD, McNeil K et al. Bronchiolitis obliterans syndrome: Incidence, natural 
history, prognosis, and risk factors. J Heart Lung Transplant 1998;17:1255-1263. 
Iacono AT, Johnson BA, Grgurich WF et al. A randomized trial of inhaled cyclosporine in lung- 
transplant recipients. N Engl J Med 2006;354(2):141-150. 
Iacono AT, Keenan RJ, Duncan SR et al. Aerosolized cyclosporine in lung recipients with 
refractory chronic rejection. Am J Respir Crit Care Med 1996;153(4 Pt 1):1451-1455. 
International Society for Heart and Lung Transplantation (ISHLT). (2017). Registry data. 

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  9 9  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
Retrie ve d fr o m htt ps:// w w w.is hlt. or g/re gistries/sli des.as p?sli des = heart L u n g Re gistr y 
I nter nati o nal S ociet y  f or H eart a n d L u n g  Tra ns pla ntati o n  (I S H L T). G ui da nce  fr o m t he 
I nter nati o nal S ociet y of Heart a n d L u n g Tra ns pla ntati o n re gar di n g t he S A R S C o V- 2 pa n de mic 
- R E VI S E D: 
A pril 4, 2 0 2 0 
Recei ve d fr o m 
htt ps://is hlt. or g/is hlt/ me dia/ d oc u me nts/ S A R S-
C o V - 2 _- G ui da nce-for - Car di ot h oracic- Tra ns pla nt-a n d- VA D -ce nters. p df 
Kiese r M , Frie de T . Si m ple pr oce d ures f or bli n de d sa m ple size a dj ust me nt t hat d o n ot a ffect t he 
t y pe I err or rate. Stat M e d 2 0 0 3; 2 2( 2 3): 3 5 7 1- 3 5 8 1. 
Le vi ne  D,  Gla n ville  A,  A b o y o u n  C et  al. A nti b o d y- me diate d  rejecti o n of t he  l u n g: A  c o nse ns us 
re p ort of t he  I nter nati o nal S ociet y  f or Heart a n d L u n g  Tra ns pla ntati o n.  J Heart  L u n g  Tra ns pla nt 
2 0 1 6; 3 5: 3 9 7- 4 0 6. 
Me yer  K D,  Ra g h u  G , Verle de n  G M,  et al. A n  i nter nati o nal I S H L T/ A T S/ E R S cli nical practice 
g ui deli ne: dia g n osis a n d ma na ge me nt of br o nc hi olitis o blitera ns s y n dr o me.  E ur Res pir J 2 0 1 4; 4 4: 
1 4 7 9 – 1 5 0 3.  
Mille r M R, Cra p o R, Ha n ki ns o n J et al. Ge neral c o nsi derati o ns f or lu n g f u ncti on testin g. E ur 
Re s pir J 2 0 0 5 b; 2 6: 1 5 3- 1 6 1. 
Mille r M R, Ha n ki ns o n J, Br usasc o V et al . Sta n dar disati o n of s pir o metr y. E ur Res pi r J 
2 0 0 5a; 2 6: 3 1 9- 3 3 8.  
Pell e grin o R, Vie gi G,  Br usasc o V et al. I nter pretati ve strate gies f or l u n g f u ncti o n tests. E ur Res pir 
J 2 0 0 5; 2 6( 5): 9 4 8- 9 6 8. 
S o u ba ni 
A O , U berti J P . Br o nc hi olitis 
o blitera ns f oll o wi n g 
hae mat o p oietic ste m 
cell 
tra ns pla ntati o n. E ur Res pir J 2 0 0 7; 2 9( 5): 1 0 0 7- 1 0 1 9. 
Ste wart S , Fis h bei n M , S nell G . R e visio n of t he 1 9 9 6 W or ki n g f or m ulatio n f or t he sta n dar dizati o n 
of n o me nclat ure in t he d ia g n osis of l u n g rejecti o n. J H eart L u n g Tra ns pla nt 2 0 0 7; 2 6: 1 2 2 9- 1 2 4 2. 
U K  S m P C Cicl os p ori n A 
). 
Verle de n  G M,  Gla n ville  A R,  Lease  E D,  et al. C hr o nic  l u n g all o graft  d ysf u ncti o n:  Defi niti o n, 
dia g n ostic  criteria  a n d a ppr oac hes  t o treat me nt. A  c o nse ns us re p ort fr o m t he P ul m o nar y  C o u ncil 
of t he I S H L T, J Heart L u n g Tra ns pla nt 2 0 1 9; 5: 4 9 3- 5 0 3. 
Wa n ge r J, Cla use n J L, C oates A et al. Sta n dar disati o n o f t he meas ure me nt of l u n g v ol u mes. E ur 
Res pir J 2 0 0 5; 2 6( 3): 5 1 1- 5 2 2. 
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 100 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
25 APPENDIX I – CORE INFORMED CONSENT FORM 
The informed consent form must be adapted to local requirements but must contain at least the 
following points: 
•
That the trial involves research.
•
The purpose of the trial.
•
The trial treatment(s) and the probability for random assignment to each treatment.
•
The trial procedures to be followed, including all invasive procedures.
•
The patient’s responsibilities.
•
Those aspects of the trial that are experimental.
•
The reasonably foreseeable risks or inconveniences to the patient and, when applicable, to an
embryo, foetus, or nursing infant.
•
The reasonably expected benefits. When there is no intended clinical benefit to the patient,
the patient should be made aware of this.
•
The alternative procedure(s) or course(s) of treatment that may be available to the patient, and
their important potential benefits and risks.
•
The compensation and/or treatment available to the patient in the event of trial related patient
injury.
•
The anticipated prorated payment, if any, to the patient for participating in the trial.
•
The anticipated expenses, if any, to the patient for participating in the trial.
•
That the patient‘s participation in the trial is voluntary and that the patient may refuse to
participate or withdraw from the trial, at any time, without penalty or loss of benefits to which
the patient is otherwise entitled.
•
That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be
granted direct access to the patient‘s original medical records for verification of clinical trial
procedures and/or data, without violating the confidentiality of the patient, to the extent
permitted by the applicable laws and regulations and that, by signing a written informed
consent form, the patient is authorizing such access.
•
That records identifying the patient will be kept confidential and, to the extent permitted by
the applicable laws and/or regulations, will not be made publicly available. If the results of
the trial are published, the patient’s identity will remain confidential.
•
That the patient will be informed in a timely manner if information becomes available that

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 101 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
may be relevant to the patient‘s willingness to continue participation in the trial. 
•
The person(s) to contact for further information regarding the trial and the rights of trial
patients, and whom to contact in the event of trial-related injury.
•
The foreseeable circumstances and/or reasons under which the patient‘s participation in the
trial may be terminated.
•
The expected duration of the patient‘s participation in the trial.
•
The approximate number of patients involved in the trial.
•
Information regarding the trial can be found on clinicaltrials.gov.

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 102 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
26 APPENDIX II – ACCEPTABLE METHODS OF CONTRACEPTION 
A woman is considered of childbearing potential, i.e. fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. The status of post-menopausal is defined 
as no menses for 12 months without an alternative medical cause and/or the age of 60 years. 
According to the Clinical Trial Facilitation Group (CTFG) dated 15/04/2014, the following 
methods are allowed for contraception during the clinical trial with a failure rate of less than 1%: 
•
combined (estrogen and progestogen containing) hormonal contraception associated with
inhibition of ovulation 1:
o oral
o intravaginal
o transdermal
•
progestogen-only hormonal contraception associated with inhibition of ovulation 1:
o oral
o injectable
o implantable 2 
•
intrauterine device (IUD) 2 
•
intrauterine hormone-releasing system (IUS) 2
•
bilateral tubal occlusion 2 
•
vasectomised partner 2,3 
•
sexual abstinence 4 
From results of previous clinical trials with aerosolized L-CsA potential interactions
between the IMP and hormonal contraceptives have not been investigated. It is
recognized that hormonal contraceptives can increase serum levels of systemically dosed
cyclosporine, but cyclosporine does not alter the efficacy of hormonal contraceptives.
Subjects in the trial will be monitored for systemic cyclosporine levels.
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the contraception method 
2 Contraception methods that in the context of this guidance are considered to have low user dependency.
3Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant
and that the vasectomised partner has received medical assessment of the surgical success. 
4 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 103 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
27 APPENDIX III – ANTIBODY-MEDIATED REJECTION 
Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte 
antigens and characteristic lung histology with or without evidence of complement 4d within the 
graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is 
not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be 
asymptomatic) or sub-clinical (normal allograft function). Both clinical and sub-clinical AMR 
were further sub-categorized into 3 mutually exclusive possibilities (definite, probable and 
possible). These categories were based on the degree of certainty related to the presence or absence of 
a number of pathologic, serologic, clinical and immunologic criteria (Table 8 and Table 9). 
Table 8. Definition and diagnostic certainty of clinical pulmonary AMR 
Allograft 
dysfunction 
Other 
causes 
excluded 
Lung 
histology 
Lung biopsy 
C4d 
DSA 
Definite 
+ 
+ 
+ 
+ 
+ 
Probable 
+ 
+ 
+ 
- 
+ 
Probable 
+ 
+ 
+ 
+ 
- 
Probable 
+ 
+ 
- 
+ 
+ 
Probable 
+ 
- 
+ 
+ 
+ 
Possible 
+ 
+ 
+ 
- 
- 
Possible 
+ 
+ 
- 
- 
+ 
Possible 
+ 
+ 
- 
+ 
- 
Possible 
+ 
- 
+ 
+ 
- 
Possible 
+ 
- 
+ 
- 
+ 
Possible 
+ 
- 
- 
+ 
+ 
DSA, donor-specific antibodies; +, item present; - item absent or missing 

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 104 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
Table 9. Definition and diagnostic certainty of sub-clinical pulmonary AMR 
Lung histology 
Lung biopsy C4d 
DSA 
Definite 
+ 
+ 
+ 
Probable 
+ 
- 
+ 
Probable 
- 
+ 
+ 
Probable 
+ 
+ 
- 
Possible 
+ 
- 
- 
Possible 
- 
+ 
- 
Possible 
- 
- 
+ 
DSA, donor-specific antibodies; +, item present; - item absent or missing 

L -Cs A:
Tr eat me nt  of  B O S  aft er  S L T  
Pr ot oc ol  N u m ber:  
B T  –  L -Cs A  –  3 0 1  –  S L T  
S p o ns or: 
Za m b o n  S p A  
Pa ge  1 0 5  of  1 0 6  
Cli ni cal  Tri al  Pr ot oc ol  B T  –  L -Cs A  –  3 0 1  –  S L T 
Versi o n 5. 0 _ 2 -Fe br uar y -2 0 2 3  
 
T he St u d y Pr ot oc ol versi o n 5. 0 ( A me n d me nt 4) 
 
 
 
 
 
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteria set f ort h i n Article 1 0(a) 
of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n. 
 
 
F ull descri pti o n of s u bsta ntial a n d ot her mi n or c ha n ges/clarificati o ns are p r o vi de d i n t he 
S u m mar y of C ha n ges D oc u me nt.  
St u d y  Pr ot oc ol  Versi o n  5. 0  d ate d  2 -Fe br u ar y -2 0 2 3  
T he St u d y Pr ot oc ol versi o n 4. 0 ( A me n d me nt 3) 
 
 
 
 
 
e O nl y disc ussi o ns (t y pe C meeti n g) a n d t he E M A g ui deli nes o n 
cli nical trial c o n d ucte d d uri n g t he C O VI D -1 9 c o nti n ge nc y was a d de d. T his a me n d me nt ha d 
c o nsi dere d t o be s u bsta ntial base d o n t he criteria set f ort h i n Article 1 0(a) of Directi ve 
2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.  
F ull descri pti o n of s u bsta ntial a n d ot her mi n or c ha n ges a re pr o vi de d i n t he S u m mar y of 
C ha n ges D oc u me nt.  
St u d y  Pr ot oc ol  Versi o n  4. 0  d ate d  1 9 -J a n u ar y -2 0 2 1  
T he St u d y Pr ot oc ol versi o n 3. 0 ( A me n d me nt 2) has bee n iss ue d t o a d d t he C O VI D -1 9 relate d 
meas ures i n or der t o e ns ure patie nt safet y a n d efficac y data c ollecti o n i n case a gi ve n o n -site 
visits ca n n ot ta ke place d ue t o C O VI D -1 9 o ut brea k, i ncl u di n g t he p ossi b ilit y t o perf or m re m ote 
visits, t o carr y o ut s pir o metr y e xa mi nati o n at patie nt h o me a n d t he I M P re -s u p pl y at patie nt 
h o me.  F urt her m ore t he Eli gi bilit y Criteria ha ve bee n re vie we d.  
T he a me n d me nt ha d c o nsi dere d t o be s u bsta ntial base d o n t he criteria set f o rt h i n Article 1 0(a) 
of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.  
F ull descri pti o n of s u bsta ntial a n d ot her mi n or c ha n ges/clarificati o ns are pr o vi de d i n t he 
S u m mar y of C ha n ges D oc u me nt.  
St u d y  Pr ot oc ol  Versi o n  3. 0  d ate d _ 9 -J u ne -2 0 2 0  
2 8  A P P E N DI X  I V –  S T U D Y  P R O T O C O L  V E R SI O N S  HI S T O R Y  O F  C H A N G E S  
C CI
C CI
C CI
C CI

L-CsA:
Treatment of BOS after SLT 
Protocol Number: 
BT – L-CsA – 301 – SLT 
Sponsor: 
Zambon SpA 
Page 106 of 106 
Clinical Trial Protocol BT – L-CsA – 301 – SLT 
Version 5.0_2-February-2023 
 
The Study Protocol version 2.0 (Amendment 1) has been issued to review the Eligibility 
Criteria, Treatment of Patients, Assessment of Efficacy and Safety, Visits Schedule and 
Statistical considerations. This amendment had considered to be substantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
Full description of substantial and other minor changes/clarifications are provided in the 
Summary of Changes Document. 
Study Protocol Version 2.0 dated 30-April-2019