Conditions: Bronchiolitis Obliterans Syndrome (BOS) GVHD, Chronic Stem Cell Transplant Complications
Keywords: stem cell hematopoietic transplant
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6
Healthy volunteers: no

Brief summary:
Primary Objective:

The primary objective of this study is to assess the tolerability and safety of two dose levels of aerosolized L-CsA vs placebo in addition to SoC therapy for BOS in adult allo-HSCT recipients.

Secondary Objectives:

The secondary objectives of this study are to assess PK and exploratory efficacy and quality of life of two dose levels of aerosolized L-CsA vs placebo in addition to SoC therapy for BOS in adult allo-HSCT recipients.

Detailed description:
This is a Phase II prospective, multi-center, single-blind, randomized clinical trial evaluating safety and tolerability in adult recipients of an allo-HSCT with BOS. Twenty-four patients were planned for enrollment; but, at the time of the premature termination of this study, a total of 11 patients were screened for the study, of whom 5 patients did not fulfill the inclusion criteria and 6 patients were randomly allocated 1:1:1 in 3 treatment groups (L-CsA 10 mg + SoC, L-CsA 5 mg + SoC, or placebo + SoC).

A total of 18 centers in 3 countries (France, Germany, and Spain) in Europe were initiated for this multi-center study.

IMP was administered for up to 12 weeks treatment period. With low patient recruitment, the BOSTON-4 safety and tolerability study was terminated early by the sponsor on 18 March 2022. This decision was made after a careful and due diligent analysis performed by Zambon of the study status and considering the impact of coronavirus disease 2019 (COVID-19) pandemic on sites activities. From the beginning of the study, in December 2019, only 6 patients were randomized. So it was estimated that continuing the trial with the current protocol and setting would have taken another 9 years for the study to complete.

Arms:
arm 1: Liposomal Cyclosporine A 10 mg (10 mg/2.5 mL) bid, once in the morning and once in the evening, for up to 12 weeks.

The inhalations were scheduled to be taken approximately 12 hours (but not less than 6 hours) apart, eg, at 08:00 and 20:00 each day. Nebulization time per inhalation dose was approximately 8 to 13 minutes for the 0- and 10-mg doses.

Standard of care included prophylaxis against common opportunistic infections, immunosuppression, and any other chronic medication arm 2: Liposomal Cyclosporine A 5 mg (5 mg/1.25 mL) bid, once in the morning and once in the evening, for up to 12 weeks. The inhalations were scheduled to be taken approximately 12 hours (but not less than 6 hours) apart, eg, at 08:00 and 20:00 each day. Nebulization time per inhalation dose was approximately 5 to 10 minutes for the 5-mg dose.

Standard of care included prophylaxis against common opportunistic infections, immunosuppression, and any other chronic medication arm 3: Liposomal Placebo 2.5 mL (0 mg L-CsA/2.5 mL) bid, once in the morning and once in the evening, for up to 12 weeks.

The inhalations were scheduled to be taken approximately 12 hours (but not less than 6 hours) apart, eg, at 08:00 and 20:00 each day. Nebulization time per inhalation dose was approximately 8 to 13 minutes for the 0- and 10-mg doses. Standard of care included prophylaxis against common opportunistic infections, immunosuppression, and any other chronic medication

Interventions: intervention 1: Liposomal Cyclosporine A intervention 2: Liposomal Placebo
Intervention descriptions: intervention 1: Liposomal Cyclosporine A is administered at different dosages in the first two arms (10 mg bid and 5 mg bid, respectively) with a new technology of nebulizing liquid drugs, creating an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm intervention 2: Liposomal Placebo is administered with the same new technology of nebulizing liquid drugs used for L-CsA, creating an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm

Protocol document:
Prot_000.pdf: 
C O N FI D E N TI A L 
C LI NI C A L T RI A L P R O T O C O L 
B O S T O N- 4: A P h ase II a M ulti- Ce nter, R a n d o mize d, Si n gle- Bli n d S afet y a n d T ol er a bilit y 
St u d y of i n h ale d Li p os o m al C ycl os p o ri n e A i n B r o n c hi olitis O bliter a ns S y n dr o me 
F oll o wi n g All o g e neic He m at o p oietic Ste m Cell Tr a ns pl a nt ati o n  
Pr ot oc ol N o: B T – L- Cs A – 2 0 1 – S C T 
( B O S T O N- 4) 
E u dra C T N o.: 2 0 1 9- 0 0 0 7 1 8- 1 3 
Versi o n: 5. 0  
Date:  3 0 A pril 2 0 2 1 
Pr ot o c ol A me n d me nt N o 4 
S P O N S O R 
Z a 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 
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 y cl os p ori ne A f or i n halati o n ( L- Cs A) 






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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 4  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
Pr ot oc ol A c k n o wle d g me nt / C o nfi d e nti alit y 
B O S T O N- 4: A P h ase II a M ulti- Ce nter, R a n d o mize d, Si n gle- Bli n d S afet y a n d T ol er a bilit y 
St u d y of i n h ale d Li p os o m al C ycl os p o ri n e A i n B r o n c hi olitis O bliter a ns S y n dr o me 
F oll o wi n g All o g e neic He m at o p oietic Ste m Cell Tr a ns pl a nt ati o n  
( Pr ot oc ol N o.: B T – L- Cs A – 2 0 1 – S C T) 
B y si g ni n g t his Pr ot oc ol, t h e Pri nci pal I n v esti g at or ac k n 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 v esti gat or will c o n d u ct t his cli ni cal trial as detail e d h erei n, i n c o m pli a 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 will ma ke e ver y reas o n a ble eff ort 
t o c o m plete t h e cli nical trial wit hi n t he ti me desi g nate d. 
T he Pr ot o c ol a n d all rele v a nt i nf or mati o n o n t h e dr u g a n d de vi ce relati n g t o n o ncli nical a n d cli nical 
e x perie n ce, w hi c h was f ur nis he d b y t h e S p o ns or, Za m b o n S p A, will be m a de a v aila ble t o all 
p h ysicia ns, n urses a n d ot her p ers o n nel w h o parti ci pate i n t he c o n d u ct of t his cli nical trial. T he 
I n v esti gat or will disc uss t his materi al wit h t he m t o ass ure t h at t he y are f ull y i nf or me d re gar di n g 
t he I n v esti g ati o nal Me dici n al Pr o d u ct a n d t he c o n d uct of t h e cli nical trial. 
T his d o c u me nt c o ntai ns i nf or mati o n t hat is pri vile g e 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 p er missi o n is gra nt e d i n writi n g b y t h e S p o ns or or s uc h discl os ure 
is re q uire d b y fe d eral or ot h er la ws or re g ulati o ns. P ers o ns t o w h o m a n y of t his i nf or m ati 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 d e nti al. T h ese 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 di cate 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 v e access t o a n y s o urce d oc u me nts fr o m w hi c h C ase R e 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 p erti n e nt t o 
t his cli nical tri al are t he s ole pr o p ert 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 ul at or y a ut h orities, or i n p u blicati o n of t h e 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 d e nti al. 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 h e res ults t here fr o m 
a n d b ot h parties s hall c o- o p erate i n t his re g ar d. 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 5  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
I h a ve rea d a n d a gree t o t he pr ot oc ol n u m bere d B T – L- Cs A – 2 0 1 – S C T. I a m a ware of m y 
res p o nsi bilities as a Pri nci p al I n vesti gat or a n d a gree t o c o n d uct t his cli nical trial acc or di n g t o 
i nter nati o nal sta n dar ds of G o o d Cli nical Practice (I nter n ati o nal C o u ncil o n Har m o nisati o n 
g ui deli nes), a p pli ca bl e g o ver n me nt re g ulati o ns, a n d I nstit uti o nal res earc h p olicies a n d pr oce d ures 
u n der t he g ui d eli n es of I nter nati o n al C o nfere nce o n Har m o nisati o n (I C H) G o o d Cli nical Practice 
( G C P), nati o n al re g ul ati o ns, a n d t h e pr ot oc ol. I a gree t o a p pr o pri atel y direct a n d assist t h e staff 
u n der m y c o ntr ol, w h o will be i n v ol ve d i n t he cli ni cal tri al. 
Pri n ci p al I n v esti g at or’s Si g n at u re 
Na me & Title _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
( Pri nt) 
Date   
Si g nat ure 
Ce nter Na m e _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
( Pri nt) 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 6  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
2  T A B L E O F C O N T E N T S 
1  SI G N A T O RI E S 
2  
2  T A BL E O F C O N T E N T S 
6  
3  A B B R E VI A TI O N S 
1 0  
4  P R O T O C OL S Y N O P SI S 
1 2  
5  I N T R O D U C TI O N 
2 0  
5. 1  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 0  
5. 1. 1 
B O S  I N H E M A T O P OI E TI C S T E M C ELL T R A N S PL A N T R E CI PI E N T S 
2 0 
6  B A C K G R O U N D I N F O R M A TI O N 
2 3  
6. 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  
2 3  
6. 1. 1 
D R U G C O M P O N E N T  
2 3 
6. 1. 2 
D E VI C E C O M P O N E N T  
2 3 
6. 1. 3 
N O N CLI NI C AL D A T A  
2 3 
6. 1. 4 
C LI NI C AL E X P E RI E N C E  
2 4 
6. 1. 5 
S U M M A R Y O F K N O W N A N D P O T E N TI AL R I S K S A N D B E N E FI T S  
2 5 
6. 1. 6 
J U S TIFI C A TI O N O F T H E R A P Y WI T H C Y CL O S P O RI N E A  A N D O F D O S E R E GI M E N 
2 7 
6. 1. 7 
S T A T E M E N T O F C O M PLI A N C E  
2 8 
6. 1. 8 
P O P UL A TI O N  
2 8 
7  T RI AL O BJ E C TI V E S A N D P U R P O S E 
2 8  
7. 1  T RI AL O BJ E C TI V E S  
2 8  
7. 2  P U R P O S E O F T H E T RI AL  
2 8  
8  T RI AL D E SI G N 
3 0  
8. 1  E N D P OI N T S  
3 0  
8. 1. 1 
P RI M A R Y A SS E SS M E N T 
3 0 
8. 1. 2 
S E C O N D A R Y A SS E SS M E N T S 
3 0 
8. 1. 3 
E X PL O R A T O R Y E FFI C A C Y A S S E SS M E N T 
3 0 
8. 1. 4 I M P  T OL E R A BILI T Y P A R A M E T E R S  
3 0 
8. 1. 5 
S A F E T Y P A R A M E T E R S  
3 0 
8. 1. 6 
P H A R M A C O KI N E TI C P A R A M E T E RS  
3 0 
8. 2  T RI AL D E SI G N 
3 1  
8. 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  
3 1  
8. 3. 1 
B LI N DI N G 
3 1 
8. 3. 2 I N 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  
3 1 
8. 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 P A C K A GI N G , L A B ELI N G A N D S T O R A G E  
3 5  
8. 4. 1 
P A C K A GI N G A N D L A B ELI N G O F I M P 
3 5 
8. 4. 2 
S T O R A G E 
3 5 
8. 4. 3 I N H AL A TI O N D E VI C E P A C K A GI N G  
3 5 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 7  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
8. 5  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  
3 6  
8. 5. 1 
P A TI E N T L E V EL 
3 6 
8. 5. 2 
C E N T E R L E V EL  
3 6 
8. 5. 3 
C LI NI C AL T RI AL L E V EL 
3 7 
8. 6  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  
3 7  
9  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 
3 8  
9. 1  P A TI E N T IN CL U SI O N C RI T E RI A  
3 8  
9. 2  P A TI E N T E X CL U SI O N C RI T E RI A  
3 8  
9. 3  P A TI E N T W I T H D R A W AL C RI T E RI A  
3 9  
9. 3. 1 
P R O C E D U R E S O F P A TI E N T W I T H D R A W AL A N D I M P DI S C O N TI N U A TI O N 
3 9 
9. 3. 2 
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 F O R P A TI E N T W I T H D R A W AL A N D I M P DI S C O N TI N U A TI O N  
4 0 
9. 3. 3 
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  
4 0 
9. 3. 4 
F OLL O W -U P OF W I T H D R A W N P A TI E N T S  
4 0 
1 0  T R E A T M E N T O F P A TI E N T S 
4 1  
1 0. 1  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  
4 1  
1 0. 1. 1 
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  
4 1 
1 0. 1. 2 I M M U N O S U P P R E SSI O N  
4 1 
1 0. 1. 3 
T R E A T M E N T F O R B O S 
4 1 
1 0. 1. 4 
O T H E R M E DI C A TI O N 
4 2 
1 0. 1. 5 
P R O HI BI T E D M E DI C A TI O N 
4 2 
1 1  A S S E S S M E N T O F E FFI C A C Y 
4 3  
1 1. 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  
4 3  
1 1. 1. 1 
S PI R O M E T R Y  
4 3 
1 1. 1. 2 
S F- 3 6  Q U ALI T Y O F LI F E Q U E S TI O N N AI R E  
4 4 
1 2  A S S E S S M E N T O F S A F E T Y 
4 5  
1 2. 1  S A F E T Y P A R A M E T E R S  
4 5  
1 2. 1. 1 
D E FI NI TI O N S  
4 5 
1 2. 1. 2 
R EL A TI O N S HI P T O C LI NI C AL T RI AL T R E A T M E N T A SSI G N M E N T 
4 7 
1 2. 1. 3 
M A XI M U M IN T E NSI T Y  
4 7 
1 2. 1. 4 
S E RI O U S A D V E R S E E V E N T ( S A E) R E P O R TI N G  
4 7 
1 2. 1. 5 
T OL E R A BILI T Y O F I M P 
4 9 
1 2. 1. 6 
C LI NI C AL L A B O R A T O R Y  
5 0 
1 2. 1. 7 
V I T AL S I G N S 
5 1 
1 2. 1. 8 
P H Y SI C AL E X A MI N A TI O N S  
5 1 
1 2. 1. 9 
C LI NI C AL G L O B AL IM P R E SSI O N ( C GI) 
5 2 
1 2. 2  D A T A M O NI T O RI N G C O M MI T T E E ( D M C) 
5 2  
1 3  VI SI T S C H E D UL E 
5 3  
1 3. 1  C LI NI C AL T RI AL F L O W C H A R T  
5 6  
1 3. 2  V I SI T S 
5 7  
1 3. 2. 1 
S C R E E NI N G  
5 7 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 8  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 3. 2. 2 
V I SI T 1  / B A S ELI N E V I SI T / R A N D O MI Z A TI O N  
5 8 
1 3. 2. 3 
V I SI T 2  T H R O U G H V I SI T 5  / E O T 
5 9 
1 3. 2. 4 
V I SI T 3  A N D V I SI T 5 
5 9 
1 3. 2. 5 
V I SI T 6  / E N D O F S T U D Y ( EO S) 
5 9 
1 3. 2. 6 
U N S C H E D UL E D V I SI T S 
5 9 
1 3. 2. 7.     R E M O T E V I SI T S 
6 0 
1 4  S T A TI S TI C S 
6 1  
1 4. 1  A N AL Y SI S D A T A S E T S  
6 1  
1 4. 2  S T A TI S TI C AL A N D A N AL Y TI C AL M E T H O D S  
6 2  
1 4. 2. 1 
D E S C RI P TI V E S T A TIS TI C S 
6 2 
1 4. 2. 2 
C H A R A C T E RI Z A TI O N A N D B A S ELI N E C O M P A R A BILI T Y O F T R E A T M E N T G R O U P S  
6 2 
1 4. 2. 3 
A N AL Y SI S O F S A F E T Y  
6 3 
1 4. 2. 4 
A N AL Y S E S O F E FFI C A C Y 
6 4 
1 4. 2. 5 
P H A R M A C O KI N E TI C V A RI A BL E S  
6 4 
1 4. 3  IN T E RI M A N AL Y SI S  
6 5  
1 4. 4  M I S SI N G D A T A  
6 5  
1 4. 5  S A M PL E S I Z E C O N SI D E R A TI O N S  
6 5  
1 5  DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S 
6 6  
1 6  Q U ALI T Y C O N T R OL A N D Q U ALI T Y A S S U R A N C E 
6 7  
1 7  E T HI C S C O M MI T T E E ( E C) 
6 8  
1 8  P A TI E N T I N F O R M E D C O N S E N T 
6 9  
1 9  H E AL T H A U T H O RI TI E S 
7 0  
2 0  D A T A H A N DLI N G A N D R E C O R D K E E PI N G 
7 1  
2 0. 1  C O NFI D E N TI ALI T Y  
7 1  
2 0. 2  C O M PL E TI O N O F E L E C T R O NI C C A S E R E P O R T F O R M S  
7 2  
2 0. 3  S O U R C E D A T A A N D P A TI E N T F IL E S 
7 3  
2 0. 4  IN V E S TI G A T O R F IL E A N D A R C HI VI N G  
7 4  
2 0. 5  M O NI T O RI N G , Q U ALI T Y A S S U R A N C E , A N D IN S P E C TI O N B Y A U T H O RI TI E S  
7 4  
2 0. 6  D A T A M A N A G E M E N T A N D D A T A C O N T R OL  
7 4  
2 1  FI N A N CI N G A N D I N S U R A N C E 
7 6  
2 2  P U BLI C A TI O N S 
7 7  
2 3  R E F E R E N C E S 
7 8  
2 4  A P P E N DI X I – C O R E I N F O R M E D C O N S E N T F O R M 
8 0  
2 5  A P P E N DI X II – A C C E P T A BL E M E T H O D S O F C O N T R A C E P TI O N 
8 2  


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Pa g e 9  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
 
LI S T O F T A B L E S 
T a bl e 1: Q u alit ati v e C o m p ositi o n of t h e I M P 
3 2  
 
LI S T O F FI G U R E S 
Fi g ur e 1:  K a pl a n- M ei er Esti m at es of S ur vi v al i n H e m at o p oi etic St e m C ell Tr a ns pl a nt R eci pi e nts 
2 1  
 
 
 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 1 0  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
3  A B B R E VI A TI O N S 
A D R  
A d verse Dr u g Reacti o n  
A E  
A d verse E ve nt  
all o-H S C T  
All o ge neic He mat o p oietic Ste m Cell Tra ns pla ntati o n  
A T S  
A m erica n T h oraci c S oci et y  
A U C  
Area U n der t h e C ur ve  
B i d 
Bis i n die , t wice dail y 
B O  
Br o n c hi olitis O blitera ns  
B O S  
Br o n c hi olitis O blitera ns S y n dr o me  
B D R M  
Bli n d Data Re vie w Meeti n g  
C GI  
Cli ni cal Gl o bal I m pressi o ns  
C G v H D  
C hr o nic Graft Vers us H ost Disease  
C ma x  
Ma xi m u m c o nce ntrati o n  
C R O  
C o ntract Researc h Or ga nizati o n  
Cs A  
C ycl os p ori ne A  
Cs A -P G  
C ycl os p ori ne A Pr o p yle n e Gl yc ol  
C S R  
Cli ni cal St u d y Re p ort  
Dl  
Deciliter  
D L T  
D o u ble L u n g Tra ns pla nt ati o n  
D M C  
Data M o nit ori n g C o m mittee  
E C  
Et hics C o m mittee  
e C R F  
Electr o n i c Case Re p ort F or m 
E o S  
E n d o f St u d y 
E o T  
E n d of Treat me nt  
E R S  
E ur o pea n Res pirat or y S ociet y  
E U  
E ur o pea n U ni o n  
E X P  
E x pirati o n dat e  
F A S  
F ull A nal ysis Set  
F E F 2 5 -7 5 
F orce d Mi d e x pirat or y Fl o w  
F E V 1 
F orce d E x pirat or y V ol u me i n O n e Sec o n d  
F V C  
F orce d Vital Ca p acit y  
G C P  
G o o d Cli ni cal Practice  
H S C T  
He mat o p oi etic Ste m Cell Tra ns pl a nt ati o n  
I B 
I n vesti gat or’s Br oc h ure 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u ma n Us e  
I M P 
I n vesti gati o nal Me dici n al Pr o d uct (L -Cs A ) 




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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 1 2  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
4  P R O T O C O L S Y N O P SI S 
Pr ot oc ol Title: 
B O S T O N- 4: A P hase IIa M ulti- Ce nt er, R a n d o mi ze d, Si n gle- Bli n d 
Safet y a n d T olera bilit y St u d y of i n h ale d Li p os o mal C ycl os p ori ne A i n 
Br o nc hi olitis O blitera ns S y n dr o me F oll o wi n g All o ge neic 
He mat o p oietic Ste m C ell 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, 
2 0 0 9 1 Bress o ( MI) 
Ital y 
Pr ot oc ol N u m ber: 
B T – L- Cs A – 2 0 1 – S C T ( B O S T O N- 4) 
E U D R A C T 
N u m b er: 
2 0 1 9- 0 0 0 7 1 8- 1 3 
I N D N u m ber: 
7 8, 8 5 4 
I n vesti g ati o n al 
Me dici n al Pr o d u ct: 
Li p os o mal C y cl os p ori n e A ( L- Cs A) I n h alati o n S ol uti o n 
1 0 m g t wice d ail y ( bi d) 
or 
Li p os o mal C y cl os p ori n e A L- Cs A I n halati o n S ol uti o n 5 m g t wice 
dail y ( bi d) 
or 
Li p os o mal Pl ace b o ( 0 m g L- Cs A) I n h al ati o n S ol uti o n t wice d ail y 
( bi d) 
Pr ot oc ol P h as e: 
P h ase IIa 
Pr ot oc ol D ate: 
Versi o n 5. 0;  3 0 A pril 2 0 2 1 
Pr ot oc ol 
A me n d me nt 
4 
Cli nic al Tri al 
Ce nters/ C o u ntries: 
U p t o 2 0 ce nters i n E ur o pe. 
Pl a n ne d Cli nic al 
Tri al Peri o d:  
D urati o n of t hera p y: 1 2 wee ks  
T otal cli nical trial d urati o n per pati e nt: u p t o 1 8 wee ks 
Pl a n ne d N u m b er of 
P atie nts: 
2 4 pati e nts ra n d o mize d 
Ra n d o mizati o n: 1: 1: 1  
Patie nts will recei ve i n vesti gati o nal treat me nt or pl ace b o vi a t h e L-
Cs A s pecific 
 Ne b uli zer S yste m ( L- Cs A 
), i n a d diti o n t o sta n d ar d of care ( S o C) t hera p y. 
C CI
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 1 3  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
Treat me nt A: L- Cs A 1 0 m g bi d pl us S o C ( n = 8) 
Treat me nt B: L- Cs A 5 m g bi d pl us S o C ( n = 8) 
Treat me nt C: L -Cs A 0 m g  ( place b o) bi d  pl us S o C ( n = 8)  
O bjecti ve: 
T he o bjecti v es of t his st u d y are t o assess t h e t olera bilit y, safet y, 
p har mac o ki n etics ( P K), e x pl orat or y efficac y a n d q ualit y of life of t w o 
d oses of aer os olize d L- Cs A vs pl ace b o i n a d diti o n t o S o C t hera p y f or 
t he treat me nt of B O S i n a d ult all o ge n eic h e mat o p oietic st e m cell 
tra ns pl a ntati o n (all o- H S C T) reci pie nts. 
Cli nic al Tri al 
Desi g n: 
P h ase IIa pr os p ecti v e, m ulti-ce nter, si n gle- bli n d, ra n d o mize d cli nical 
trial assessi n g t w o d oses of i n h ale d L- Cs A a n d place b o.  
Eli gi bilit y Criteri a: 
I ncl usi o n Criteri a: 
1.
A ge  1 8 years
2.
Patie nts 
m ust 
ha ve 
u n der g o n e 
h e mat o p oi etic 
ste m 
cell
tra ns pla ntati o n a n d ha v e d oc u me nte d dia g n osis of c hr o nic Graft
vers us H ost Diseas e (c G v H D), g ui de d b y t he NI H c o ns e ns us
criteria.
3.
Patie nts m ust ha v e bee n di a g n ose d wit h B O S wit hi n > 6 m o nt hs a n d
≤3 y ears at Scree ni n g visit.
4.
S pir o metr y test carrie d o ut at Scree ni n g visit m ust s h o w:

A F E V 1 a b o v e 5 1 % of pre dicte d
A N D

A ≥ 1 0 % decli n e i n F E V 1 ( L) wit hi n 2 years
5.
P atie nt m ust be ca pa ble of u n derst a n di n g t h e p ur p oses a n d ris ks
of t he st u d y, has gi ve n writte n i nf or m e d c o nse nt, a n d a grees t o
c o m pl y wit h t h e st u d y re q uire me nts.
6.
W o me n of c hil d beari n g p ote ntial m ust ha ve a n e gati ve ser u m or
uri ne pre g na n c y test wit hi n 7 d a ys pri or t o ra n d o mizati o n a n d m ust
a gree t o use o ne of t he m et h o ds of c o ntrace pti o n list e d i n A p pe n di x
II t hr o u g h t heir E n d of St u d y Visit.
E xcl usi o n Cri teri a: 
1.
Ot her ac ute or c hr o ni c restri cti ve or o bstr ucti v e l u n g dis eases,
i ncl u di n g b ut n ot li mite d t o: acti v e ast h ma ( varia bl e a n d rec urri n g
s y m pt o ms of airfl o w o bstr u cti o n (re versi ble t o beta- 2 a g o nists) a n d
br o nc hial h y p er-res p o nsi ve ness), c hr o nic o bstr ucti ve p ul m o n ar y
disease, i nterstitial l u n g disease, or cr y pt o ge nic or ga nizi n g
p n e u m o ni a , ne ur o m usc ul ar wea k n ess or dia p hra g matic paral ysis.
2.
A n y ac ut e p ul m o nar y b acterial, viral (as c o nfir m e d b y m ulti ple x
P C R) or f u n g al i nfecti o n n ot s u ccessf ull y res ol v e d at least 4
wee ks pri or t o t he Scree ni n g Visit.




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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Pa g e 1 5  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
S o C t h era p y 
Tre at me nt B ( L- Cs A 5 m g tre at me nt pl us S o C): 
L- Cs A 5 m g/ 1. 2 5 m L bi d f or a ma xi m u m of 1 2 wee ks 
pl us 
S o C t h era p y 
Tre at me nt C ( 0 m g L- Cs A ( pl ace b o) pl us S o C ): 
L- Cs A 0 m g/ 2. 5 m L bi d f or a ma xi m u m of 1 2 wee ks 
pl us 
S o C t h era p y  
E n d p oi nts: 
Pri m ary assess me nt:   
I M P t olera bilit y a n d safet y d uri n g t he first 4 wee ks of treat me nt 
Sec o n d ary assess me nts:   
 I M P t olera bilit y a n d safet y d uri n g t he first 1 2 wee ks of 
treat me nt; 
 Cs A P K 
E x pl or at ory effic acy assess me nts:   
 F E V 1 % pre dicte d at ra n d o mizati o n c o m pare d t o Wee k 2, 
Wee k 4, Wee k 8, a n d W ee k 1 2 
 F E V 1/ F V C at ra n d o mizati o n c o m p are d t o Wee k 2, Wee k 4, 
Wee k 8, a n d Wee k 1 2 
 
S F- 3 6 Q ualit y of Life Q u esti o n naire at Baseli n e, Wee k 2, 
Wee k 4, Wee k 8, a n d W ee k 1 2 visits  
 
C ha n ges i n t he d ose of c ortic oster oi ds a n d i m m u n os u p pressi v e 
t hera p y a d mi nistere d t hr o u g h o ut trial d urati o n 
I M P T oler a bilit y P ar a meters: 
 L oc al T oler a bilit y: 
o  C o u g h 
o  W h eezi n g 
o  Br o nc h os pas m 
o  T hr oat irritati o n 
o  C ha n ge i n F E V 1 
 Over all T oler a bilit y: 
o  Cli ni cal Gl o b al I m pressi o ns ( C GI) scale ( o n-site o nl y)  
o  I n v esti gat or’s t olera bilit y assess me nt at Visit 3 a n d 
Visit 5  
S afety P ar a meters: 
 A d verse e ve nts ( A Es) 
 Seri o us a d verse e v e nts ( S A Es) 
 Cli ni cal la b orat or y v al ues 
 Vit al si g ns 
 P h ysical E xa mi nati o n 
 
 
 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 1 6  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
P h ar m ac o ki n etic P ar a meters: 

P K: ( Wee k 0) at pre- d ose; directl y after e n d of i n h alati o n; 1 5,
3 0, a n d 4 5 mi n utes, a n d 1, 1. 5, 2, a n d 4 h o urs aft er e n d of
i n h al ati o n:
o
C ma x
o
tma x
o
A U C 0- 4 h

W h ole bl o o d tr o u g h le vels (at Wee ks 2, 4, 8, a n d 1 2)
Assess me nts 
Cli nic al Tri al Pl a n: 
At t otal of 7 visits ( S cree ni n g, Ra n d o mizati o n ( Wee k 0), Wee k 2, 
Wee k 4, Wee k 8, We e k 1 2 ( E n d of Treat me nt [ E o T]) a n d Wee k 1 4 
( E n d of St u d y [ E o S]) will be perf or m e d d uri n g t he cli nical trial. 
A Es a n d c o nc o mita nt me dicati o ns will b e rec or d e d at all visits. 
Scree ni n g:  Aft er i nf or m e d c o nse nt has b ee n o btai n e d. S cree ni n g Visit 
pr oce d ur es will be carrie d o ut t o c hec k g e n eral eli gi bilit y f or 
partici pati o n u p t o 4 wee ks pri or t o ra n d o mizati o n. 
Bl o o d will be dra w n f or safet y pr ofil es. 
Visit 1, W ee k 0 ( B aseli n e Visit, R a n d o miz ati o n):  Bl o o d f or baseli n e 
meas ures will be c olle cte d. S pir o metr y will be perf or me d. A 
pre g na nc y test will b e p erf or me d f or all fe m ales of c hil d beari n g 
p ote nti al pri or t o ra n d o mizati o n. A p h ysical e xa m, i ncl u di n g vital 
si g ns, will be perf or me d. T he C GI Q uesti o n n aire will b e a d mi nistere d. 
T he S F- 3 6 Q u alit y of Life Q uesti o n naire will b e a d mi nistere d.  
Patie nts will b e ra n d o mize d t o st u d y treat me nt a n d i nstr ucte d o n use 
of t h e L- Cs A  
. 
T he first d ose of I M P will be a d mi nistere d u n der o bser vati o n a n d 
safet y will be m o nit ore d. S pir o metr y will be re p eate d 1 h o ur  2 0 mi n 
after c o m pleti o n of t h e first d ose of I M P. 
Bl o o d will be dra w n f or safet y pr ofiles a n d P K d ata at pre- d os e. P K 
sa m ples will be o btai n e d directl y after e n d of first i n h alati o n, at 1 5, 
3 0, a n d 4 5 mi n utes, a n d 1, 1. 5, 2, a n d 4 h o urs aft er e n d of i n halati o n. 
If n o t olera bilit y iss u es are o bser ve d, p atie nts will be per mitte d t o 
lea ve t h e cli nic. 
Patie nts will recei ve t he f ull I M P s u p pl y f or t he 1 2 wee ks treat me nt 
peri o d. 
T he sec o n d d os e of I M P a n d all s u bse q u e nt d oses s h o ul d be i n hale d 
a p pr o xi m atel y 1 2 h o urs after t he first d ose.  
Visit 2, W ee k 2:  S pir o metr y will be o btai n e d. 
Bl o o d will be dra w n f or safet y pr ofil es a n d tr o u g h le vels of Cs A. A 
pre g na nc y test will b e p erf or me d f or all fe m ales of c hil d beari n g 
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 1 7  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
p ote nti al. A p h ysical e xa m, i n cl u di n g vit al si g ns, will be p erf or me d. 
T he C GI Q u esti o n n aire will be a d mi nistere d. T he S F- 3 6 Q u alit y of 
Life Q u esti o n n aire will be a d mi nistere d.  
A d ose of t he I M P will be a d mi nistere d u n der o bs er vati o n. 
Patie nts will bri n g use d a n d u n use d vials of t he I M P f or a vail a bilit y 
c hec k. 
Visit 3, W ee k 4:  D uri n g o n-site visits, s pir o metr y will b e o btai ne d. 
Bl o o d will be dra w n f or safet y pr ofil es a n d tr o u g h le vels of Cs A. A 
pre g na nc y test will b e p erf or me d f or all fe m ales of c hil d beari n g 
p ote nti al. A p h ysical e xa m, i n cl u di n g vit al si g ns, will be p erf or me d. 
T he C GI Q u esti o n n aire will be a d mi nistere d. T he S F- 3 6 Q u alit y of 
Life Q u esti o n n aire will be a d mi nistere d. A n I n v esti gat or’s T olera bilit y 
Assess me nt will b e perf or m e d. 
A d ose of t he I M P will be a d mi nistere d u n der o bs er vati o n d uri n g o n-
site visits. 
Patie nts will bri n g use d a n d u n use d vials of t he I M P f or a vail a bilit y 
c hec k at o n-site visits. 
Visit 4, W ee k 8:  D uri n g o n-site visits, s pir o metr y will b e o btai ne d. 
Bl o o d will be dra w n f or Cs A tr o u g h le vel a n d safet y para met ers. A 
pre g na nc y test will b e p erf or me d f or all fe m ales of c hil d beari n g 
p ote nti al. A p h ysical e xa m, i n cl u di n g vit al si g ns, will be p erf or me d. 
T he C GI Q u esti o n n aire will be a d mi nistere d. T he S F- 3 6 Q u alit y of 
Life Q u esti o n n aire will be a d mi nistere d. 
A d ose of t he I M P will be a d mi nistere d u n der o bs er vati o n d uri n g o n-
site visits. 
Patie nts will bri n g use d a n d u n use d vials of t he I M P f or a vail a bilit y 
c hec k at o n-site visits. 
Visit 5, W ee k 1 2 ( E o T):  S pir o metr y will be o btai ne d. 
Bl o o d will be dra w n f or Cs A tr o u g h le vel a n d safet y p ara met ers. A 
pre g na nc y test will b e p erf or me d f or all fe m ales of c hil d beari n g 
p ote nti al. A p h ysical e xa m, i n cl u di n g vit al si g ns, will be p erf or me d. 
T he C GI Q u esti o n n aire will be a d mi nistere d. T he S F- 3 6 Q u alit y of 
Life Q u esti o n n aire will be a d mi nistere d. A n I n v esti gat or´s t olera bilit y 
assess me nt will be p erf or me d. 
Patie nts will ret ur n all use d a n d u n use d vials of t h e I M P. Dr u g 
acc o u nt a bilit y will b e perf or me d. 
T he L- Cs A  
 will b e ret ur n e d. 
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 1 8  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
Visit 6, W ee k 1 4 ( E o S):   
Bl o o d will be dra w n f or safet y para meters. A pre g na nc y test will be 
perf or me d f or all fe males of c hil d b eari n g p ote ntial. A p h ysical e xa m, 
i ncl u di n g vital si g ns, will b e p erf or me d. 
Safet y a n d t olera bilit y will be m o nit ore d b y d o c u me ntati o n of A Es 
t hr o u g h o ut t h e st u d y.  
E ver y eff ort will be ma d e t o h a 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 a n d Visit 1, Visit 
2 a n d Visit 5.  
H o we ver, if o ne of t h e visits V 3, V 4 a n d V 6 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 tel e p h o ne) are p ossi ble. 
C O VI D -1 9 relat e d A d v erse E v e nts will b e re p ort e d as S A Es.  
D at a M o nit ori n g 
C o m mittee: 
A Dat a M o nit ori n g C o m mittee ( D M C) is esta blis he d t o m o nit or t he 
safet y of I M P. T h e D M C will m o nit or safet y b y e val uati n g t he safet y 
a nal yses ge nerate d b y t h e i n d e pe n de nt st atisticia n d uri n g t he c o urse of 
t he cli nical trial. Details of t he safet y a nal yses will b e i n cl u de d i n t he 
D M C C harter. 
T he D M C will e val uate treat me nt gr o u ps f or p ossi ble tre n ds i n A Es, 
det er mi ne w het h er t he b asic pr ot oc ol ass u m pti o ns re mai n v ali d, 
e val uate w het h er t he o v erall i nte grit y, scie ntific m erit a n d c o n d uct of 
t he cli nical trial re mai n acce pt a bl e, a n d ma ke rec o m m e n dati o ns t o t he 
S p o ns or. 
St atistic al 
C o nsi der ati o ns: 
E x pl orat or y statisti cal a nal yses will be p erf or me d usi n g met h o ds of 
des cri pti ve data a nal ysis. 
A n al ysis of s afet y:  Me d D R A c o de d, treat me nt e mer ge nt a d verse 
e ve nts ( T E A Es) will be ta b ulate d at t h e Preferre d Ter m ( P T) a n d t he 
S yste m Or ga n Cl ass ( S O C) le vels. Treat me nt gr o u p c o m p aris o ns of 
t he pr o p orti o n of patie nts wit h T E A Es will be b ase d o n Wils o n s c ore 
c o nfi de nce i nter vals. Pair wise gr o u p c o m paris o ns will be pr o vi de d at 
t he S O C le vel as w ell as f or t he e v e nts i d e ntifie d as l ocal t ol era bilit y 
meas ures ( c o u g h, w heezi n g, br o nc h os pas ms, t hr oat irritati o n, c ha n ge 
i n F E V1), wit h se parate a nal yses f or all e v e nts wit h o nset d uri n g t h e 
first 4 wee ks of treat me nt a n d f or e ve nts wit h o nset at a n y ti m e d uri n g 
ra n d o mize d treat me nt. C GI scales will be a nal yse d a n d c o m par e d 
bet wee n t he treat me nt gr o u ps. 
A n al ysis of effic ac y:  S pir o metric v ari a bles a n d S F- 3 6 sc ales will be 
a nal yze d a n d c o m pare d b et wee n t h e treat me nt gr o u ps usi n g mi xe d 
m o dels f or re p eate d meas ures ( M M R M). 
P h a r m ac o ki neti c m e as u res:  T h e statistical a n al ysis will be carrie d 
o ut b ase d o n a m ulti pli cati ve m o del f or A U C 0- 4 h a n d Cma x  val ues, 
w hile t ma x  a n d tr o u g h le vels will be e val u ate d o n t h e basis of a n 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 1 9  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
a d diti ve m o del. A nal yses of varia n ce will b e perf or m e d t o c o m pare 
t he treat me nt gr o u ps. 
S a m ple size d eter mi n ati o n:  T he sa m ple si ze f or t h e st u d y was 
esta blis he d base d o n c o nsi derati o ns of feasi bilit y rat her t ha n o n p o wer 
calc ul ati o ns. A t ot al of 2 4  p atie nts ( 3 ar ms x 8 p atie nts eac h) are 
pla n n e d t o b e ra n d o mize d. 






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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 2 2  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
T he first st u dies of a n i n hale d i m m u n os u p pressi ve f or B O S were c o n d ucte d i n p atie nts wit h l u n g 
tra ns pla nt ati o n. T h ese st u di es use d c ycl os p ori n e i n a f or m ulati o n t h at c o nt ai ne d pr o p yle n e gl yc ol 
( Cs A- pr o p yl e ne gl y c ol [ Cs A- P G]). I n t h ese st u di es, 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 us e air wa y i nfla m mati o n. H o we v er, 
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 n creasi n g t olera bilit y as w ell as i m pr o vi n g air wa y de p ositi o n, a li p os o mal 
f or m ulati o n of Cs A ( L- Cs A) was d e 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 
 N e b ulizer S yste m ( L- Cs A  
) f or o pti mal aer os ol d y n a mics. 
T wi ce dail y ( bi d) i n h alati o n of L- Cs A was w ell t olerate d i n a 2- year pre ve nti o n st u d y a n d a 6-
m o nt h treat me nt st u d y of B O S after l u n g tra ns pla nt. T here are o ver 1 1 0 0 pati e nt m o nt hs of 
e x perie n ce wit h L- Cs A i n l u n g tra ns pl a nt reci pie nts wit h B O S. T his st u d y will be t h e first st u d y 
t o e val uat e safet y a n d t ol era bilit y of L- Cs A i n pati e nts wit h B O S f oll o wi n g all o- H S C T.   
C CI
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 2 3  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
6  B A C K G R O U N D I N F O R M A TI O N 
6. 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 di ci nal Pr o d uct (I M P) is a dr u g/ de vice c o m bi n ati o n c o nsisti n g of L- Cs A 
a n d t he L- Cs A  
. 
6. 1. 1  D r u g C o m p o n e nt 
L- Cs A c o nsists of t h e acti ve s u bsta nce Cs A a n d e xci pie nts as des cri b e d i n t h e I n vesti gat or’s
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 h eref ore a dj uste d t o a p h ysi ol o gical t olera ble v al u e of p H 6. 5
± 0. 3 a n d a n os m olalit y of 4 3 0- 5 5 0 m Os m ol/ k g i n t h e rec o nstit ut e d f or m ulati o n.
T he li p os o me size i n t he rec o nstit ute d f or m ul ati 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 p ersit y i n de x ( PI) of n ot m ore t h a n 0. 5 0, w hic h i n dicates t he wi dt h of t h e size distri b uti o n. 
PI val ues a b o ve 0. 5 i n dicate a br o a d distri b uti o n. 
T he d oses of 0 m g a n d 1 0 m g L- Cs A are rec o nstit ute d i n a t otal v ol u me of 2. 5 m L. T he 5 m g L-
Cs A d ose is rec o nstit ut e d i n a t otal v ol u me of 1. 2 5 ml. T he e ntire v ol u m e of t h e rec o nstit ut e d 
s ol uti o n is use d per aer os ol a d mi nistrati o n.  
A d diti o n al i nf or mati o n ca n be f o u n d i n t he I B.  
6. 1. 2  D e vi c e C o m p o n e nt 
T he L- Cs A  
 (
) utilizes a ne w tec h n ol o g y of n e b uli zi n g 
li q ui d dr u gs wit h a perf orate d vi brati n g me m bra ne res ulti n g i n a n aer os ol wit h a l o w ballistic 
m o me nt u m a n d a hi g h perce nta g e of dr o plets i n a res pira ble size ra n g e of 3- 5 µ m.  
T he L- Cs A  
 t o be use d i n t his cli nical trial is a m o difi e d v ersi o n of t h e  
  
 
Ne b ulizer S yste m f or a n o pti mize d deli ver y of t he i n v esti g ati o n al dr u g f or t he desi g nate d p atie nt 
gr o u p. T he c o nfi g urati o n of t he o pti mize d L- Cs A  
h as 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 n ati o n of t he e n vir o n me nt b y usi n g a n e x hal ati o n filt er. T he 
de vice is C E- mar k e d i n E ur o pe. T he L- Cs A  
was use d i n t h e n o ncli nical a n d cli nical trials 
of L- Cs A.  
A d diti o n al i nf or mati o n ca n be f o u n d i n t he I B. 
6. 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 ni cal p har m ac ol o gic, p har mac o ki neti c ( P K), a n d 
t o xicit y pr ofiles of s yste mic Cs A are w ell esta blis h e d [U K S m P C Cicl os p ori n A ( Ne oral ® )]. 
C CI
C CI
C CI
C CI
C CI
C CI
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 2 4  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
F or aer os olize d a d mi nistrati o n of L- Cs A, a d diti o n al n o ncli nical st u dies ha ve bee 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 h eral bl o o d
m o n o n uclear cells. Acr oss 3 n o ncli ni cal 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 v e d-a d verse-effect-le vel is c o nsi dere d t o be 2. 0 m g/ k g/ da y via
i n h al ati 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 h e 2 6- wee k
i n h al ati o n st u d y i n rats.
N o ncli ni cal a n d cli nical data t o d ate wit h L- Cs A s h o w ne gli gi ble i n crease i n ser u m l e vels of 
calci n e uri n i n hi bit ors a n d d o n ot s h o w a n i n creas e d ris k of n e p hr ot o xicit y, res pirat or y i nfecti o ns, 
or mali g na ncies. 
A d diti o n al i nf or mati o n ca n be f o u n d i n t he I B. 
6. 1. 4  Cli ni c al E x p eri e n c e 
L- Cs A h as bee n e v al uate d i n 3 cli nical trials i n a d ult pati e nts w h o recei ve d a si n gle-l u n g
tra ns pla nt ati o n ( S L T) or d o u ble-l u n g tra ns pla ntati o n ( D L T): ( 1) a P hase 1 b st u d y of t h e d e p ositi o n
a n d P K of aer os olize d L- Cs A i n pati e nts wit h l u n g tra ns pla nt ati 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 h e a d diti o n of aer os oliz e d L- Cs A t o sta n dar d of care ( S o C)
s yste mic i m m u n os u p pressi o n t h era p y vs aer os olize d pl ace b o pl us S o C t h era p y i n t he pre v e 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 g at or-i nitiate d st u d y of t he efficac y, safet y, a n d P K of t h e a d diti o n of
aer os oli ze 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 oll ecti vel y, t hese st u dies pr o vi d e d
safet y, efficac y, a n d P K dat a t o s u p p ort f urt her e v al uati o n i n 2 P hase 3 st u dies of t he effic ac y a n d
safet y of t h e 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 h e treat me nt of B O S f oll o wi n g S L T ( B T – L- Cs A – 3 0 1 – S L T) or d o u bl e l u n g
tra ns pla nt ati o n ( B T – L- Cs A – 3 0 2 – D L T). I n partic ul ar:

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 L- Cs A  
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) i n l u n g tra ns pla nt reci pi e nts. Aer os ol a p pli cati o n of 1 0 m g L- Cs A was
ass ociate d wit h a n acce pt a bl e i n hal ati o n ti me of a p pr o xi matel y 9 mi n utes.

I n t he P h ase 3 st u d y i n v esti gati n g pre v e nti o n of B O S ( 1 2 0 1 1. 2 0 1), t h e pri mar y e n d p oi nt f or
pre ve nti o n of B O S ( B O S-fre e s ur vi v al) 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 t er mi nati o n of t he trial d u e t o b usi ness reas o ns.

I n t h e i n v esti g at 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 h e res p o n d er
a nal ysis of B O S pr o gressi o n-free s ur vi v al base d o n Ka pla n- Meier esti mates re veale d a
treat me nt s uccess rat e of 8 1. 8 % i n t he L- Cs A + S o C gr o u p ( 9 of 1 1 p atie 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 v er ti me res ulte d i n m o nt hl y d ecre me nts
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
of - 0. 0 0 8 L i n t h e 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 h e pr o gressi o n of t he dise ase. T h e be n eficial 
effect of L- Cs A w as als o refle cte d i n c o nsiste ntl y p ositi ve tre n ds fa v ori n g t h e L- Cs A + S o C 
gr o u p i n ot h er l u n g f u ncti o n para meters, i ncl u di n g f orce d mi de x pirat or y fl o w ( F E F 2 5- 7 5), F V C, 
a n d F E V 1 % pre dicte d. Fi ve years after t he st art of St u d y AI 0 0 1 (as of Se pte m ber 2 0 1 7), 5 of 
1 1 pati e nts treate d wit h L- Cs A + S o C were ali v e, c o m p are d wit h 0 of 1 0 c o ntr ol pati e nts w h o 
recei v e d S o C al o ne. 
Wit h res pect  t o s afet y, i n hale d L- Cs A  w as g e nerall y well t olerate d  acr oss  all cli nical tri als. T he 
o verall a nal ysis of a d verse e ve nts ( A Es), 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 pe cte d i n a 
p o p ulati o n of l u n g tra ns pla nt a n d i m m u n os u p presse d patie nts a n d di d n ot differ 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 h a n ges 
o ver ti me. 
N o ncli ni ca l a nd cli ni cal dat a t o d ate wit h L- C s A d o n o t s h o w a n i ncrease d ris k of ne p hr ot o xi cit y, 
res pirat or y i nfecti o ns, or mali g na ncies. 
A d diti o n a l i nf or mati o n ca n be f o u n d i n the I B. 
6. 1. 5  S u m m a r y of K n o w n a n d P ot e nti a l Ri s k s a n d B e n efit s 
C hr o nic G v H D, w hic h 
ma nifests cli nicall y i n t he res pirat or y tract as B O S, is a c o m m o n 
c o m plicati o n of he mat o p oietic ste m cell tra ns pla ntati o n ( H S C T) ( A g uilar 2 0 1 6 ; Ber ger o n 2 0 1 3 ). 
De vel o p me nt of B O S after H S C T is a maj or ca use of m or bi dit y a n d m ortalit y; b e nefi ci al treat me nt 
o pti o ns are li mite d t hera pe utic i nter ve nti o ns w hic h ha ve n ot bee n vali date d b y well-c o n d ucte d 
cli nical trials ( A g uilar 2 0 1 6). Wit h t he dia g n osis of B O S p ost-tra ns pla ntati o n a 1. 6-f ol d i ncrease 
i n ris k f or m ortalit y is c o nferre d. 
Br o nc hi olitis  o blitera ns  (a di a g n osis  ma de  b y  hist o pat h ol o g y)   a n d B O S  (a dia g n osis  ma de 
cli nicall y i n hi g h  ris k p ati e nts)  is t h e sa me u n derl yi n g  disease  re gar dl ess of t he  i n citi n g i nj ur y. 
[Bar k er N EJ M 2 0 1 4 ].  Earl y efficac y st u dies h a ve d e m o nstrate d a b e nefi ci al effe ct of L- Cs A f or 
t he treat me nt of B O S i n p atie nts wit h B O S f oll o wi n g l u n g tra ns pla nt ati o n.   
T his trial is t he first t o e val u ate t h e safet y, t olera bilit y, e x pl orat or y effic ac y a n d p har mac o ki n etics 
of L- Cs A f or t he tre at me nt of B O S i n p atie nts wit h B O S f oll o wi n g all o ge neic he mat o p oi etic ste m 
cell tra ns pla ntati o n. T he p har mac o ki neti c pr ofile of L- Cs A has bee n e val u ate 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 tra ns pla ntati o n ( S L T) or d o u ble-l u n g tra ns pl a ntati o n 
( D L T). I n t he c urre nt trial f or t h e first ti me t h e p h ar ma c o ki neti c  pr ofile  will be e v al uate d i n  p atie nts 
wit h  B O S  f oll o wi n g all o ge neic  H S C T  t o g et  i nf or mati o n of  t he P K  pr ofile  i n t his p atie nt 
p o p ulati o n a n d t o s u p p ort f urt h er e v al uati o n i n t his i n dic ati o n.  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 2 5  of 8 2  
Cli nica l Tr ial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0 ; 3 0 A pri l 2 0 2 1 
 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 2 6  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
P atie nts i n cli nical trials g e nerall y ca n n ot e x pect t o recei ve direct b e nefit fr o m treat me nt d uri n g 
partici pati o n, as cli ni cal tri als are desi g ne d t o pr o vi de i nf or mati o n a b o ut t he safet y a n d 
effecti v e ness of a n i n v esti g ati o n al me di ci ne.  
T here are p ossi ble ris ks a n d dis c o mf orts ass o ciate d wit h t h e bl o o d dra w f or P K a nal ysis. T he 
ge neral k n o w n ris ks i n cl u di n g disc o mf ort at t h e p u ncti o n site of t he bl o o d dra w ca n be br uisi n g, 
blee di n g, i nfecti o n, a n d rarel y, fai nti n g or ner ve d a ma ge. 
L- Cs A is c o ntrai n dicate d i n pers o ns wit h a hist or y of aller g y t o c ycl os p ori n e or t o a n y of t he
i n gre die nts i n t h e f or m ul ati o n.
S yste mic f or m ulati o ns of c ycl os p ori ne are k n o w n t o ha ve c o ntrai n dicati o ns relate d t o St. J o h n’s 
W ort a n d me dici nes t h at are s u bstrates of P- g p or or g a ni c a ni o n-tra ns p orti n g p ol y pe pti de ( O A T P). 
Pri or st u dies of L- Cs A ha ve de m o nstrate d ne gli ble ser u m le vels a n d n o acc u m ulati o n o ver ti me of 
c ycl os p ori n e.  N o p ote nti al dr u g i nt eracti o ns d uri n g cli nical st u dies ha ve bee n re p orte d. Dr u g- dr u g 
i nteracti o ns are u nli kel y beca use t h e s yste mic c ycl os p ori ne e x p os ure wit h L- Cs A is m uc h l o wer 
t ha n f or a p pr o ve d t hera p e uti c d oses of oral a n d I V c y cl os p ori ne.  
Base d o n cli ni cal e x p erie nce t o dat e 
wit h L- Cs A, t h ere ar e n o s pecial preca uti o ns f or 
a d mi nistrati o n of L- Cs A i n cli nical st u dies usi n g t he dr u g pr o d uct a n d de vice c o m p o n e nt. 
P har m ac o ki netic st u dies ha ve s h o w n t hat t h e s yst e mic c ycl os p ori n e e x p os ure wit h L- Cs A is m u c h 
l o wer t h a n f or a p pr o ve d t hera p e uti c d oses of oral a n d I V c ycl os p ori ne. C o ns ult oral or I V 
c ycl os p ori n e prescri bi n g i nf or mati o n f or vari o us preca uti o ns ass oci at e d wit h t h e hi g her s yste mic 
e x p os ures t hat ma y occ ur after oral or I V d osi n g of c ycl os p ori ne. 
P atie nts w h o are gi v e n L- Cs A ma y als o recei v e ot her i n hale d me dicati o ns. 
W he n L- Cs A is 
a d mi nistere d c o nc o mit a ntl y wit h ot h er i n h al e d me dici n al pr o d ucts, t he or d er of i n halati o n s h o ul d 
be as f oll o ws: i n hale d br o nc h o dilat ors, i n hale d c orti c oster oi ds, i n h ale d a ntif u n g als/ a nti bi otics, 
a n d t he n i n hale d L- Cs A. L- Cs A i n h alati o n s h o ul d o cc ur at l east 1 h o ur after a d mi nistrati o n of a n y 
ot h er i n hal e d me dicati o ns. 
N o e ve nt ass ociate d wit h o ver d ose has bee n re p orte d i n a n y L- Cs A cli nical trial t o d ate. As has 
bee n de m o nstrate d t hr o u g h P K st u dies, s yste mic e x p os ure is si g nifica ntl y l o w c o m pare d wit h t he 
a p pr o v e d t hera pe utic d os es of oral or I V c y cl os p ori ne.  
C O VI D- 1 9 c o nsi derati o ns: At t his ti m e, it is u n k n o w n if s p ecific patie nt p o p ulati o ns are at hi g h er 
ris k of S A R S- C o V- 2 i nfecti o n. F urt her m ore, t he me dical s ur v eilla nce of tra ns pla nte d p atie nts is 
alrea d y bas e d o n s pecifi c preca uti o ns t y pical t o all patie nts t a ki n g i m m u n os u p pressi v e a ge nts. T he 
me di cal val ue of t his trial re mai ns u nc ha n g e d.  




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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 2 8  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
T h us, L- Cs A 5 m g bi d is b ei n g e x pl ore d i n t his s p ecific p o p ulati o n.  A nal o u g o usl y, c hil dre n a ge 
6- 9 y ears ha ve s uffi ci e ntl y l o wer br o nc hial air wa y s urface area c o m pare d t o a d ults wit h t w o
f u ncti o ni n g l u n gs a n d t h us L- Cs A 5 m g bi d will be e x pl ore d i n f ut ure pe diatric st u dies t hat i ncl u de
t his a ge gr o u p.
T o date, t here is 1 1 0 0 patie nts- m o nt hs of t olera bilit y d ata f or L- Cs A deli vere d t o patie nts w h o are 
l u n g tra ns pla nt reci pie nts.  It is a ntici pate d t h at L- Cs A 1 0 m g bi d will be well t olerate d i n p atie nts 
wit h nati ve l u n gs affecte d b y B O S as well.  H o we ver, t he c urre nt st u d y will c o m pare t he 
t olera bilit y of L- Cs A 1 0 m g vs 5 m g bi d i n t he tar get patie nt p o p ulati o n.    
6. 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 v e d b y t he a p pr o priate Et hics 
C o m mitt ees ( E C) a n d healt h a ut h orities, acc or di n g t o I nter n ati o nal C o m mittee o n Har m o nisati o n 
(I C H) a n d a p plic a ble G o o d Cli ni cal Practi ce ( G C P) sta n dar ds, a n d i n acc or da nce wit h t h e et hical 
pri nci pl es t h at ha ve t heir ori gi n i n t h e Declarati o n of Helsi n ki ( F ort aleza, 2 0 1 3). 
6. 1. 8  P o p ul ati o n 
Reci pie nts of a n all o g e neic st e m cell tra ns pla nt, ≥ 1 8 years of a ge, wit h d oc u me nt e d dia g n osis of 
c G v H D i n a n y or ga n ot h er t ha n t he l u n g a n d c o nfir me d dia g n osis of B O S.  
7  T RI A L O BJ E C TI V E S A N D P U R P O S E 
7. 1  T ri al O bj e cti v e s 
7. 1. 1  P ri m a r y O bj e cti v e: 
T he pri mar y o bjecti v e of t his st u d y is t o assess t he t olera bilit y a n d safet y of t w o d ose l e vels of 
aer os oli ze d L- Cs A vs place b o i n a d diti o n t o S o C t hera p y f or B O S i n a d ult all o- H S C T reci pi e nts. 
7. 1. 2  S e c o n d a r y O bj e cti v e s: 
T he sec o n d ar y o bjecti ves of t his st u d y are t o assess P K a n d e x pl orat or y efficac y a n d q ualit y of life 
of t w o d ose le vels of aer os olize d L- Cs A vs place b o i n a d diti o n t o S o C t h era p y f or B O S i n a d ult 
all o- H S C T reci pi e nts. 
7. 2  P u r p o s e of t h e T ri al 
C urre ntl y, t here is n o a p pr o ve d me di ci nal pr o d uct f or t h e pre ve nti o n or treat me nt of B O S after 
all o ge neic ste m cell tra ns pl a nt. All atte m pts f or t h era pe utic i nt er ve nti o n t o alter t he i nci de nce or 
t he pr o gressi o n of B O S are e m pirical a n d i n vesti gati o nal. T his circ u msta nce e x plai ns t h e di v ersit y 
a n d dis har m o n y of t hera pe utic c o nce pts i n t he H S C T c o m m u nit y. T here are S o C practices 
esta blis he d t o ma na ge B O S t h at d e vel o ps after all o- H S C T, b ut n o t h era pe utic re gi me ns h a ve 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 2 9  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
c o ncl usi vel y de m o nstrate d e vi d e nce of si g nifica nt be nefit i n t he pr e v e nti o n or treat me nt of B O S. 
A de q uatel y d esi g ne d a n d e xec ute d, ra n d o mi ze d, c o ntr olle d trials t o assess efficac y a n d safet y are 
nee de d t o i d e ntif y o pti mal t hera pies f or esta blis he d B O S.  
T he h y p ot h esis t hat l o cal d eli ver y of Cs A b y aer os ol i n halati o n will ac hie ve hi g her i ntra p ul m o nar y 
c o nce ntrati o n t ha n b y s yste mic a d mi nistrati o n al o ne, wit h li mit e d t o xicit y c o m pare d t o si milar 
s yste mic d oses d ue t o mi ni m al a bs or pti o n of dr u g i nt o t h e bl o o d circ ul ati o n has bee n s u bsta ntiat e d 
b y t h e st u di es descri be d i n S ecti o n 6. 1. 4 . 
I n p artic ular, t h e i n v esti g at or-i nitiate d trial AI 0 0 1 pr o vi d e d e vi de n ce of L- Cs A’s p ote ntial t o dela y 
pr o gressi o n of B O S w he n a d mi nistere d as a d d- o n i n h alati o n t h era p y as c o m p are d t o S o C f or 
s yste mic B O S t h era p y. I n c o m bi nati o n wit h t h e acce pta bl e safet y pr ofile of L- Cs A, o bser ve d i n 
cli nical trial 1 2 0 1 1. 2 0 1 w he n patie nts were treat e d f or u p t o 2 years, L- Cs A has t he p ote ntial t o 
pr o vi d e s u peri or efficac y o ver c urre nt b est practic e B O S t h era p y.  
T he p ur p ose of t his trial is t o assess t he safet y a n d t olera bilit y of L- Cs A i n patie nts wit h all o- H S C T 
as c urre nt u n d ersta n di n g ass u mes i de ntical pat h o p h ysi ol o g y of B O S after l u n g tr a ns pla nt a n d 
H S C T.  


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 3 0  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
8  T RI A L D E SI G N 
8. 1  E n d p oi nts 
8. 1. 1  P ri m a r y A ss e ss m e nt 
I M P t olera bilit y a n d safet y d uri n g t h e first 4 wee ks of treat me nt. 
8. 1. 2  S e c o n d a r y A s s e s s m e nt s 
I M P t olera bilit y a n d safet y d uri n g t he first 1 2 wee ks of treat me nt; Cs A P K. 
8. 1. 3  E x pl o r at o r y Effi c a c y A s s es s m e nt 

F E V 1 % pre dicte d at ra n d o mizati o n c o m pare d t o Wee k 2, Wee k 4, Wee k 8, a n d Wee k 1 2

F E V 1/ F V C at ra n d o mizati o n c o m p are d t o Wee k 2, Wee k 4, Wee k 8, a n d Wee k 1 2

S F- 3 6 Q ualit y of Life Q u esti o n naire at Wee k 2, W ee k 4, Wee k 8, a n d We e k 1 2

C ha n ges i n t he d ose of c ortic oster oi ds a n d i m m u n os u p pressi v e t hera p y a d mi nistere d
t hr o u g h o ut trial d urati o n
8. 1. 4  I M P T ol e r a bilit y P a r a m et e r s 

L ocal T olera bilit y :
o
C o u g h
o
W heezi n g
o
Br o nc h os pas m
o
T hr oat irritati o n
o
C ha n ge i n F E V 1

O verall T ol era bilit y :
o
Cli ni cal Gl o b al I m pressi o ns ( C GI) scale
o
I n v esti gat or’s t olera bilit y assess me nt at Visit 3 a n d Visit 5
8. 1. 5  S af et y P a r a m et er s 

A Es

S A Es

Cli ni cal la b orat or y val u es

Vit al si g ns

P h ysical E xa mi nati o n
8. 1. 6  P h a r m a c o ki n eti c P a r a m et e r s

P K: ( Wee k 0) at pre- d ose; directl y after e n d of i n h alati o n; 1 5, 3 0, a n d 4 5 mi n utes, a n d 1,
1. 5, 2, a n d 4 h o urs aft er e n d of i n halati o n:
o
C ma x


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 3 1  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
o
tma x
o
A U C 0- 4 h

W h ole bl o o d tr o u g h le vels (at Wee ks 2, 4, 8, a n d 1 2)
8. 2  T ri al D e si g n 
T his is a P hase II pr os pecti ve, m ulti-ce nt er, si n gl e- bli n d, ra n d o mize d cli nical trial e v al uati n g 
safet y a n d t ol era bilit y i n i n a d ult reci pie nts of a n all o- H S C T wit h B O S. T we nt y-f o ur patie nts are 
pla n n e d f or e nr oll me nt. T he cli nical trial will be c o n d uct e d i n u p t o 2 0 ce nters i n E ur o p e. Patie nts 
will be ra n d o ml y all oc at e d 1: 1: 1 t o recei ve eit h er L- Cs A ( 1 0 m g bi d or 5 m g bi d) pl us S o C or 0 
m g L- Cs A ( place b o) pl us S o C. I M P will be a d mi nist ere d f or u p t o 1 2 wee ks. 
8. 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  S ecti o n 1 3. 2. 2), aft er all i ncl usi o n a n d e xcl usi o n criteria ha v e bee n f ull y 
e val uate d, eli gi bl e patie nts will be assi g ne d t o o ne of t h e t hree treat me nt gr o u ps at a rati o of 1: 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 statisti cia n ot h er wise 
n ot i n v ol ve d wit h t he trial, usi n g v ali d ate d ra n d o m n u m ber ge nerat or s oft w are. T he r a n d o mi zati o n 
c o de of eac h p atie nt will be pr o vi d e 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 h e electr o ni c C ase Re p ort F or m (e C R F) i nt o w hic h t he ge nerat e d 
ra n d o m c o d e list will b e u pl o a de d. Eac h p atie nt will be assi g ne d a n u m b er as part of t he 
ra n d o mizati o n pr o cess. T he n u m b er assi g ne d t o a patie nt will bec o me t h at pati e 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 p atie nt. 
N o stratificati o n will b e p erf or m e d. 
8. 3. 1  Bli n di n g 
T his is a si n gle- bli n d trial. D ue t o t he differe nt a p peara n ce of t he t hree teste d stre n gt hs of I M P, a 
f ull bli n di n g of t he st u d y was n ot p ossi ble. O nl y t he ra n d o mize d st u d y p atie nts will be bli n d e d t o 
st u d y treat me nt assi g n me nt.  F or details of t he bli n di n g of t he Data M o nit ori n g C o m mitt ee 
me m bers, see  Se cti o n 1 2. 2.  
8. 3. 2  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 os a g e a n d A d mi ni st r ati o n 
8. 3. 2. 1  F o r m ul ati o n of L- Cs A 
T he c o m p ositi o n of t h e L- Cs A f or m ul ati o n is s h o w n i n Ta ble 1 . It is a l y o p hilis ate i nte n de d f or 
rec o nstit uti o n wit h 0. 2 5 % N a Cl. T he f or m ulati o n is de vel o pe d f or i n h al ati o n use a n d a dj uste d t o 
p h ysi ol o gi cal t olera ble v al ues of p H ( 6. 5 ±  0. 3) a n d os m olalit y 4 3 0- 5 5 0 m Os m ol/ k g). 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 3 2  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
T a bl e 1: 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 
Li p oi d S 1 0 0 
Carrier  
n o n c o m p e n dial 
P ol ys or bate 8 0 
S urfacta nt 
P h E ur 
Dis o di u m h y dr o g e n p h os p hate d o deca h y drate  
B uffer 
P h E ur 
S o di u m di h y dr o ge n p h os p hate di h y drat e 
B uffer 
P h E ur 
Dis o di u m e d etate di h y drate 
Sta bili zer 
P h E ur 
S u cr ose 
L y o pr otecta nt  
P h E ur 
Water 
Dis persi o n me di u m  
P h E ur/ U S P 2 
1: E ur o p ea n P h ar mac o peia 
2: U nite d States P h ar mac o peia 
T he p article si ze of t he li p os o mes is i n t h e ra n ge of 4 0- 1 0 0 n m wit h a PI of n ot m ore t h a n 0. 5 0, 
w hic h i n dicat es t he wi dt h of t h e 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 d al dis p erse 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 % Na Cl f or rec o nstit uti o n will be s u p plie d b y t he I M P d e p ot o n 
be half of t h e s p o ns or: 
 
 
 
Ger ma n y 
P P D


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 3 3  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
8. 3. 2. 2  T r e at m e nt a n d D os a g e 
After Scree ni n g, patie nts c o m pl yi n g wit h all i n cl usi o n a n d e xcl usi o n crit eri a (see Secti o ns 9. 1  
a n d 9. 2 ) will be ra n d o mi ze d t o o ne of t he f oll o wi n g treat me nts: 
Tre at me nt A ( L- Cs A 1 0 m g tr e at me nt pl us S o C): 
L- Cs A 1 0 m g/ 2. 5 m L bi d f or a ma xi m u m of 1 2 wee ks
pl us
S o C t h era p y
Tre at me nt B ( L- Cs A 5 m g tre at me nt pl us S o C): 
L- Cs A 5 m g/ 1. 2 5 m L bi d f or a ma xi m u m of 1 2 wee ks
pl us
S o C t h era p y
Tre at me nt C ( L- Cs A 0 m g ( Pl ace b o) pl us S o C ): 
L- Cs A 0 m g/ 2. 5 m L bi d f or a ma xi m u m of 1 2 we e ks
pl us
S o C t h era p y
8. 3. 2. 3  A d mi nist r ati o n of I M P 
I n cli nical trials 1 2 0 1 1. 2 0 1 a n d cli nical trial AI 0 0 1 t otali n g > 1 1 0 0 patie nt m o nt hs of e x p os ure, 
L- Cs A was w ell t olerat e d. Patie nts will be e d ucate d r e g ar di n g us e of t he L- Cs A  
 a n d
a d mi nistrati o n of t h e first d ose will be o bser v e d. At s u bse q ue nt st u d y visits, it will be re q uest e d
t hat t he p atie nt self-a d mi nist er a d ose of I M P w hil e o bser ve d b y st u d y p ers o n n el.
Eac h patie nt will recei v e t w o I M P a d mi nistrati o ns per d a y, o ne i n t h e m or ni n g a n d o ne i n t he 
e ve ni n g. T h e i n halati o ns are sc he d ul e d t o be ta ke n a p pr o xi matel y 1 2 h o urs ( b ut n ot less t ha n 
6 h o urs) a part, e. g., at 8: 0 0 a. m. a n d 8: 0 0 p. m. eac h da 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 d escri be d i n t he I nstr ucti o ns F or Use. 
Ha n dli n g of I M P I n hal ati o n: 
Eac h p atie nt will o p e n a gl ass vial b y lifti n g u p t he plastic dis k/ca p, lifti n g u p t he metal fla p t o 
re m o ve t he metal ri n g, m etal ca p, a n d t he r u b ber st o p per. T he pl astic a m p o ule c o ntai ni n g 1. 2 ml 
or 2. 4 m L of t he 0. 2 5 % Na Cl as s ol ve nt will be o pe ne d b y t wisti n g t he hea d part se veral ti mes i n 
o ne directi o n. T h e N a Cl s ol uti o n will be s q ueeze d i nt o t h e glass vial c o ntai ni n g t he w hitis h 
l y o p hilisate ca ke. T he gl ass vial will be re-cl os e d wit h t he r u b b er st o p p er a n d s wirle d ge ntl y 
wit h o ut s pilli n g a n y li q ui d f or a mi ni m u m of 1 mi n ute a n d u p t o 5 mi n utes, u ntil t he visi ble 
particles are c o m pl etel y diss ol ve d. S h a ki n g of t h e vial m ust b e a v oi de d t o pre ve nt f o a mi n g of t he 
rec o nstit ute d s ol uti o n.  
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 3 4  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
Ne xt, t h e rec o nstit ute d I M P s h o ul d be p o ure d i nt o t he L- Cs A  
 c ha m b er. T he ne b ulizer 
s h o ul d be k e pt h oriz o ntal d uri n g o perati o n. D uri n g i n halati o n, t he pati e nt s h o ul d sit i n a n u pri g ht 
p ositi o n a n d i n hale a n d e x hale de e pl y t hr o u g h t he m o ut h piece of t he ne b uli zer wit h o ut i nterr u pti o n 
u ntil n e b uli zati o n s h uts off a ut o mati call y. T h e s ol uti o n is f or si n gl e use o nl y, a n d n o re mai ni n g 
s ol uti o n s h o ul d be l eft i n t h e glass vi al. All ot h er cli nical tri al materials, i n cl u di n g u n use d I M P, 
m ust be br o u g ht b ac k t o t he cli nical trial ce nter at eac h sc he d ul e d visit f or dr u g a n d d e vice 
acc o u nta bilit y. After c o m pleti o n of t h e i n h alati o n, t he patie nt s h o ul d re m o v e all e xcess I M P i n t he 
m o ut h a n d p har y n x b y ri nsi n g a n d gar gli n g wit h water a n d s u bse q u e ntl y dis c har gi n g t h e s ol uti o n. 
I nterr u pti o n of I M P I n h alati o n: 
If a patie nt n ee ds t o te m p oraril y i nterr u pt I M P i n halati o n (e. g., d ue t o c o u g hi n g), t h e p atie nt s h o ul d 
t ur n off t he de vice a n d t ur n it bac k o n w he n rea d y t o res u me i n hal ati o n.  
I M P ma y be te m p oraril y disc o nti n ue d as dee me d necessar y b y t he i n vesti gat or (see Secti o n 9. 3. 1 ) 
a n d will be d oc u me nte d i n t h e e C R F.  
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 3 5  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
8. 4  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 
8. 4. 1  P a c k a gi n g a n d L a b eli n g of I M P 
P ac ka gi n g 
T he I M P will be pr o vi de d as 0 m g a n d 1 0 m g L- Cs A l y o p hilis ate i n glass vials t y p e I wit h gre y 
r u b b er st o p p ers a n d a n al u mi n u m ca p wit h a yell o w pl astic dis k a n d st ore d i n a n o uter pac ka gi n g 
b o x c o nsisti n g of 6 0 vi als wit h t h e L- Cs A/ place b o a n d 7 0 plastic a m p o ules c o nt ai ni n g 2. 4 m L 
0. 2 5 % N a Cl f or r ec o nstit uti o n. T he 5 m g L- Cs A l y o p hilisate will be s u p plie d i n glass vi als t y p e I 
wit h gre y r u b ber st o p pers a n d a n al u mi n u m ca p wit h a gree n plastic dis k a n d st ore d i n a n o uter 
pac ka gi n g b o x c o nsisti n g of 6 0 vi als wit h t he L- Cs A a n d 7 0 plasti c a m p o ules c o ntai ni n g 1. 2 m L 
0. 2 5 % N a Cl f or r ec o nstit uti o n. 
T he I M P will be la belle d i n c o m pli a n ce wit h G o o d M a n ufact uri n g Practice ( G M P) s p ecificati o ns 
acc or di n g t o a p plic a ble re g ulati o ns.  
8. 4. 2  St o r a g e 
T he u n o p e ne d I M P m ust be k e pt i n a sec ure, l oc k e d, te m perat ure-c o ntr olle d l ocati o n wit h access 
t o a ut h orize d st aff o nl y. I M P s h o ul d be st ore d n ot a b o ve 2 5 ° C pr otect e d fr o m li g ht.  
8. 4. 3  I n h al ati o n D e vi c e P a c k a gi n g 
T he I n vesti g ati o nal  
 Ne b ulizer S yst e m c o nsists of t he f oll o wi n g t w o pac ka ges: 
1) C o ntr oll er Kit
T he c o ntr oller kit will be pr o vi d e d at ra n d o miz ati o n visit a n d i ncl u des 
•
1 x e Trac k C o ntr oll er
•
1 x Ne b ulizer H a n dset i n cl u di n g c o n n ecti o n c or d, a n A C p o w er s u p pl y a n d
4 “ A A” b atteries
•
1 x Eas ycare clea ni n g ai d
•
1 x Carr yi n g ba g
•
1 x I nstr ucti o ns F or Us e
•
2 x Aer os ol Hea ds
2) 
 
 i n c o m bi nati o n wit h L- Cs A Kit bel o w
M o nt hl y S u p pl y – At E ac h f oll o wi n g Cli nic Visit
•
 
C CI
C C
C CI C CI
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 3 6  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
8. 5  St o p pi n g R ul es a n d Di s c o nti n u ati o n C rit eri a 
8. 5. 1  P ati e nt L e v el 
Re g ular ter mi nati o n of cli nical trial parti ci pati o n: 
T he i n vesti gati o nal treat me nt will be ter mi n ate d after 1 2 w ee ks ( E n d of Treat me nt [ E o T]). T he 
treat me nt peri o d will b e f oll o we d b y a 2- wee k f oll o w- u p peri o d ( E n d of St u d y [ E o S]). A n y p atie nts 
wit h o n g oi n g A Es a n d S A Es will b e f oll o we d- u p u ntil rec o v er y or st a bilizati o n of t he A E/ S A E.  
Pre mat ure t er mi nati o n of cli nical tri al partici pati o n: 

P atie nts ma y disc o nti n ue partici pati o n i n t he cli nical tri al at a n y ti me b y re v o ki n g t heir
i nf or me d c o nse nt.

T he I n v esti gat or ma y wit h dra w a patie nt at a n y ti me if it is i n t h e b est i nterest of t he p atie nt
base d u p o n cli nical ass ess me nts.

P atie nt is l ost t o f oll o w- u p

Pre g na nc y (t h e pati e nt will be f oll o we d via  t h e s p o ns or’s safet y d e part me nt)

T er mi nati o n of t he cli nic al trial as a w h ole b y Z a m b o n S p A as d efi n e d i n secti o n 8. 5. 3.
If t he partici p a nt fails t o ret ur n f or cli nical f oll o w- u p, t he patie nt will be c o nt act e d b y t el e p h o ne or 
a letter will be se nt re q u esti n g a cli ni c visit ( E o S), a n d t he reas o n f or n o n-c o m pli a n ce will be 
d oc u me nt e d. T he fi n al visit will e nc o m pass t he ass ess m e nts liste d u n d er E o S Visit ( Visit 6; 
S ecti o n 1 3. 2. 5 ). A d diti o nall y, use d a n d u n use d I M P a n d i n h alati o n de vice will be retrie ve d, if 
a p pli ca ble. Z a m b o n S p A will be n otifie d t h at t he p ati e nt has ter mi n at e d cli nical trial p artici p ati o n. 
8. 5. 2  C e nt e r L e v el 
Re g ular ter mi nati o n of cli nical trial ce nters: 
All ce nters will b e cl ose d after patie nts h a ve c o m plete d cli nical trial parti ci pati o n a n d t he data base 
has bee n l oc k e d. 
Pre mat ure t er mi nati o n of a cli nical trial ce nter: 
T he s p o ns or ma y cl os e a ce nt er f or t h e f oll o wi n g reas o ns: 

I n case of re p eate d a n d c o nti n u o us vi olati o ns of G C P a n d a p plica ble re g ul ati o ns

I n acc urate or i nc o m plete d ata c ollecti o n

Falsificati o n of rec or ds

Fail ure t o a d h ere t o t h e pr ot oc ol

Or ga nizati o nal or str uct ural c ha n g es i n t h e ce nter w hic h c halle n g e t he re q uire me nts or
q u alificati o n f or cli nical trial partici pati o n (e. g., c ha n ge of i n vesti gat or, s hift of ce nter
acti vities)


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 3 7  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
I n cas e 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 b e ma de t o e ns ure t he safet y 
a n d data r elia bilit y of o n g oi n g patie nts u ntil cli nical tri al c o m pleti o n. 
8. 5. 3  Cli ni c al T ri al L e v el 
Re g ular ter mi nati o n of t h e cli nical trial: 
T he cli nical trial will be c o nsi dere d c o m plete aft er t h e pre- defi ne d n u m b er of p atie nts h a ve b ee n 
ra n d o mize d a n d c o m plete d t h eir cli nical trial partici pati o n. T he last visit of t he l ast p atie nt is t h e 
defi n e d e n d of t h e st u d y. 
Pre mat ure t er mi nati o n of t he cli nical trial: 

S eri o us safet y c o ncer ns t hat i n dicate a p ote ntial healt h h azar d ca us e d b y treat me nt wit h t he
I M P (ter mi nati o n d ue t o s afet y iss ues)

T he cli nical trial ma y b e dis c o nti n ue d at a n y ti me f or reas o ns s u c h as b ut n ot li mite d t o me dical
f utilit y a n d a d mi nistrati ve reas o ns, u p o n t h e dis creti o n of Za m b o n S p A.
I n t his case, a n a b bre vi ate d cli ni cal st u d y re p ort will be re p orte d t o C o m p ete nt A ut h orities a n d 
Et hi cs C o m mittees acc or di n g t o a p plica ble re g ulat or y re q uire m e nts. T he I n v esti g at or m ust n otif y 
his/ h er E C of cli nical trial cl os ure. 
8. 6  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 g at or is res p o nsi ble f or e ns uri n g t hat d eli veries of I M P vi als a n d b o x es, L- Cs A  
 
a n d ot h er cli nical trial m aterials are c orrectl y recei ve d a n d rec or d e d, t hat t h ese are h a n dle d a n d 
st ore d safel y i n a l oc ke d a n d t e m perat ure c o ntr oll e d st ora ge place wit h access f or a ut h orise d st u d y 
staff o nl y a n d t h at t he y are use d i n acc or da nce wit h t his pr ot o c ol. I n a d diti o n, t he I n v esti gat or will 
m o nit or eac h p atie nt’s treat me nt c o m plia nce b y c o u nti n g t he use d/ u n use d dr u g vials at eac h visit. 
F or t he p ur p ose of t his trial patie nts will be re gar d e d as c o m plia nt if n o m ore t h a n 4 5 vials of I M P 
o ver t h e e ntire treat me nt peri o d of 1 2 wee ks are ret ur ne d as u n use d – t his c orres p o n ds t o 
a p pr o xi m atel y 7 5 % treat m e nt c o m pli a nce. T he reas o n f or n o n-c o m plia nce s h all be d oc u me nt e d 
acc or di n g o n t he res pecti v e e C R F. 
U n use d I M P vials, a m p o ules, b o xes, a n d L- Cs A  
 m ust be ret ur n e d  or destr o y e d o n-site 
after a cc o u nta bilit y has bee n c o m plete d a n d d estr ucti o n is a p pr o ve d b y Za m b o n S p A. A list of 
I M P, L- Cs A  
, a n d ot h er materials recei ve d, use d, ret ur ne d, or d estr 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 p a nci es m ust be acc o u nte d f or. 
C O VI D- 1 9 s pecifi c c o nsi derati o n: t he pati e nts will be s u p plie d d uri n g V 1 wit h t h e f ull a m o u nt of 
st u d y me dicati o n nee de d, t o c o ver t h e t otal treat m e nt peri o d of 1 2 w ee ks. Patie nt has t o bri n g all 
st u d y me dicati o n bac k t o t h e site at E o T Visit V 5 f or Dr u g Acc o u nta bilit y. 
C CI
C CI
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 3 9  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 4. Ps yc hiatric dis or ders or alt ere d me ntal stat us precl u di n g u n dersta n di n g of t h e i nf or me d
c o nse nt pr ocess a n d/ or c o m pl eti o n of t h e necessar y pr oce d ures.
1 5. A n y c o-e xisti n g m e dical c o n diti o n t h at i n t h e 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 o ci ate d wit h t h e patie nt’s parti ci pati o n i n t he cli nical trial.
1 6. Pre-sc he d ul e d h os pitalizati o ns, s ur g eries or i nter v e nti o ns pl a n n e d t o be perf or me d aft er
o btai ni n g I nf or me d C o nse nt f or t his st u d y.
9. 3  P ati e nt Wit h d r a w al C rit e ri a 
I n t he e ve nt of p atie nt wit h dra wal, t he I n vesti gat or m ust c o m plete t h e a p pr o pri at e 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 aft er wit h dra wal, stati n g t h e reas o n a n d date of wit h dra wal. 
A n a ut o mate d e- m ail al ert will be g e nerate d b y t he e C R F s yste m a n d will be s e nt t o t he Cli nical 
Researc h Or ga nizati o n ( C R O). 
9. 3. 1  P r o c e d u r e s of P ati e nt Wit h d r a w al a n d I M P di s c o nti n u ati o n 
Wit h dra wal: 
T he p atie nt is free t o wit h dra w fr o m t h e cli ni cal tri al 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 di ce. T he I n vesti g at 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 tri al at a n y ti me if t h e patie nt’s cli ni cal c o n diti o n warra nts it. 
I n cas e of earl y wit h dra w al, t he pati e nt will be e n c o ura ge d t o perf or m a fi n al visit. T h e fi nal visit 
will e nc o m p ass t h e assess me nts liste d u n d er E o S Visit ( S ecti o n 1 3. 2. 5 ).  
A d diti o n all y, use d a n d u n use d I M P a n d i n hal ati o n de vice will be retrie ve d, if a p plica ble. Za m b o n 
S p A will be n otifie d b y t h e I n v esti g at or via e ntr y i n a n d n otificati o n b y t he e C R F t h at t he patie nt 
has ter mi nate d cli nical tri al partici pati o n. 
I M P disc o nti n uati o n 
T he I n vesti g at or or p atie nt is free t o disc o nti n u e re g ular i nta ke of I M P, if t he cli nical c o n diti o n 
of t h e patie nt or ot her s eri o us reas o ns warra nt it. Reas o ns f or disc o nti n uati o n of I M P ma y 
i ncl u de ( b ut are n ot li mite d t o) t h e f oll o wi n g: 

Si g nifica nt res pirat or y i nfecti o n re q uiri n g t hera p y

Res pirat or y fail ure fr o m a n y ca use

Mec h a ni cal v e ntilati o n
If 1 0 or m ore c o ns ec uti ve d oses of I M P are miss e d, re gar dless of reas o n, t he n I M P will be 
c o nsi d ere d as disc o nti n u e d a n d s h o ul d n ot be res u me d.  If I M P i n hal ati o n is disc o nti n ue d, t he 
patie nt 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 h all n ot recei v e I M P. 
St o p pi n g criteria are o utli ne d i n detail i n S ecti o n 8. 5. 1 . 




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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 4 1  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 0  T R E A T M E N T O F P A TI E N T S 
P atie nts will recei ve L- Cs A (eit h er 1 0 m g, 5 m g or 0 m g bi d) i n a d diti o n t o S o C as prescri b e d b y 
t he treati n g p h ysicia n a n d as descri be d i n S ecti o n 8. 3. 2 . L- Cs A will b e a d mi nistere d as 1 0 m g/ 2. 5 
m L, 5 m g/ 1. 2 5 m L, or 0 m g/ 2. 5 m L i n h alati o n vi a t he L- Cs A  
 f or u p t o 1 2 wee ks. 
A n y c ha n ges i n S o C treat me nt will be d o c u me nte d i n t he e C R F. 
1 0. 1  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 will mai ntai n t h eir us ual care t hr o u g h o ut t he c o urse of t h e st u d y. S o C i n cl u des 
pr o p h yla xis a gai nst c o m m o n o p p ort u nisti c i nfecti o ns, i m m u n os u p pressi o n, a n d a n y ot h er c hr o nic 
me di cati o n. All c o nc urre nt treat me nt or me dicati o ns gi ve n wit hi n 3 0 d a ys pri or t o R a n d o mi zati o n 
u ntil E o S ( Visit 6) will be rec or de d i n t h e e C R F,  t his als o i ncl u des vacci nati o n f or S A R S- C o V- 
2. 
1 0. 1. 1  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 n s 
All patie nts will recei ve sta n d ar d i nfecti o us disease pr o p h yla xis a n d t h era p y c o nsisti n g of 
a p pr o priatel y t ar 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 st art a n d st o p or c ha n ge i n d osa ge will be rec or d e d o n t he res pecti ve e C R F. 
1 0. 1. 2  I m m u n o s u p p r e s si o n 
I m m u n os u p pressi v e t hera p y is per mitte d a n d will be perf or me d t o ce nt ers’ sta n dar d re gi me n. 
T he use of differe nt f or m ulati o ns of aer os olize d C y cl os p ori ne A ot h er t ha n L- Cs A is strictl y 
pr o hi bit e d d uri n g t h e c o m plete cli nical trial peri o d. S yst e mi c a d mi nistrati o n of Cs A is per missi ble 
if me dicall y necessar y at t he decreti o n of t he i n vesti g at or. 
1 0. 1. 3  T r e at m e nt f o r B O S 
T he f oll o wi n g me dicati o ns will be per mitte d: 

I n h ale d c ortic oster oi ds are all o we d a n d p atie nts s h o ul d be o n a sta bl e d ose f or 4 wee ks
pri or t o ra n d o mizati o n a n d t hr o u g h o ut t he st u d y.

F or all ot h er i n h ale d me dicati o ns please refer t o S ecti o n 1 0. 1. 4 .

S yste mic c ortic oster oi d treat me nt f or B O S ( or c G V H D) will be p er mitt e d, b ut a p ulse d ose
has t o b e c o m plete d pri or t o scree ni n g.

E xtrac or p oreal p h ot o p h oresis ( E C P) f or treat me nt of B O S is per mitte d wit hi n 4 wee ks
pri or t o ra n d o mizati o n.

M o ntel u k ast will be p er mitte d, b ut p atie nts s h o ul d be o n a st a ble d ose f or 4 wee ks pri or t o
ra n d o mizati o n a n d t hr o u g h o ut t h e st u d y.
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 4 2  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 0. 1. 4  Ot h er M e di c ati o n 
All i n hale d me di cati o ns, e xce pt i n v esti g ati o n al i n hale d m e dicati o ns, are p er missi ble d uri n g t he 
trial.  
P atie nts o n br o n c h o dilat ors s h o ul d be o n a sta ble d ose 4 wee ks pri or t o ra n d o mizati o n a n d 
t hr o u g h o ut t h e st u d y.  All ot h er i n hale d m e dicati o n s h o ul d b e a d mi nistere d after s pir o metr y i n t he 
f oll o wi n g or der: i n h ale d c ortic ost er oi ds, i n hale d a ntif u n gals/a nti bi otics, a n d t h e n i n hal e d I M P. F or 
details wit h re gar d t o s pir o metr y meas ure m e nts, please refer t o S ecti o n 1 1. 1. 1 . 
1 0. 1. 5  P r o hi bit e d M e di c ati o n 
Azit hr o m yci n will n ot be p er mitte d. I n t h e e v e nt a patie nt has use d c hr o ni c azit hr o m y ci n, it m ust 
be disc o nti n u e d f or at l east 4 wee ks pri or t o ra n d o mizati o n.  
Zafirl u kast will n ot be per mitte d. 
Treat me nts wit h ot h er I n vesti gati o n al Me di ci nal Pr o d ucts (I M Ps) or pr e vi o us t hera pies wit hi n 
f o ur wee ks or fi ve ti mes h alf-life of t he dr u g, w hi c he ver is l o n ger, is pr o hi bite d pri or t o st u d y 
scree ni n g a n d d uri n g t h e st u d y. 




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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 4 4  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 

T he t w o lar g est v al 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 crit eria are met, t he test sessi o n ma y be c o ncl u de d. 
If b ot h of t hese crit eria are n ot m et, 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 t ests ha v e b ee n p erf or m e d ( o pti o n al)
or

T he p atie nt ca n n ot or s h o ul d n ot c o nti n u e
T he t hree b est v al u es o ut of t he p erf or me d ma n e u vers will be rec ore d i n t h e e C R F. 
Ti mi n g of s pir o metr y meas ures is pr o vi de d i n Secti o n 1 0. 1. 4 . Ti mi n g of s pir o metr y meas ures i n 
relati o n t o a d mi nistrati o n of I M P is pr o vi d e d i n Secti o n 1 3. 2 . 
1 1. 1. 2  S F- 3 6 Q u alit y of Lif e Q u e sti o n n ai r e 
T he S F- 3 6 Versi o n 1. 0 is a sta n dar dize d, s h ort f or m m eas ure of ge neric healt h stat us, d esi g ne d f or 
self-a d mi nistrati o n. It ta kes 5- 1 0 mi n ut es f or t h e pati e nt t o c o m plete t h e q uesti o ns. Patie nts will 
be as ke d t o c o m plete t h e q u esti o n n aire at Visits 1 ( Baseli ne), 2, 3, 4, 5, a n d res ults will be e nt ere d 
i nt o t h e e C R Fs b y t h e sit e staff. 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 4 5  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 2  A S S E S S M E N T O F S A F E T Y 
1 2. 1  S af et y P a r a m et e r s 
S afet y assess me nts at e ver y visit i ncl u d e A E re p orti n g, p h ysical e xa mi nati o n, C GI assess me nt, 
vital si g ns a n d cli nical l a b orat or y p ara meters ( perf or me d at t he l ocal l a bs i n eac h st u d y site). 
L- Cs A p har mac o ki neti c meas ure m e nts at Visits 1 t o 5 are a n al y ze d at t h e Ce ntral La b or at or y A C C
G m b H i n Ger ma n y, a n d als o liste d i n t his secti o n, alt h o u g h t h e y will n ot be a vaila bl e f or i m me diate
safet y assess me nt b y t h e D M C or I n v esti gat or.
C O VI D- 1 9 s p ecific c o nsi d erati o n: I n case t he pla n ne d o n-site visit ca n n ot be perf or me d d u e t o
C O VI D- 1 9 restricti o ns, t h e PI or t he S u b-I n v esti g at or a n d/ or a n a p pr o priat el y q ualifie d sit e st u d y
tea m me m ber m ust call t he pati e nt. A re m ot e visit m ust be perf or me d t o assess 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 p atie nt’s stat us a n d well- bei n g (see als o S ecti o n 1 3. 2. 7 ).
1 2. 1. 1  D efi niti o n s 
A d verse E v e nt ( A E) 
A n A E is a n y u nt o war d me dical occ urre n ce i n a patie nt after a d mi nistrati o n of a p har mace utical 
pr o d uct a n d w hi c h d oes n ot necessaril y h a ve a ca usal relati o ns hi p wit h t his treat me nt. A n A E ca n 
t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i n cl u di n g a n a b n or m al la b orat or y fi n di n g), 
s y m pt o m, or disease te m p orall y ass ociate d wit h t h e use of a me dici nal (i n v esti g ati o nal) pr o d uct, 
w het her or n ot relate d t o t he me dici n al (i n vesti gati o nal) pr o d u ct (I C H G ui d eli nes f or G o o d Cli nical 
Practice E 6( R 2), 9 N o v e m ber 2 0 1 6). 
T his i ncl u des w orse ni n g of a pr e-e xisti n g c o n diti o n or i n crease i n fre q ue nc y of a pr e-e xisti n g 
c o n diti o n. A n A E is c o nsi dere d seri o us if it meets a n y of t he seri o us criteria liste d b el o w. T o e ns ure 
n o c o nf usi o n or mis u n d ersta n di n g of t he differe nce b et wee n t he t er ms “seri o us” a n d “se vere”, 
w hic h are n ot s y n o n y m o us, t h e f oll o wi n g clarific ati o n is pr o vi d e d: 
T he ter m “s e vere” is ofte n use d t o descri be t he i nte nsit y (se verit y) of a s pecific e ve nt (as i n mil d, 
m o derate, or se vere m y o car dial i nfarcti o n); t he e v e nt itself, h o we ver, ma y be of relati vel y mi n or 
me di cal si g nifica nce (s uc h as se vere h ea dac h e). T his is n ot t he sa me as “seri o us”, w hic h is b ase d 
o n pati e nt/ e v e nt o ut c o me or acti o n criteria us uall y ass ociate d wit h e ve nts t h at p ose a t hreat t o a 
patie nt’s life or f u n cti o ni n g. Seri o us ness ( n ot se verit y) ser v es a g ui de f or d efi ni n g re g ul at or y 
re p orti n g o bli g ati o ns. 
T he official d efi niti o n als o e xte n ds t o A Es occ urri n g d uri n g t he off-treat me nt f oll o w- u p peri o d. 
Eac h p atie nt will be cl osel y o bser ve d a n d q u esti o ne d f or A Es t hr o u g h o ut t he cli nical tri al p eri o d 
wit h n o n-lea di n g q uesti o ns (e. g., h o w d o y o u feel ?). T he pati e nts will be i nstr uct e d t o re p ort t o t he 
cli nical trial staff i m me diatel y a n y s y m pt o ms a n d/ or si g ns w hic h occ ur bet w ee n t h e sc he d ul e d 
o bser v ati o n ti mes. 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 4 6  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
All A Es re p orte d b y t he patie nt or o bs er ve d b y t h e I n vesti gat or or h os pital p ers o n nel will be 
d oc u me nt e d i n t he res pecti ve e C R F. T h e f oll o wi n g i nf or mati o n re gar di n g eac h A E will be 
o btai ne d: date a n d ti me of o nset a n d res ol uti o n ( d urati o n), s eri o us or n o n-seri o us (as d efi n e d 
bel o w), se v erit y, treat me nt re q uire d, o ut c o me, relati o ns hi p t o certai n m e dicati o n, a n d if t h e A E 
ca use d wit h dra wal fr o m t h e cli nical trial. 
I n a d diti o n t o t h e I n vesti gat or’s o w n descri pti o n of t he A E, eac h A E e ve nt will be c o de d b y data 
ma na ge me nt acc or di n g t o t h e Me dical Di cti o nar y f or Re g ulat or y Acti viti es ( Me d D R A) c o d e list. 
T he v er b ati m ter m will be rec or de d i n t h e e C R F. 
A b n or mal la b orat or y test res ults will be re p orte d as A Es if t h e y are i n dicati v e of a cli nical 
c o n diti o n t hat meets t he criteria f or a n A E. 
A d verse Dr u g R eacti o n ( A D R) 
A d verse dr u g reacti o ns ( A D Rs) are all n o xi o us a n d u ni nte n d e d res p o nses t o a me dici nal pr o d u ct 
relate d t o a n y d ose t h at a ca usal relati o ns hi p bet wee n t he me dici nal pr o d u ct a n d a n A E is at least 
a reas o na bl e p ossi bilit y, i.e., t he rel ati o ns hi p ca n n ot be r ule d o ut. A n u n e x pecte d A D R is a n y 
a d verse reacti o n n ot i de ntifie d i n nat ure, fre q u e nc y, or i nt e nsit y list e d i n t h e referre nt safet y secti o n 
of t h e c urre nt I B. 
S eri o us A d verse E v e nt ( S A E) 
Eac h A E is t o be cl assifie d b y t he I n v esti g at or as S E RI O U S or N O N- S E RI O U S. 
T he I nter n ati o nal C o nfere nce o n Har m o nisati o n (I C H) of Tec h nical Re q uir e me nts f or Re gistrati o n 
of P har mace uticals f or H u ma n Use d efi n es a n S A E as a n y A E occ urri n g at a n y d os e t hat res ults i n 
a n y of t h e f oll o wi n g o utc o mes: 

Deat h

A life-t hre ate ni n g e ve nt (i m me diate ris k of deat h at t he ti me of t he e ve nt)

I n p atie nt h os pit alizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n

A persist e nt or si g nifica nt disa bilit y/i nca pacit y

A c o n g e nit al a n o mal y/ birt h d efect

Ot her i m p orta nt me dical e ve nt ( Me dical a n d scie ntific j u d g me nt s h o ul d be e xercise d i n
deci di n g w het her e x p e dit e d re p orti n g is a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt
me dical e v e nts t hat 
m a y n ot be i m m e di atel y life-t hreate ni n g or res ult i n deat h or
h os pit alizati o n b ut ma y j e o par dize t h e patie nt or m a y re q uire i nter ve nti o n t o pre v e nt o ne of
t he ot her o ut c o mes liste d i n t he defi niti o n a b o v e. T hese s h o ul d als o us uall y be c o nsi d er e d
seri o us.)


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 4 7  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 2. 1. 2  R el ati o n s hi p t o Cli ni c al T ri al T r e at m e nt A s si g n m e nt 
All A Es will be e val uate d b y t he I n v esti g at or f or p ote ntial relati o ns hi p t o t h e cli ni cal trial treat me nt 
assi g n me nt ( L- Cs A or pl ace b o) i n t h e f oll o wi n g c ate g ori es: 

U nrel ate d : A n A E wit h a k n o w n ca use ot h er t ha n t h e use of I M P ( n o reas o na ble relati o ns hi p).

P ossi ble : A n A E t hat mi g ht be d u e t o t h e use of t h e I M P. 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 bl e; t heref ore t he ca usal relati o ns hi p ca n n ot b e e xcl u de d (reas o na ble rel ati o ns hi p).

Defi nite : A n A E t h at 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 I M P;
t hat f oll o ws a k n o w n or e x pecte d res p o nse p atter n t o t h e s us p ecte d cli nical trial treat me nt
assi g n me nt (reas o n a bl e relati o ns hi p).
I n t h e a bse nce of i nf or mati o n o n ca usalit y pr o vi de d b y t he re p orti n g i n v esti gat or, t he s p o ns or will 
c o ns ult t he i n vesti gat or a n d e nc o ur a ge hi m/ h er t o gi ve a n o pi ni o n o n t his e ve nt. T he ca usalit y 
assess me nt gi v e n b y t h e i n vesti gat or will n ot b e d o w n gra de d b y t he s p o ns or. If t h e s p o ns or 
disa grees wit h t he i n vesti gat or's ca usalit y assess m e nt, t he o pi ni o n of b ot h t h e i n v esti g at or a n d t he 
s p o ns or will be pr o vi d e d. 
1 2. 1. 3  M a xi m u m I nt e n sit y 
All A Es will be gra d e d a cc 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 u al
acti vities.

M o der ate : E v e nt t h at i m p airs us ual acti vities b ut ma y be a meli orate d b y si m pl e t h era pe utic
ma ne u vers.

S e vere *: E v e nt w hi c h i m p airs us ual acti viti es a n d re q uires i nter v e nti o n.
* T here is a disti ncti o n bet wee n a se ver e A E a n d a n S A E; a se ver e reacti o n is n ot a n S A E u nless
it meets o ne of t h e criteria f or seri o us e ve nts (see S ecti o n 1 2. 1. 1 ).
1 2. 1. 4  S e ri o us A d v e r s e E v e nt ( S A E) R e p o rti n g 
A n y S A E occ urri n g 

bet wee n t h e first cli nical trial pr oce d ure aft er o bt ai ni n g i nf or me d c o nse nt a n d wit hi n 2 wee ks
after t he c o m pleti o n of t he E o T Visit, w het h er or n ot c o nsi d ere 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 aft er c o m pleti o n of t h e 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 v esti g at or, if it is j u d ge d as rel ate d t o t h e p atie nt’s partici p ati o n i n t h e cli ni cal trial
m ust be re p orte d t o t he S p o ns o r’s Dr u g S afet y ( 
) 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 wl e d g e, as f oll o ws: 
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 4 8  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 

D oc u me nt t he e v e 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 n e 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 d ates i n t h e 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 o ntacts of t he S p o ns or’s Dr u g Safet y are as f oll o ws: 
 
 
 
 
 
Bel gi u m 
F a x: 
P h o n e: 
E- M ail:
 
1 2. 1. 4. 1  T i m eli n es f o r S us p e ct e d U n e x p ect e d S e ri o us A d v ers e R e a cti 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 e s a n d 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 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 hreat e ni n g S U S A Rs wit hi n a ma xi m u m of 7 d a 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 ni cat e d 
s u bse q ue ntl y wit hi n a n a d diti o n al 8 da ys. 
1 2. 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 nt s 
E x p os ure t o dr u g d uri n g pre g na nc y/lact ati o n: 
I n pri nci ple, pre g na nc y a n d t he lactati o n p eri o d are e xcl usi o n criteri a. I n t h e e ve nt of a pre g n a n c y 
occ urri n g d uri n g t h e c o urse of t h e cli nical trial, t h e 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 n e ntl y. T he S p o ns or 
m ust be n otifie d wit h o ut d ela y b y 
c o m pleti n g t he Pre ga nc y F or m A a n d t he patie nt f oll o we d d uri n g t h e e ntire c o urse of t he 
pre g na nc y a n d p ost p art u m peri o d. Pre natal a n d n e o nat al o utc o mes m ust b e rec or de d e ve n if t h e y 
are c o m pletel y n or mal a n d wit h o ut A Es. T he pre g na nc y re p orti n g ti m eli nes are t he sa me as 
descri be d f or S A E re p orti n g pr oce d ure i n secti o n 1 2. 1. 4.  
If a n y cli nical trial pati e nt bec o mes pre g n a nt d uri n g t h e cli nical trial peri o d, t he I n v esti g at or m ust 
c o ntact Za m b o n S p A as t he S p o ns or of t he cli nical trial or its desi g nee t o dis c uss t he ma n a ge me nt 
of t h e patie nt. 
A d verse D e vice Effect 
I n pri nci ple, seri o us a d vers e ve nts ca us e d b y a de vice iss ue s h o ul d be re p orte d as S A Es as 
descri be d a b o ve.  
C CI
C CI
C CI
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 4 9  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
Ot h er de vice defici e ncies a n d malf u ncti o ns n ot ass ociate d wit h t h e a d v erse e ve nt s h o ul d be 
re p orte d via t h e  
 C o m plai nt F or m, pr o vi de d i n t he I M P ma n ual.  
C O VI D- 1 9 s pecific c o nsi derati o ns: 
All c o nfir me d c ases of C O VI D- 1 9, occ urri n g after t he p atie nt has pr o vi de d i nf or m e d c o nse nt a n d 
u ntil 4 wee ks after t h e 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 s eri o us ness crit eri o n f or C O VI D- 1 9 h os pitali ze d patie nts s h o ul d be “ h os pit alizati o n”; if t he 
patie nt was n ot a d mitt e d t o a h os pital or t he e v e nt is n ot res ulti n g i n pr ol o n ge d h os pit alizati o n, t he 
seri o us ness crit eri o n “ me dicall y si g nifica nt” s h o ul d b e use d. 
I n all cas es, details of t h e pati e nt's s y m pt o ms, treat me nt a n d a n y cli ni call y rele va nt i nf or mati o n, 
s h o ul d be e ntere d i n t h e S A E f or ms, as a p pr o pri at e. 
1 2. 1. 4. 3  I n v esti g ati o n al M e di ci n al Pr o d u ct (I M P) O v e r d o si n g 
A n o v er d ose is a deli berate or i na d vert e nt a d mi nistrati o n of a treat me nt at a d ose hi g h er t h a n 
s pecifie d i n t h e 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 p atie nt t hat e xcee ds t he d ose f oresee n i n t h e pr ot oc ol b y m ore t h a n 5 0 % o v er 
4 wee ks s h o ul d b e re p ort e d as a n o ver d ose. A n y o cc urre n ce of o ver d ose are t o be re p orte d t hr o u g ht 
t he S A E pr oce d ures descri be d a b o ve. 
1 2. 1. 4. 4  E v e nts n ot r e g ar d e d as A d v e rs e E v e nts / S e ri 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 d e d as A Es/ S A Es: 

N ot a p plica ble
1 2. 1. 4. 5  D u r ati o n of F oll o w- u p aft er A d v e rs e E v e nts 
All A Es s h o ul d b e f oll o we d u ntil t h e y are res ol v e d or u ntil a sta ble cli ni cal e n d p oi nt is reac he d. 
T he o cc urre n ce of A Es a n d S A Es will be m o nit ore d u ntil 2 wee ks aft er t he E o T visit.  
1 2. 1. 5   T ol e r a bilit y of I M P 
L ocal t olera bilit y fi n di n gs will be rec or d e d as A Es i n t h e a p pr o pri ate e C R F. 
T he p atie nt will be o bs er ve d f or l o cal t olera bilit y fi n di n gs f or 1 h o ur after i n halati o n at eac h o n-
site st u d y visit.  
L ocal t olera bilit y e ve nts are: 

C o u g h

W heezi n g

Br o nc h os pas m
C CI
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 5 0  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 

T hr oat irritati o n

C ha n ge i n F E V 1
I n a d diti o n, t hese e ve nts will be s oli cite d acti v el y bef ore I M P i n halati o n at eac h st u d y visit 
(e xce pt E o S) b y q u esti o ni n g t h e patie nt w h et her h e/s he has e x perie nce d a n y of t he e ve nts i n-
bet wee n t he st u d y visits. If a p plica bl e, a n A E re p ort f or m will be c o m plet e d.  
O verall t ol era bilit y ass ess me nt b y t he i n vesti gat or i n cl u des: 

C GI q u esti o n naire ( G u y 1 9 7 6 )

I n v esti gat or’s t olera bilit y ass ess m e nts at Visit 3 a n d Visit 5, ass esse d b y mea ns of a fi ve-
p oi nt ver bal rati n g scale wit h t h e res p o ns e o pti o ns ‘ ver y g o o d’, ‘ g o o d’, ‘satisfact or y’,
‘ m o derate’, a n d ‘ p o or’
1 2. 1. 6  Cli ni c al L a b or at o r y 
La b orat or y assess me nts will be perf or me d f oll o wi n g t h e r o uti ne pr ot o c ols at eac h o n-site visit b y 
t he l o cal l a b orat or y at eac h site.  
T he f oll o wi n g cli nical la b orat or y p ara meters ha ve t o b e d oc u me nt e d: 

W hite bl o o d cell c o u nt wit h differe ntial

Re d bl o o d cell c o u nt

Platelet c o u nt

Al kali ne p h os p hatase

Ala ni ne a mi n otra nsferas e

As partate a mi n otra nsferase

Ga m ma gl uta m yl tra nsferase

Bl o o d urea nitr o ge n

S er u m bilir u bi n

S er u m creati ni ne
La b orat or y assess me nts liste d a b o ve will be p erf or me d at a l oc al facilit y, c hec ke d a n d i nt er prete d 
b y t h e i n vesti gat or a n d e ntere d i nt o t he a p pr o priate secti o n of t he e C R F. T h e N or mal La b or at or y 
Ra n ges of eac h l ocal la b orat or y will be use d f or t he t he assess me nt of cli nical si g nifica nce. 
1 2. 1. 6. 1  P r e g n a nc y T est 
S er u m or uri ne sa m ples fr o m w o me n of c hil d beari n g p ote ntial will b e c ollecte d f or pre g na nc y 
tests at S cree ni n g, a n d o n-site Visits 1, 2, 3, 4, 5, a n d 6. P ositi v e res ults will be rec or de d i n t h e 
e C R F a n d a p pr o pri at e acti o ns will be ta ke n. 
1 2. 1. 6. 2  P h ar m a c o ki n eti c P ar a m et e rs 
W h ole bl o o d sa m ples f or deter mi nati o n of c ycl os p ori ne A will be c ollecte d at Visit 1 pre- d ose, 
directl y after e n d of i n halati o n; a n d 1 5, 3 0, a n d 4 5 mi n utes ( +/- 5 mi n ut es), a n d 1, 1. 5, 2, a n d 4 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 5 1  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
h o urs ( +/- 1 5 mi n utes) after e n d of i n hal ati o n f or deter mi n ati o n of C ma x , tma x , a n d A U C0- 4 h. P K 
a nal ysis will b e perf or me d i n a ce ntral la b orat or y (
).  
All sites will be pr o vi d e d wit h s p ecific La b orat or y Kits f or c oll ecti n g t he P K bl o o d sa m ples. 
Bl o o d s h o ul d be c ollecte d i nt o t h e res pecti ve pre-l a belle d K 2- E D T A T u b es a n d s h o ul d be st ore d 
at - 2 0° C i m me diatel y aft er c ollecti o n u ntil s hi p me nt t o t he ce ntral la b orat or y.  
I nstr u cti o n o n ha n dli n g, pr ocessi n g, st ora ge a n d s hi p me nt are i n detaile d d escri b e d i n t he 
La b orat or y M a n ual f or P har mac o ki netic Bl o o d Sa m pli n g.  
1 2. 1. 6. 3  C y cl os p o ri n e A W h ol e Bl o o d T r o u g h L e v els 
A w h ole bl o o d sa m pl e f or t he deter mi n ati o n of c ycl os p ori ne A tr o u g h le vel will be c ollecte d at 
Visit 2 t o Visit 5 at eac h o n-site visit. T he sa m ple s h o ul d be c oll ect e d 1 5 mi n utes b ef ore i n halati o n 
T he tr o u g h l e vels of Cs A at visit 2 t o 5 will be a nal ysis will be perf or me d i n a ce ntral la b orat or y 
(
).  
All sites will be pr o vi d e d wit h s p ecific La b orat or y Kits f or c oll ecti n g t he P K bl o o d sa m ples. 
Bl o o d s h o ul d be c ollecte d i nt o t h e res pecti ve pre-l a belle d K 2- E D T A T u b es a n d s h o ul d be st ore d 
at - 2 0° C i m me diatel y aft er c ollecti o n u ntil s hi p me nt t o t he ce ntral la b orat or y.  
I nstr u cti o n o n ha n dli n g, pr ocessi n g, st ora ge a n d s hi p me nt are i n detaile d d escri b e d i n t he 
La b orat or y M a n ual f or P har mac o ki netic Bl o o d Sa m pli n g.  
1 2. 1. 7  Vit al Si g n s 
Vit al si g ns will b e assess e d at eac h o n-site visit. 
T he f oll o wi n g vital si g ns will be rec or d e d: 

S yst oli c a n d diast olic bl o o d press ure (sitti n g, after mi ni m u m 5 mi n ut es of rest),

p uls e rate (sitti n g, after mi ni m u m 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 ea c h patie nt a n d t hr o u g h o ut t he
cli nical trial),

res pirat or y rate.
1 2. 1. 8  P h y si c al E x a mi n ati o n s
A p h ysi cal e xa mi nati o n will b e carrie d o ut at t h e S cree ni n g Visit a n d at e ver y s u bse q ue nt o n-site 
visit. T h e f oll o wi n g b o d y s yste ms will b e e xa mi ne d: b o d y wei g ht a n d hei g ht (at S cree ni n g visit 
o nl y), car di o v asc ul ar, res pirat or y, n er v o us, gastr oi ntesti nal, he patic, r e n al, der mat ol o gical, 
m usc ul os kel etal, e xtre mities, e yes, ears, n ose, t hr o at, a n d l y m p h atic. 
A b n or mal fi n di n gs will be s u m m arize d f or eac h p atie nt a n d will be d oc u me nte d as A E. 
C CI
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 5 2  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 2. 1. 9  Cli ni c al Gl o b al I m p r e s si o n ( C GI) 
T he C GI is a 3-ite m o bser ver-rat e d scale t hat meas ures ill n ess se verit y, gl o bal i m pr o ve me nt or 
c ha n ge a n d t hera pe uti c res p o nse. A m o difie d v ersi o n of t he C GI will be use d i n t his trial t o assess 
“ill ness” i nstea d of “ m e ntal” ill ness. I n v esti g at ors will c o m pl ete t he q uesti o n naire at Visits 1 
( Baseli ne), 2, 3, 4, 5, a n d res ults will be e ntere d i nt o t he e C R Fs b y t h e site staff. A C GI ca n o nl y 
be assess e d d uri n g a n o n-site visit a n d n ot be assesse d re m otel y. 
1 2. 2  D at a M o nit o ri n g C o m mitt e e ( D M C) 
A n i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C) will be esta blis he d t o m o nit or t he safet y of 
I M P t hr o u g h o ut st u d y B T – L- Cs A – 2 0 1 – S C T. T h e D M C, re prese nte d b y f o ur me m bers i n t ot al, 
t hree e x p ert p h ysici a ns i n t h e fiel d of B O S a n d o n e n o n- me di cal e x p ert, will m o nit or safet y b y 
e val uati n g t h e safet y a nal yses pre pare d b y t he i n d e pe n de nt D M C statiscia n d uri n g t h e c o urs e of 
t he cli nical trial. Details of t he c o m p ositi o n, meeti n g fre q u e nc e a n d safet y a n al yses will be 
i ncl u de d i n t he D M C’s C harter. 
T he D M C will e v al u ate treat me nt gr o u ps f or p ossi ble tre n ds i n A Es, deter mi n e w het her t he basic 
cli nical trial ass u m pti o ns re m ai n vali d, e val uate w het h er t he o verall i nte grit y, sci e ntific merit a n d 
c o n d uct of t h e cli nical trial re mai n acce pt a bl e, a n d ma ke re c o m me n dati o ns t o S p o ns or.  
Me m b ers of t he D M C will be u n bli n de d. 
T he D M C will pef or m a c o m paris o n b et wee n t he rat e of o bser ve d C O VI D- 1 9 cas es a n d rate of 
patie nts wit h dra wal a m o n g trial parti ci pa nts i n b ot h treat me nt ar ms. 
D M C rec o m me n dati o ns ma y i ncl u de a d vice re gar di n g c o nti n uati o n, m o difi cati o n, s us pe nsi o n or 
disc o nti n u ati o n of t he trial base d o n safet y ( b ut n ot o n efficac y) reas o ns. H o we ver, t he fi nal 
decisi o n f or trial c o nti n uati o n, m o dificati o n, s us p e nsi o n or disc o nti n uati o n rests s olel y wit h t he 
S p o ns or  


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 5 3  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 3  VI SI T S C H E D U L E 
All cli nical trial visits, i n v esti g ati o ns a n d acti vities are liste d i n t he Cli nical Trial Sc he d ul e of 
Acti vities bel o w. F urt h er details o n t he met h o d ol o g y of t h ese i n vesti gati o ns a n d acti viti es are 
descri be d i n detail i n S ecti o n 1 1  a n d S ecti o n 1 2 . T he i n vesti gat or will a d here t o t h e visit a n d 
pr oce d ur e sc he d ul e 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 nt f or f oll o w- u p is wit h dra w n. T h e 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 h ese visits/e val uati o ns, if a p plica bl e, m ust be 
resc he d ul e 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. 
Pr o per patie nt u n dersta n di n g a n d c o m pet e nc y of t h e L- Cs A  
 us e will be e ns ure d i n a n 
i n di vi d ual trai ni n g b y t h e res p o nsi ble cli ni c pers o n nel. T he p atie nt will b e a d mi nisteri n g t h e dr u g 
i n d e 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 h e e q ui p me nt a n d dr u g 
t olera bilit y. 
F or e m er g e nc y a n d ot h er u nsc h e d ule d visits t o a me di cal facilit y ot h er t ha n t h e cli nical trial site, 
me di cal re c or ds of t he visit s h o ul d be o btai n e d b y t h e I n v esti g at or. 
If a patie nt pre mat urel y disc o nti n u es cli nical trial partici pati o n f or a n y reas o n, e. g., t he patie nt 
wit h dra ws c o nse nt f or f urt h er p artici p ati o n i n t h e cli nical trial, t h e e val uati o n liste d u n d er “ E n d of 
St u d y Visit ( E o S)” ( Visit 6) s h o ul d be c o m pl ete d 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 w a ys be d oc u me nte d). 
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Z a m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 5 4  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
Sc he d ule of Acti viti es 
Cli nic al Tri al P eri o d  
Scree ni n g 
Tre at me nt 
F oll o w- U p 
Visit N u m ber 
-
V 1  
V 2 
V 3 
V 4  
V 5 / E O T 
Re m ote Visits 
V 6 / E o S 
Wee k & Wi n d o w 
W - 4 t o W 
0 
W 0 D a y 1 
W 2 
 3 D a ys 
W 4 
 3 D a ys 
W 8 
 7 D a ys 
W 1 2 
 7 D a ys 
V 3, V 4 a n d V 6 
ca n be perf or m e d 
r e m otel y 
W 1 4 
 3 D a ys 
I nf or m e d C o nse nt1  
X 
De m o gra p hi cs/ Me di cal 
Hist or y  
X 
- 
I n cl usi o n/ E xcl usi o n 
criteria 
X 
Ser u m/ Uri n e 
P re g n a nc y Test 
X 
X 
X 
X 
X 
X 
X 
P h ysical E xa mi n ati o n 2  
X 
X 
X 
X 
X 
X 
X 
Vital si g ns 3 
X 
X 
X 
X 
X 
X 
X 
Cli nical L a b orat or y 
Tests 4 
X 
X 
X 
X 
X 
X 
X 
P K Bl o o d Sa m pli n g 5 
X 
X 
X 
X 
X 
S pir o metr y 7 
X 
X 6  
X6 
X 6 
X 6 
X 6 
Ra n d o mi zati o n 
X 
S F- 3 6 
X 
X 
X 
X 
X 
X 8 
C GI Q uesti o n n aire 
X 
X 
X 
X 
X 
I n v esti g at or’s 
T ol era bilit y 
Assess me nt  
X 
X 
L ocal I M P T ol era bilit y 
X 
X 
X 
X 
X 
I M P A d mi nistrati o n 
T wice d ail y a d mi nistrati o n 
X 
C o n c o mita nt 
Me dicati o n  
X 
X 
X 
X 
X 
X 
X 
X 
A d v erse E v e nts 
Per ma ne nt assess m e nt t hr o u g h o ut t h e c o m plete cli nical trial peri o d 
Dr u g 
Acc o u nta bilit y/I M P 
a vaila bilt y c hec k 
X 
X 
X 
X 
X 
1
C o n d uct pri or t o a n y scree ni n g a cti vities. 




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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 5 6  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 3. 1  Cli ni c al T ri al Fl o w C h a rt 




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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 5 8  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 3. 2. 2  Visit 1 / B as eli n e Vi sit / R a n d o mi z ati o n 
B aseli n e 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 D e m o gra p hics/ M e di cal Hist or y

Re peat Uri ne/ S er u m Pre g na nc y T est ( Uri ne sa m pl es ca n be c oll ecte d at t he Ra n d o mi zati o n
Visit i n or der t o o btai n res ults q ui c kl y w hile t he p atie nt is i n t he cli nic a n d n ot del a y
ra n d o mizati o n)

P h ysical e xa mi n ati o n

Vital si g ns

Cli nical la b orat or y tests

P K bl o o d sa m ple pre- d os e

S pir o metr y

Ra n d o mizati o n

C o n c o mit a nt me dicati o ns/t hera pies

A Es

C GI (Ite m 1 o nl y)

S F- 3 6 q uesti o n naire
St art of Tre at me nt 
F oll o wi n g acti vities will be p erf or me d: 

Trai n p atie nt o n L- Cs A 
 use, dr u g st ora g e, a n d i n h alati o n tec h ni q ue

I M P A d mi nistrati o n. S u p er vis e first i n halati o n f or pr o per us e of t he ne b ulizer a n d f or
t olera bilit y iss u es.

Verif y pati e nt is fa miliar wit h dr u g a d mi nistrati o n a n d use of ne b ulizer de vi ce

E m p h asize i m p orta nce of a d here n ce t o I M P

E m p h asize i m p orta nce of a d h ere n ce t o us u al me dicati o ns as ta ke n pri or t o p artici pati n g i n t he
trial

S pir o metr y: ( 1 h o ur ± 2 0 mi n utes after c o m pl eti o n of d osi n g wit h I M P)

P K bl o o d sa m ples directl y after e n d of i n halati o n, 1 5, 3 0, a n d 4 5 mi n ut es ( +/- 5 mi n), a n d 1,
1. 5, 2, a n d 4 h o urs ( +/- 1 5 mi n.) aft er e n d of i n hal ati o n

L ocal I M P t olera bilit y
Pri or t o rel eas e fr o m cli nic, st u d y dr u g a n d t h e n e b ulizer s yste m f or h o m e use will be dis pe nse d t o 
eac h p ati e nt. Pati e nt will recei ve f ull I M P s u p pl y f or t he 1 2 wee ks treat me nt peri o d.  
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 6 1  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 4  S T A TI S TI C S 
T his secti o n prese nts a n o ver vie w of t he pla n ne d a nal yses. Fi nal a nal yses are n ot li mit e d t o t he 
s u m mari es d escri be d h erei n. T he Statistical A nal ysis Pla n ( S A P) will pr o vi de a d etail e d 
descri pti o n of t h e pl a n ne d statisti cal a n al yses a n d dat a s u m maries, a n d will be fi nali ze d b ef ore 
data base l o c k or a n y u n bli n di n g f or t his st u d y. If circ u mst a nces aris e d uri n g t he cli nical tri al t hat 
ma ke t hese a nal yses i n a p pr o priate or if i m pr o ve d met h o ds bec o me a vail a ble, t h e S A P ma y be 
re vise d. If discre pa nci es e xist bet wee n t he te xt of t h e st atistical a nal ysis as pla n ne d i n t he pr ot oc ol 
a n d t h e fi n al S A P, t he fi nal S A P will defi n e t h e pla n n e d a nal ysis of rec or d. Reas o ns f or s uc h 
discre pa n cies will b e d escri be d i n t he fi nal Cli ni cal St u d y Re p ort ( C S R).  
T his is a P h ase IIa, pr os pecti ve, m ultice nt er, ra n d o mize d, pl ace b o-c o ntr olle d trial wit h a fi xe d 
sa m ple size d esi g n. 
All a nal yses will be e x pl orat or y, a n d he nce a n y p- val u es will b e i nter prete d descri pti v el y wit h o ut 
a dj ust me nt. 
Data will be liste d b y pati e nt a n d treat me nt gr o u p. 
1 4. 1  A n al y si s D at a S et s 
T he f oll o wi n g a nal ysis d at a sets will be a nal y ze d: 
S afet y A n al ysis Set ( S A F S et) 
T he S A F is defi ne d as all ra n d o mize d patie nts w h o h a ve recei v e d a parti al d ose of I M P at least 
o nce. All data c ollecte d after b aseli n e t o t h e e n d of cli nical trial parti ci pati o n will b e i n cl u de d i n 
t he safet y s u m mari es.  
F ull A n al ysis S et ( F A S) 
T he F A S is defi ne d as all ra n d o mize d patie nts f or w h o m at l east o ne p ost- baseli ne meas ure m e nt 
of a n effi cac y o utc o me meas ure is a v aila ble, i.e. f or s pir o metr y or q ualit y of life meas ures is 
a vaila bl e.  
A Bli n d Data Re vie w M eeti n g ( B D R M) will be use d t o deter mi n e if patie nts s h o ul d b e e xcl u d e d 
fr o m t he F A S i n cases of si g nifica nt, maj or pr ot oc ol d e viati o ns t hat precl u de a n assess me nt of 
treat me nt effi cac y (e. g., ra n d o mize d patie nts n ot s ufferi n g fr o m t he c o n diti o n u n der i n vesti g ati o n). 
Per Pr ot oc ol Set ( P P S) 
T he P P S is defi n e d as all patie nts i n cl u de d i n t h e F A S 

w h o c o m plete ra n d o mize d treat me nt as sc he d ule d or w h o are wit h dra w n pre mat urel y d ue t o
lac k of efficac y or lac k of t olera bilit y of t he cli nic al trial treat me nt, a n d


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 6 2  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 

f or w h o m n o maj or pr ot oc ol de viati o ns was i de ntifie d d uri n g t he dat a re vie w meeti n g. T he
maj or pr ot oc ol d e viati o n crit eria will be defi ne d i n t he pr ot o c ol de viati o n list a n d re vi e w e d
bef ore d ata base cl os ure. T he re vie w e d pr ot oc ol de vi ati o n list will be i n cl u de d i nt o i n t he
cli nical st u d y re p ort as a p pe n di x. .
Eli gi bilit y f or t h e a nal ysis data s ets will b e d eter mi ne d i n a B D R M h el d after cl osi n g t h e data base 
bef ore u n bli n di n g. Pr ot o c ol de viati o ns will be classifie d as ‘ maj or’ w he n a si g nifica nt i nfl u e nce 
o n t he assess me nt of treat me nt efficac y ca n n ot b e e xcl u de d. C o m pre he nsi v e j ustificati o n f or t he 
classificati o n of a pr ot oc ol de viati o n as ‘ maj or’ will be gi v e n i n t h e B D R M mi n utes as well as i n 
t he i nte grate d C S R. A n y e xcl usi o n of patie nts fr o m t he F A S will re q uire i n di vi d u al j ustificati o n. 
A n y dat a p ert ai ni n g t o safet y a n d t olera bilit y will b e a nal yze d i n t he S A F. T h e a nal ysis of treat me nt 
efficac y will b e perf or me d i n t he F A S. A n a d diti o nal effi cac y a n al ysis i n t he P P S will be pr o vi d e d 
as a s e nsiti vit y a nal ysis. F or s afet y o ut c o mes p atie nts will be a nal yse d acc or di n g t o t h e treat me nt 
act u all y recei ve d. F or efficac y meas ures p atie nts will be a nal yse d as ra n d o mi ze d. 
1 4. 2  St ati sti c al a n d A n al yti c al M et h o d s 
1 4. 2. 1  D e s c ri pti v e St ati sti c s 
T he d ata rec or de d i n t h e case re p ort f or ms will be s u m m arize d as a p pr o priate, p er treat me nt gr o u p 
a n d f or t h e t otal gr o u p, usi n g t he f oll o wi n g descri pti v e meas ures: 

All c o nti n u o us assess m e nts will be s u m marize d usi n g descri pti ve st atistics (i. e., N, mea n,
sta n dar d d e vi ati o n, 
me di a n, l o wer q u artile ( Q 1), u p per q uartile ( Q 3), 
mi ni m u m, a n d
ma xi m u m).

All cate g orical assess me nts will b e s u m mari ze d b y ti me p oi nt, as a p plica bl e, usi n g fre q ue n c y
c o u nts a n d perce nta g es.

Discrete or di nal or metric data will b e s u m mariz e d as c o nti n u o us d ata, b ut a ta b ul ati o n of
cate g ories m a y b e i ncl u de d a d diti o n all y d e pe n di n g o n t he n u m ber of cate g ori es.
F or all meas ures a nal y ze d d escri pti v el y (i. e., me as ures t o c haracterize t h e treat me nt gr o u ps a n d 
t heir b aseli n e stat us, effi cac y, a n d safet y o utc o mes), ta b ul ati o ns c o m pari n g t h e treat me nt gr o u ps 
will be pre pare d. F or o ut c o mes meas ure d m ore t h a n o nce, t he a nal yses will i n cl u de ta b ulati o ns of 
t he meas ure d val ues b y visit as well as a n a nal ysis of c ha n ge fr o m baseli n e. W here pr o vi d e d, all 
c o nfi de nce i nter vals will b e t w o-si de d 9 5 % c o nfi de nce i nter v als. 
1 4. 2. 2  C h a r a ct e ri 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 nt a ge of p ati e nts w h o c o m plet e a n d disc o nti n u e t he cli nical trial as w ell as 
reas o ns f or earl y disc o nti n uati o n will be prese nte d. 
Descri pti v e statistics will b e prese nt e d f or de m o gra p hic, a nt hr o p o metric, a n d me dical d ata. 




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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 6 4  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 4. 2. 3. 3  M e as u r es of O v e r all T ol er a bilit y 
F or t he meas ures of o ver-all t olera bilit y i de ntifi e d i n Secti o n 1 2. 1. 5 , d escri pti ve statistics will be 
prese nte d b y visit (see S ecti o n 1 4. 2. 1 ). P air wise treat m e nt gr o u p c o m p aris o ns will b e p erf or m e d 
f or a p plica bl e visits usi n g e xact Wil c o x o n- M a n n- W hit ne y U-t ests. 
1 4. 2. 3. 4  L a b o r at o r y a n d Ot h er S af et y E v al u ati o ns 
F or cli ni cal safet y l a b orat or y test res ults a n d vit al si g ns, t he n u meric val u es a n d c orres p o n di n g 
c ha n ges fr o m b aseli ne will be s u m marize d usi n g d escri pti v e statistics b y p ara meter a n d ti m e p oi nt. 
I n a d diti o n t o t he ta bl es s h o wi n g t he distri b uti o n para meters, la b orat or y me as ures will be prese nt e d 
i n ‘s hift ta bles’ t hat s h o w t h e p ositi o n of all p atie nts relati v e t o t h e a p plic a ble refere nce ra n ge at 
cli nical trial e ntr y, br o k e n d o w n b y t h e p ositi o n at cli nical trial e xit. 
1 4. 2. 4  A n al y s e s of Effi c a c y 
A nal yses of efficac y will be b ase d o n t he F A S a n d o n t h e P P S a nal ysts p o p ul ati o ns. 
S c ori n g of t h e ei g ht scal es a n d t w o s u m m ar y sc ores of t he S F- 3 6 will b e perf or me d acc or di n g t o 
t he i nstr ucti o ns pr o vi d e d f or t h e A ustrali a n L o n git u di n al St u d y o n W o ma n’s Healt h.). 
F or t he s pir o metr y meas ures i d e ntifie d i n S ecti o n 1 1. 1. 1  as well as f or t he scales a n d s u m mar y 
sc ores of t he S F- 3 6, t he n u meric val u es a n d c orres p o n di n g c ha n g es fr o m baseli ne will be 
s u m mari ze d usi n g descri pti ve st atisti cs b y p ara meter a n d ti me p oi nt. 
T he a nal ysis will be carrie d o ut wit h a mi xe d m o del f or re peat e d meas ur es ( M M R M), usi n g all 
a vaila bl e meas ure m e nts of t h e o utc o m e of i nt erest. T he de pe n de nt v aria bl es will be t h e a bs ol ute 
c ha n ge fr o m b aseli n e of t h e o ut c o me of i nterest at t he visits sc he d ule d f or Wee ks 2 t hr o u g h 1 2, 
usi n g fi xe d effects f or tre at me nt, visit, a n d t h e treat m e nt x visit i nteracti o n a n d t h e b aseli n e val ue 
as a fi xe d effect c o vari ate. Ttreat me nt gr o u p c o m p aris o ns at eac h visit will be esti m ate d b y 
differe n ces b et wee n t he mar gi nal (a dj uste d) mea ns fr o m t he treat me nt x visit i nteracti o n, weit h 
acc o m pa n yi n g p- valies a n d 9 5 % c o nfi d e nce i nt er vals. F urt her details of t h e a n al ysis will be 
descri be d i n detail i n t he S A P. 
Descri pti v e s u m mar y me as ures will be pr o vi d e d b ase d o n all o bser ve d v al u es as w ell as b ase d o n 
t he mar gi n al mea ns deter mi ne d vi a M M R M a nal yses. 
1 4. 2. 5  P h a r m a c o ki n eti c V a ri a bl es 
T he st atistical a nal ysis will be perf or m e d as a vali d case a nal ysis i ncl u di n g all p atie nts of t he F A S. 
N o s u b gr o u p a n al ysis is pl a n ne d. 
Descri pti v e statistics will b e use d b y t he 
 ( N, arit h meti c mea ns, 
sta n dar d d e vi ati o n, ge o metric mea ns, g e o metric c oefficie nt of v ari ati o n, me dia ns, mi ni m u m a n d 
ma xi m u m) a n d will be prese nte d f or all P K p ara meters i n dicate d i n S ecti o n 8. 1. 6 , s e paratel y f or 
eac h treat me nt b y usi n g t h e 
.  
C CI
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 6 5  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
T he plas ma c o nce ntrati o n le vels i n t he 
 are meas ure d usi n g a 
vali d ate d L C- M S / M S met h o d. T he pr oce d ure f or vali dati o n a n d t he acce pt a nce li mits are bas e d 
o n t h e re q uire me nts of t he E M A G ui d eli n e ( G ui deli n e o n bi oa nal ytical met h o d vali dati o n ( E M E A 
/ C H M P / E W P / 1 9 2 2 1 7/ 2 0 0 9 Re v. 1 C orr. 2 * *), J ul y 2 0 1 1). 
T he statistical a nal ysis will be carrie d o ut o n a l o g scale f or A U C 0- 4 h a n d Cma x - val u es, w hil e tma x  
a n d tr o u g h le vels will be e val uat e d o n a li n ear scal e. A nal yses of varia nce will b e p erf or me d t o 
c o m p are t h e treat me nt gr o u ps. 
1 4. 3  I nt e ri m A n al ysi s  
N ot a p plica bl e. 
1 4. 4  Mi s si n g D at a 
N o missi n g data i m p utati o n will b e perf or me d. F or efficac y o ut c o mes, ti me c o urses will be 
m o dele d via M M R M (see Secti o n 1 4. 2. 4 ). 
1 4. 5  S a m pl e Si z e C o n si d e r ati o n s 
T his is a P hase IIa st u d y i n a rare i n di cati o n wit h v er y li mite d a vaila bilit y of eli gi ble p atie nts a n d 
a p urel y descri pti ve st atistical c o nce pt. Acc or di n gl y, t he sa m ple si ze f or t he st u d y was esta blis he d 
base d o n c o nsi d erati o ns of feasi bilit y rat h er t h a n o n p o wer calc ul ati o ns. 
A t ot al of 2 4  p atie nts ( 3 ar ms x 8 p atie nts eac h) are pla n ne d t o be ra n d o mi ze d. 
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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 6 6  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 5  DI R E C T A C C E S S T O S O U R C E D A T A / D O C U M E N T S 
S o urce dat a is all i nf or mati o n, ori gi nal rec or ds of cli nical fi n di n gs, o bser vati o ns, or ot her acti vities 
i n a cli nical trial necess ar y f or t h e rec o nstr ucti o n a n d e v al uati o n of t h e trial. S o urce dat a are 
c o ntai ne d i n s o urce d o c u me nts. E x a m pl es of t h ese ori gi n al d oc u m e nts a n d dat a rec or ds i ncl u de 
b ut are n ot li mite d t o: h os pital rec or ds, cli nical a n d office c harts, l a b orat or y n otes, me m ora n d a, 
patie nts’ diaries or q u esti o n naires or e val u ati o n c hec klists, p har mac y dis pe nsi n g rec or ds, rec or de d 
data fr o m a ut o mat e d i nstr u me nts, c o pies or tra nscri pti o ns certifie d after verificati o n as b ei n g 
acc urate a n d c o m plete, micr ofic hes, p h ot o gra p hic n e gati ves, mi cr ofil ms or ma g netic me di a, X-
ra ys, p atie nt fil es, a n d rec or ds ke pt at t he p har ma c y, at t h e la b orat ories, a n d at me dic o-tec h nical 
de part me nts i n v ol ve d i n t he cli nical trial. T h e e C R F is n ot c o nsi dere d t o b e s o urce data. 
Case re p ort f or ms, all c o pies of test res ults, a n d cli ni cal trial-relate d re g ul at or y d oc u me nts (e. g., 
I nf or me d C o nse nts, E C fa v o ura bl e o pi ni o n / c orres p o n de nce) m ust be a vaila bl e al wa ys f or 
re g ul at or y a g e nc y i ns p ecti o n a n d re vie w b y t h e S p o ns or or its d esi g nee. D uri n g t he peri o di c site 
m o nit ori n g visits, t he s o urce d oc u me nts will b e v erifie d a gai nst d ata e nt ere d o nt o t he e C R F t o 
ass ure t hat all data is acc uratel y a n d c o m plet el y reflecte d o n t he p atie nt’s e C R F. 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 6 7  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 6  Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E 
T his cli nical trial will b e m o nit ore d b y t he S p o ns or or its desi g nee acc or di n g t o I C H G C P 
g ui deli nes. A sit e visit will be h el d pri or t o i nitiati o n of patie nt e nr oll me nt. T h e pr ot oc ol, e C R Fs, 
I M P s u p pli es, a n d rele va nt pr oce d ures will be e x plai ne d i n detail at t he Site I nitiati o n Visit. 
S u bse q u e nt t o p atie nt e nr oll me nt, a site m o nit or fr o m t he S p o ns or or its d esi g nee will re vie w t he 
e C R Fs a n d s o urce d o c u me nts t o e ns ure t h at t he cli nical trial is c o n d uct e d ac c or di n g t o t h e pr ot o c ol 
a n d I C H G C P g ui deli nes. 
T o e ns ure c o m plia nce wit h I C H G C P g ui d eli n es a n d all a p plica bl e re g ulat or y re q uire me nts, t he 
S p o ns or or its desi g n ee ma y c o n d uct q u alit y ass ura nce a u dits. A n y p ote ntial seri o us G C P n o n-
c o m pli a n ce will b e pr o m ptl y re p orte d t o s p o ns or b y t he C R O a n d Healt h A ut h orities a n d Et hics 
C o m mitees, as a p plica ble. 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 6 8  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 7  E T HI C S C O M MI T T E E ( E C) 
T he pr ot oc ol a n d I C F(s) f or t his cli nical trial m ust h a ve recei v e d a fa v o ura bl e o pi ni o n b y a n 
a p pr o priatel y c o nstit ute d Et hics C o m mittee ( E C) as defi ne d b y l ocal re q uire me nts. A list of t he 
E C v oti n g me m bers, t heir titl es or occ u pati o n, a n d t heir i nstit uti o nal affiliati o ns (if a vaila ble a n d 
all o wa ble u n der E U l a w) a n d/ or t h e E C ge neral ass ura nce n u m b er, if a p plica bl e, m ust be s u b mitt e d 
t o t he S p o ns or or its desi g nee t o be arc hi ve d i n t he Trial Master Fil e. 
A n y d o c u me nts t hat t h e E C ma y n ee d t o f ulfill its res p o nsi bilities, s u c h as pr ot oc ol a me n d me nts, 
a n d i nf or m ati o n c o n cer ni n g patie nt recr uit m e nt, pa y me nt or c o m p e ns ati o n pr oce d ures, or 
i nf or mati o n fr o m Za m b o n S p A will be s u b mitte d t o t he E C. T he E C’s writte n fa v o ura ble o pi ni o n 
of t h e pr ot o c ol a n d t he I C F/ pati e nt i nf or m ati o n l eaflet will be i n t he p oss essi o n of t h e I n vesti gat or 
bef ore t he cli nical tri al is i nitiate d. T he E C’s fa v o ura ble o pi ni o n state me nt will be tra ns mitte d b y 
t he I n vesti g at or t o Za m b o n S p A or its d esi g nee pri or t o s hi p me nt of I M P s u p plies t o t he site. T his 
fa v o ura bl e o pi ni o n m ust refer t o t he cli nical trial b y e xact pr ot oc ol title a n d n u m ber, a n d s h o ul d 
i de ntif y t h e d oc u me nts re vie we d a n d t he d ate of re vie w. 
Pr ot oc ol m o difi cati o ns or c h a n ges ma y n ot b e i nitiate d wit h o ut pri or writte n E C f a v o ura bl e 
o pi ni o n e xce pt w he n necessar y t o eli mi n at e i m me diate hazar ds t o t h e patie nts or w he n t he 
c ha n ge(s) i n v ol ves o nl y l o gisti cal or a d mi nistrati ve as pects of t he cli nical tri al. S uc h m o difi cati o ns 
will be s u b mitte d t o t he E C a n d writte n verificati o n t hat t he m o dificati o n was s u b mitte d s h o ul d be 
o btai ne d. 
T he E C m ust be i nf or me d b y t he I n v esti g at or of i nf or me d c o nse nt c ha n g es or re visi o ns of ot h er 
d oc u me nts ori gi nall y s u b mitte d f or re vie w; s eri o us a n d/ or u n e x pect e d A Es occ urri n g d uri n g t he 
cli nical trial; ne w i nf or mati o n t hat ma y a d versel y affect t he safet y of t he patie nts or t he c o n d u ct of 
t he cli nical trial; a n a n n u al u p d ate a n d/ or r e q u est f or re vi e w a n d o pi ni o n; a n d w he n t he cli nic al 
trial has bee n c o m pl et e d. 
T he I n vesti gat or will e ns ure t h at t h e c o n d uct of t he cli ni cal trial c o nf or ms t o t h e Declarati o n of 
Helsi n ki (c urre nt re visi o n) a n d wit h a p plica ble n ati o nal la ws a n d re g ul ati o ns f or cli nical rese arc h. 
Bef ore starti n g t his cli nical trial, t he pr ot oc ol will be s u b mitt e d t o eac h ce nter’s Et hics C o m mittee 
f or e val uati o n at eac h site. As re q uire d, t h e cli nic al trial will n ot start bef ore t h e E C has gi ve n 
fa v o ura bl e o pi ni o n. 
P eri o dic stat us re p orts a n d S A Es m ust be s u b mitt e d t o t h e E C acc or di n g t o t h e E C re p orti n g 
re q uire me nts. T he E C m ust als o b e n otifie d of c o m pleti o n of t h e cli nical trial a n d a fi nal re p ort 
m ust b e s u b mitte d t o t h e E C i n acc or da nce wit h t he E C re p orti n g re q uire m e nts. T he I n vesti gat or 
m ust mai ntai n a n acc urat e a n d c o m plete rec or d of all c o m m u nicati o n, re p orts a n d s u b missi o ns t o 
t he E C. 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 6 9  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 8  P A TI E N T I N F O R M E D C O N S E N T 
P atie nts will be re q uire d t o si g n a state me nt of i nf or me d c o ns e nt t h at meets t h e re q uire me nts of 
E ur o pea n a n d l ocal re g ulati o ns, I C H E 6 ( R 2) g ui deli nes, a n d t he E C of t he ce nter. T h e me di cal 
rec or d will i n cl u de a st at e me nt t hat writt e n i nf or me d c o nse nt was o btai ne d bef ore t h e patie nt was 
e nr olle d i n t h e cli nical trial a n d t he d ate writte n c o nse nt was o btai ne d. 
Me m b ers of t h e treati n g tea m will re vi e w t he n at ur e of t he cli nical trial, its p ur p ose, t he pr oc e d ures 
i n v ol ve d, t he e x pect e d d urati o n, t he p ote ntial ris ks a n d be nefits a n d alter n ati ve t hera pies i n cl u di n g 
best s u p p orti ve care. P atie nts m ust b e i nf or me d t hat p artici p ati o n i n t h e cli nical trial is v ol u ntar y, 
he/s he ma y wit h dra w fr o m t h e cli ni cal tri al at a n y ti me a n d wit h dra wal fr o m t he trial will n ot affect 
his/ h er s u bse q ue nt me dical treat me nt or relati o ns hi p wit h t h e treati n g p h ysicia n. Fi n a ncial c osts 
t hat will or ma y be i n c urre d as a res ult of partici p ati o n i n t he trial, as well as t he eff orts t o mai ntai n 
patie nt c o nfi de ntialit y will als o b e disc usse d. 
T his c o nse nt m ust be wit n esse d a n d d ate d a n d retai ne d b y t he I n vesti gat or as part of t h e cli nical 
trial rec or ds. A c o p y of t h e I C F m ust be gi v e n t o t he patie nt. If t h e p atie nt si g ne d t he i nf or m e d 
c o nse nt m ore t ha n 3 0 da ys pri or t o t h e d ate of ra n d o mi zati o n, it s h o ul d b e d o c u me nte d t h at c o nse nt 
has n ot bee n resci n de d. Alter nati v el y, t h e site s h o ul d f oll o w t he E C’s re q uire me nt f or re-
c o nse nti n g a p atie nt. 
A c o p y of t he E C a p pr o ve d c o nse nt f or m m ust be s u b mitte d t o Z a m b o n S p A or its desi g nee pri or 
t o s hi p me nt of I M P s u p pli es t o t h e I n v esti gat or. Eac h pati e nt’s si g ne d i nf or me d c o ns e nt m ust be 
ke pt o n file b y t h e I n vesti gat or f or re g ulat or y a ut h orit y a n d S p o ns or i ns pecti o n at a n y ti me. 
T he Decl arati o n of H elsi n ki, as a me n d e d ( v ersi o n of F ortaleza, Brazil, 2 0 1 3), rec o m me n dati o ns 
g ui di n g d o ct ors i n cli nical researc h s h o ul d b e f oll o we d b y t he I n v esti gat or.  


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 7 0  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 9  H E A L T H A U T H O RI TI E S 
T he pr ot o c ol a n d a n y rel at e d d o c u me ntati o n i ncl u di n g all s u bse q u e nt c ha n g es (s u bsta ntial 
a me n d me nts) of t h ese d oc u me nts will be s u b mitt e d f or a p pr o v al t o t he re g ul at or y a ut h orities i n 
c o m pli a n ce wit h a p plica ble E ur o pea n re g ul ati o ns. 
N o n-s u bsta ntial a me n d m e nts will be s u b mitt e d acc or di n g t o l ocal re g ul at or y re q uire me nts f or 
n otificati o n.  
A n y pre mat ure ter mi nati o n of t he cli nical trial will be s u b mitte d wit hi n 1 5 d a ys, a n d re g ul ar e n d 
of t h e st u d y will be n otifie d as well. 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 7 1  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
2 0  D A T A H A N D LI N G A N D R E C O R D K E E PI N G 
2 0. 1  C o nfi d e nti alit y 
T o mai ntai n c o nfi de nti alit y, all la b orat or y s p eci m e ns, e val uati o n f or ms, re p orts a n d ot h er rec or ds 
will be i d e ntifie d b y a c o de d n u m ber a n d i nitials o nl y. All cli ni cal trial rec or ds will be ke pt at eac h 
ce nt er i n a l o c ke d fil e ca bi n et. Cli nical i nf or m ati o n will n ot be releas e d wit h o ut writte n per missi o n 
of t h e patie nt, e xce pt as n ecessar y f or m o nit ori n g or i ns pecti o ns b y t he a ut h oriti es or a d esi g nee of 
t he S p o ns or as d escri b e d i n t h e i nf or me d c o nse nt f or m.  
T he I n v esti gat or m ust ass ure t hat t he pri v ac y of t he p atie nts, i n cl u di n g t h eir pers o nal i de ntit y a n d 
all pers o nal me dical i nf or mati o n, will be mai ntai ne d at all ti mes. I n e C R Fs a n d ot her d o c u me nts 
patie nts will n ot b e i d e ntifie d b y t heir na mes, b ut b y a n i de ntificati o n c o de (e. g., b y a n ar bitrar y, 
u ni q ue patie nt n u m b er). 
T he I n vesti g at or a grees t hat all i nf or mati o n recei ve d fr o m Z a m b o n S p A i ncl u di n g b ut n ot li mit e d 
t o t his pr ot oc ol, e C R F, a n d a n y ot her cli ni cal trial i nf or mati o n, re mai n t he s ole a n d e x cl usi ve 
pr o pert y of Z a m b o n S p A d uri n g t he c o n d u ct of t he cli nical trial a n d t h ereafter. T his i nf or mati o n 
is n ot t o be discl ose d t o a n y t hir d p art y ( e x ce pt e m pl o yees or a ge nts directl y i n v ol v e d i n t he 
c o n d uct of t he trial or as re q uire d b y l a w) wit h o ut pri or writte n c o nse nt fr o m Za m b o n S p A. T he 
I n v esti gat or f urt her a gr ees t o ta k e all reas o n a bl e preca uti o ns t o pr e ve nt t h e discl os ure b y a n y 
e m pl o y ee or a g e nt of t h e i n vesti gati ve site t o a n y t hir d part y or ot her wise i nt o t he p u blic d o mai n. 
Wit h refere nce t o E U Re g ul ati o n n o. 6 7 9/ 2 0 1 6 of E ur o pea n P arlia me nt a n d of t h e C o u ncil of 2 7 
A pril 2 0 1 6, t he Ge neral Data Pr otecti o n Re g ulati o n ( G D P R), a n d ot her l o cal la w pr o visi o ns t he 
data pr ot ecti o n r ol es wit hi n t h e st u d y are t he f oll o wi n g: 

t he s p o ns or a n d t h e i n vesti gati o nal ce nter are a ut o n o m o us d ata c o ntr ollers, a n d will pr ocess
t he pers o n al a n d st u d y d at a of t h e partici pa nts e x cl usi vel y f or st u d y relate d p ur p oses a n d f or
p har mac o vi gil a n ce p ur p oses.

T he C R O will pr o cess t he parti ci p a nt’s data o n b e half of t h e s p o ns or a n d will be a p p oi nte d as
a dat a pr o cess or b y t he s p o ns or. T he C R O ma y a vail itself of s u b c o ntract ors, w h o will be
a p p oi nte d as s u b pr ocess ors as well, p urs ua nt t o art. 2 8 of G D P R.

T he pri n ci pal i n vesti gat ors will pr ocess t he data as a data pr ocess or, o n be half of t h e st u d y
ce nt er.
As c o ncer ns t he d ata pr ot ecti o n i nf or mati o n/ n otice, partici pa nts m ust be i nf or me d pr o perl y a b o ut 
all t he dat a pr otecti o n ele me nts pr o vi d e d b y art. 1 3 a n d 1 4 of G D P R. I n v esti g at or or his/ h er 
re pres e ntati ve will gi v e t o t he partici pa nt a pr o per data pr otecti o n i nf or mati o n n otice c o m plia nt 
wit h G D P R, a n d will c o nse q ue ntl y as k t o t h e parti ci pa nt a data pr otecti o n c o nse nt, t o get her wit h 
t he st u d y i nf or me d c o nse nt. Acc or di n g t o t he pr o visi o ns of t he G D P R, t he le vel of discl os ure i n 
t he i nf or me d c o nse nt m ust als o be e x plai ne d t o t he partici pa nt. T h e p artici pa nt m ust b e i nf or me d 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 7 2  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
t hat his/ her me dical rec or ds ma y b e e xa mi ne d b y A u dit ors or ot her a ut h ori ze d pers o n n el a p p oi nt e d 
b y t h e s p o ns or, b y a p pr o priate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities. 
As re g ar ds t h e or ga nizati o nal a n d sec urit y meas ures a d o pte d, t he o p erati o ns of c ollecti o n, st ora ge, 
circ ulati o n of bi ol o gical sa m ples as well as all t he data pr ocessi n g o p erati o ns re gar di n g t he st u d y 
data are perf or me d i n c o m plia nce wit h G D P R. T he i n vesti g at or or his/ her re prese ntati ve will 
assi g n t o t h e p artici pa nts a u ni q ue i d e ntifier. I n v esti g at or will be t h e o nl y o ne w h o ca n matc h t he 
partici pa nt’s i de ntit y wit h t he dat a referre d t o t he st u d y. A n y p artici pa nt rec or ds or d atasets t h at 
are tra nsferre d t o t he s p o ns or will c o nt ai n t he i d e ntifier c o d e o nl y; parti ci pa nt na mes or a n y ot h er 
i nf or mati o n w hic h w o ul d ma ke t he partici p a nt i de ntifia ble will n ot be tra nsferre d t o t he s p o ns or. 
2 0. 2  C o m pl eti o n of El e ct r o ni c C a s e R e p o rt F o r m s 
A n e C R F will be use d i n t his cli nical trial. Staff a ut h orize d t o e nter or m o dif y dat a o n t he e C R F 
will be assi g ne d a n a p pr o priate user r ole: 

st u d y c o or di n at ors or n urses ma y e nter, m o dif y, or d elete d ata a n d ma y e nter, m o dif y, or delete
res p o nses t o q ueri es;

i n v esti g at ors ma y perf or m t h e sa me acti vities as st u d y c o or di n at ors. M ore o ver, t he y ma y
a ut h orize d ata b y e nteri n g a n electr o ni c si g nat ure.
A n y dat a e ntries, m o dificati o ns, a n d deleti o ns will be re c or de d i n a n a ut o mat e d a u dit trail t o get her 
wit h a ti me sta m p a n d t he i de ntificati o n c o de of t he pers o n perf or mi n g t h e e ntr y / m o dificati o n / 
deleti o n. 
T o access t h e e C R F a ut h orize d users will recei v e a u ni q u e user na me a n d pass w or d t h at will als o 
be re q uire d f or d ata a ut h orizati o n (i n vesti g at ors o nl y). T hese cre de ntials are strictl y pers o n al a n d 
c o nfi de ntial a n d m ust n ot be s hare d wit h a n y o ne. 
I n v esti gat ors will be pr o vi d e d wit h d et aile d e C R F C o m pleti o n G ui d eli n es t hat will i de ntif y t he 
re q uire d d at a p oi nts t o be c oll ect e d, h o w t o d o c u me nt t he m a n d w he n t hese data s h o ul d be 
d oc u me nt e d. A p pr o priate trai ni n g i n electr o nic d ata ca pt ure a n d s u p p ort will be pr o vi de d. 
It is t he res p o nsi bilit y of t he I n vesti gat or t o mai ntai n a d e q uate a n d acc urate e C R Fs t o rec or d 
(acc or di n g t o t he e C R F C o m pleti o n G ui d eli n es) all o bser vati o ns a n d ot h er d ata perti ne nt t o t h e 
cli nical trial o btai n e d d uri n g sc he d ul e d or u nsc he d ule d visits. All e C R Fs s h o ul d be f ull y c o m plete d 
t o e ns ure acc urate data i nter pretati o n. 
All e C R F e ntries s h o ul d b e ma de wit hi n a ma xi m u m of 5 da ys of a visit b y a desi g nate d a n d trai n e d 
me m ber of t he site staff. T he I n vesti gat or m ust e ns ure t he acc urac y, c o m plete ness l e gi bilit y a n d 
ti meli ness of d ata re p ort e d i n t he e C R F a n d all re q uire d re p orts. A n y c ha n g e or c orrecti o n t o a n 
e C R F m ust be d oc u me nte d as i nstr uct e d a n d e x plai ne d (if n ecessar y) i n t h e cli nic n otes, t his 
a p pli es t o b ot h writte n a n d electr o nic c h a n ges. T he pati e nt’s me dical s o urce d oc u me nts m ust 
s u p p ort a n y c ha n ges ma d e. 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 7 3  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
Data re p orte d i n t h e e C R F t hat are d eri v e d fr o m s o urce d o c u me nts s h o ul d be c o nsiste nt wit h t he 
s o urce d o c u m e nts or t he discre p a ncies s h o ul d be e x plai n e d. 
T he i n vesti g at or m ust re vi e w a n d electr o ni call y si g n t he c o m pl et e d e C R F case b o o k t o verif y its 
acc urac y. 
T he mai n o bjecti v e is t o o bt ai n t h ose data re q uire d b y t he pr ot oc ol i n a c o m plete, acc urate, le gi ble, 
a n d ti m el y fas hi o n. T hese data i n t he e C R F s h o ul d b e c o nsiste nt wit h t he rele va nt s o urc e 
d oc u me nts. 
T he e C R Fs a n d t h e c orres p o n di n g electr o ni c dat a base s h all b e pr ocess e d, e v al u at e d, a n d st ore d i n 
a n o n y m o us f or m i n acc or da nce wit h t he data- pr otecti o n re g ulati o ns. 
T hese d at a rec or de d i n t h e c o urse of t his cli nical trial ma y peri o dicall y be r e m otel y re vie we d a n d 
c o m p are d t o t he el ectr o ni c dat a base. T he c o m p uteri ze d ha n dli n g of t h ese d at a after recei pt of t he 
e C R Fs ma y ge nerate a d diti o n al re q uests vi a electr o ni c q ueries t o w hi c h t he I n v esti g at or is o bli ge d 
t o res p o n d b y c o nfir mi n g or m o dif yi n g t h ese d ata q uesti o ne d. T hese re q u ests wit h t h eir res p o nses 
will be a p pe n de d t o t he e C R Fs hel d b y t h e I n vesti gat or a n d S p o ns or. 
I n t he case of missi n g data/re m ar ks, t he e ntr y s paces pr o vi de d f or i n t h e e C R F s h o ul d b e ca ncell e d 
o ut t o a v oi d u n necess ar y f oll o w- u p i n q uiries. T he e C R Fs are re g ul at or y d oc u me nts a n d m ust be 
s uita ble f or ele ctr o nic s u b missi o n t o a ut h oriti es. 
T he I n vesti gat or m ust k ee p a s e p arat e pati e nt i de ntifi cati o n list s h o wi n g c o de n u m bers, na m es, 
a n d dates of birt h t o all o w u na m bi g u o us i d e ntificati o n of eac h pati e nt i ncl u de d i n t he cli ni cal trial. 
A n ote will be ma de i n t h e h os pital me dical r ec or ds t h at t h e patie nt is partici p ati n g i n a cli nical 
trial. T he e C R F will be c o m plete d a p pr o priatel y. 
2 0. 3  S o u r c e D at a a n d P ati e nt Fil e s 
T he I n vesti g at or has t o k ee p a p a per or electr o ni c pati e nt file f or e ver y patie nt partici pati n g i n t he 
cli nical trial. I n t his p atie nt file, t h e a vail a ble d e m o gra p hi c a n d m e dical i nf or mati o n of a p atie nt 
has t o b e d oc u me nte d, i n partic ul ar t he f oll o wi n g: na me, d ate of birt h, se x, h ei g ht, wei g ht, p atie nt 
hist or y, c o nc o mita nt dise ases a n d c o nc o mita nt me dicati o n (i ncl u di n g c ha n ges d uri n g t h e cli nical 
trial), state me nt of e ntr y i nt o t h e cli nical trial, trial i de ntifi cati o n, p atie nt n u m b er, t he dat e of 
i nf or me d c o nse nt, all visit dat es, pre- d efi n e d perf or me d e xa mi nati o ns a n d cli nical fi n di n gs, 
o bser v e d A Es (if a p pli ca ble) a n d reas o n f or wit h dra wal fr o m cli nical trial treat me nt or fr o m t he 
trial (if a p plica ble). It s h o ul d be p ossi ble t o verif y t he i ncl usi o n a n d e x cl usi o n criteri a f or t he 
cli nical trial fr o m t h e a v aila ble d ata i n t his fil e. It m ust be p ossi ble t o i de ntif y eac h p atie nt b y usi n g 
t his pati e nt file. 
A d diti o n all y, a n y ot her d o c u me nts wit h s o urce data, es peciall y ori gi nal pri nt o uts of data t hat were 
ge nerat e d b y tec h ni cal e q ui p me nt ha ve t o be file d. T his m a y i n cl u de la b orat or y v al ue listi n gs, 
electr ocar di o gra m rec or di n gs, X-ra ys, c o m p ute d t o m o gra p h y sca ns, et c. (if a p pli ca ble). All t hese 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 7 4  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
d oc u me nts ha ve t o be ar at least t h e patie nt i d e ntificati o n a n d t h e pri nti n g date pri nt e d b y t he 
rec or di n g d e vice t o i n dic ate t o w hi c h patie nt a n d t o w hic h pr oce d ure t h e d oc u me nt bel o n gs. T he 
me di cal e val u ati o n of s uc h rec or ds s h o ul d be d oc u me nte d as necess ar y a n d si g n e d/ d ate d b y t he 
I n v esti gat or. 
Pri nt o uts of c o m p uterize d pati e nt files m ust be si g ne d a n d date d b y t he I n v esti gat or, a n d k e pt as a 
s o urce d o c u m e nt. 
2 0. 4  I n v e sti g at o r Fil e a n d Ar c hi vi n g 
T he S p o ns or will pr o vi de, a n d t he i n vesti gat or will mai ntai n a n I n v esti g at or Site File (I S F) 
c o ntai ni n g all esse ntial d oc u me nts f or t he cli nical trial. T h e I S F will c o nt ai n eac h p atie nt’s e C R F 
p df after t he data base has bee n l o c ke d. T h e i n v esti g at or s h o ul d mai ntai n a rec or d of t he l ocati o n(s) 
of t heir res pecti ve esse nti al d oc u me nts i n cl u di n g s o urce d oc u me nts. T he st ora ge s yste m use d 
d uri n g t he trial a n d f or arc hi vi n g (irres p ecti ve of t he t y p e of me di a use d) s h o ul d pr o vi de f or 
d oc u me nt i d e ntificati o n, versi o n hist or y, searc h a n d retri e val. 
Esse ntial d o c u me nts ar e s u bject t o a u dit a n d i ns pe cti o n at all ti mes a n d will be arc hi v e d acc or di n g 
t o a p plica bl e re g ul at or y re q uire me nts. 
2 0. 5  M o nit o ri n g, Q u alit y As s u r a n c e, a n d I n s p e cti o n b y A ut h o riti e s 
T his cli ni cal trial is t o be c o n d ucte d i n acc or da n ce wit h I C H E 6 ( R 2) a n d a p pli ca ble E ur o pea n 
re g ul ati o ns. M o nit ori n g a n d a u diti n g of t he trial will b e t he res p o nsi bilit y of t he S p o ns or or a 
desi g nee a ut h ori ze d b y t he S p o ns or. 
T o e ns ure c o m plia nce wit h I C H G C P g ui d eli n es a n d all a p plica bl e re g ulat or y re q uire me nts, t he 
S p o ns or or its desi g nee m a y c o n d uct q ualit y ass ura nce a u dits. R e g ulat or y a ge ncies ma y als o 
c o n d uct a re g ulat or y i ns p ecti o n of t his cli ni cal trial. S uc h a u dits or i ns pecti o ns ca n o cc ur at a n y 
ti me d uri n g or after c o m pleti o n of t he cli nical trial. If a u dits or i ns pecti o ns occ ur, t h e I n vesti gat or 
a n d t he i nstit uti o n a gree t o all o w t he a u dit or/i ns p ect or direct access t o all rel e va nt d oc u me nts a n d 
t o all ocate his/ her ti m e a n d t h e ti me of his/ her staff t o t h e a u dit or/i ns pect or t o disc uss fi n di n gs a n d 
a n y rel e va nt iss ues. 
2 0. 6  D at a M a n a g e m e nt a n d D at a C o nt r ol 
T he S p o ns or will be res p o nsi ble f or t h e pr oc essi n g a n d q ualit y c o ntr ol of t he data. Data 
ma na ge me nt a n d fili n g will b e carrie d o ut as descri b e d i n t he c o ntracte d C R O’s Sta n dar d 
O perati n g Pr oce d ures f or cli ni cal tri als. 
Pri or a n d c o nc urre nt me dicati o ns wit hi n 3 0 da ys of ra n d o mizati o n will be liste d. Pri or/c o n c urre nt 
me di cati o ns will be c o de d usi n g t h e W orl d Healt h Or ga nizati o n Dr u g Di cti o nar y classifi cati o n 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 7 5  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
s yste m a n d gr o u pe d b y dr u g class a n d pr eferre d ter m. A Es a n d c urre nt me dical c o n diti o ns f or 
c o nc o mita nt me dicati o ns will be c o de d usi n g M e d D R A.  
T he e C R F dat a a n d pati e nt data listi n gs will be arc hi ve d b y t he S p o ns or f or t h e lifeti me of t he 
pr o d uct. N o cli nical trial d oc u me nt s h o ul d be destr o ye d wit h o ut pri or writte n a gree me nt b et wee n 
t he S p o ns or a n d t he I n vesti gat or. S h o ul d t he I n vesti gat or wis h t o assi g n t h e cli nical trial rec or ds 
t o a n ot her part y or m o ve t h e m t o a n ot h er l ocati o n, a d va nce writte n n otice s h o ul d be gi ve n t o t he 
S p o ns or. 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 7 6  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
2 1  FI N A N CI N G A N D I N S U R A N C E 
A se parat e fi na ncial a gree me nt ( Cli nical I n vesti gat ors' A gr ee me nt) will be ma de bet w ee n eac h 
I n v esti gat or a n d t he S p o ns or bef ore t h e I M P is deli v ere d. T he S p o ns or will e ns ure fi n a nci n g of t he 
c o m plete cli nical tri al. 
T he cli nical trial is c o vere d u n der a S p o ns or gr o u p c o m bi n e d lia bilit y i ns ura nce p olic y. T he 
certifi cate of i ns ura nce a n d a n i nf or mati o n leaflet c o ntai ni n g ess e ntial i nf or mati o n a b o ut t he 
i ns ura nce c o vera ge will be pr o vi de d u p o n re q uest. 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 7 7  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
2 2  P U B LI C A TI O N S 
After c o ncl usi o n of t he cli nical trial, a n i nte grat e d cli nical a n d statistical st u d y re p ort will be 
pre pare d b y t h e S p o ns or or d esi g ne e. T he first p u blicati o n of t he cli nical trial will c o m prise of data 
fr o m t he e ntire cli ni cal tri al p o p ulati o n e nr oll e d at all sites. A n y p u blicati o ns of t he res ults, eit h er 
i n part or i n t otal (a bstracts i n j o ur nals or ne ws p a pers, oral prese ntati o ns, etc.) b y I n vesti g at ors or 
t heir re prese nt ati ves will re q uire pre-s u b missi o n re vie w b y t h e S p o ns or. T he S p o ns or is e ntitle d t o 
dela y p u blicati o n i n or der t o o bt ai n pate nt pr otecti o n. F or m ore details re g ar di n g p u blicati o ns, refer 
t o t he cli ni cal trial a gree me nt/I n v esti gat or trial a gree me nt. 
T he res ults of t h e cli nical trial will be p u blis h e d a n d/ or prese nt e d i n scie ntific meeti n gs i n a ti mel y 
ma n n er. A n y f or mal p u blicati o n of cli nical trial res ults will be a c olla b or ati ve eff ort b et wee n t he 
S p o ns or a n d t he I n vesti gat or(s). All ma n uscri pts a n d a bstracts will be re vi e we d a n d a p pr o ve d i n 
writi n g b y t he S p o ns or pri or t o s u b missi o n.  
P oli cies re gar di n g t h e p u blicati o n of t he cli nical trial res ults are defi n e d i n t he Cli nical 
I n v esti gat or’s A gr ee me nt. 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Pa g e 7 8  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
2 3  R E F E R E N C E S 
1.  A g uilar 
P R, 
Mi c hels o n 
A P, Isa k o w 
W. 
O bliterati ve br o nc hi olitis. 
Tra ns pla ntati o n 
2 0 1 6; 1 0 0( 2): 2 7 2- 8 3.  
2.  A u B K, A u M A, C hie n J W. Br o n c hi olitis o blitera ns s y n dr o me e pi de mi ol o g y aft er all o ge n eic 
he mat o p oietic cell tra ns pl a ntati o n. Bi ol Bl o o d Marr o w Tra ns pla nt 2 0 1 1; 1 7( 7): 1 0 7 2- 8. 
3.  Bar ker A F, Ber ger o n, A R o m 
W N et al. O blit erati v e br o nc hi olitis. N E n gl J 
M e d 
2 0 1 4; 3 7 0: 1 8 2 0- 1 8 2 8. 
4.  Be hr J, Zi m m er ma n n G, Ba u m g art n er R et al. L u n g de p ositi o n of a li p os o mal c ycl os p ori n e A 
i n halati o n s ol uti o n i n patie nts after l u n g tra ns pl a ntati o n. J Aer os ol M e d P ul m Dr u g Deli v 
2 0 0 9; 2 2( 2): 1 2 1- 1 3 0. 
5.  Ber ger o n A, C he vret S, Gra nata A et al. Effect of azit hr o m yci n o n airfl o w decli ne-free s ur vi v al 
after all o g e neic he mat o p oietic st e m cell tra ns pla nt: t he A L L O ZI T H R O ra n d o mi ze d cli nical 
trial. J A M A 2 0 1 7; 3 1 8( 6): 5 5 7- 5 6 6. 
6.  C orc ora n T E, S mal d o ne G C, Da u ber J H et al. Preser vati o n of p ost-tra ns pl a nt l u n g f u ncti o n 
wit h aer os ol c ycl os p ori n. E ur Res pir J 2 0 0 4; 2 3( 3): 3 7 8- 3 8 3. 
7.  C orc ora n T E. I n h ale d deli ver y of aer os olize d c y cl os p ori ne. 
A d v 
Dr u g 
Deli v 
R e v 
2 0 0 6; 5 8: 1 1 1 9- 1 1 2 7. 
8.  Este n ne M, Ma urer J R, B o e hl er A et al. Br o nc hi olitis o blitera ns s y n dr o me 2 0 0 1: a n u p date of 
t he dia g n osti c criteria. J Heart L u n g Tra ns pla nt 2 0 0 2; 2 1( 3): 2 9 7- 3 1 0. 
9.  G u y W, e dit or. E C D E U Assess me nt M a n u al f or Ps y c h o p har mac ol o g y. 1 9 7 6. R oc k ville, M D, 
U. S. De part me nt of H ealt h, E d ucati o n, a n d Welfare. 
1 0.  Hall ora n P F. I m m u n os u p pressi ve a ge nts i n cli ni cal trials i n tra ns pla ntati o n. A m J M e d Sci 
1 9 9 7; 3 1 3( 5): 2 8 3- 2 8 8. 
1 1.  Iac o n o A T, Kee na n RJ, D u nca n S R et al. Aer os oli ze d c ycl os p ori n e i n l u n g reci pie nts wit h 
refract or y c hr o nic r ejecti o n. A m J R es pir Crit Care M e d 1 9 9 6; 1 5 3( 4 Pt 1): 1 4 5 1- 1 4 5 5. 
1 2.  Iac o n o A T, J o h ns o n B A, Gr g uric h W F et al. A ra n d o mize d trial of i n h ale d c ycl os p ori n e i n 
l u n g-tra ns pla nt reci pie nts. N E n gl J Me d 2 0 0 6; 3 5 4( 2): 1 4 1- 1 5 0. 
1 3.  Ja gasia M H, Grei ni x H T, Ar ora M et al. N ati o n al I nstit utes of Healt h C o nse ns us De vel o p me nt 
Pr oject o n Crit eria f or Cli nical Tri als i n C hr o nic Graft- vers us- H ost Disease: I. T h e 2 0 1 4 
Dia g n osis a n d 
Sta gi n g 
W or ki n g 
Gr o u p 
Re p ort. 
Bi ol 
Bl o o d 
Marr o w 
Tra ns pla nt 
2 0 1 5; 2 1( 3): 3 8 9- 4 0 1. 
1 4.  Mill er M R, Ha n ki ns o n J, Br usasc o V et al. St a n dar dis ati o n of s pir o metr y. E ur Res pir J 
2 0 0 5a; 2 6: 3 1 9- 3 3 8. 


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 7 9  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
1 5.
Mill er M R, Cra p o R, Ha n ki ns o n J et al. Ge n eral c o nsi derati o ns f or l u n g f u ncti o n t esti n g. E ur
Res pir J 2 0 0 5 b; 2 6: 1 5 3- 1 6 1.
1 6. P elle gri n o R, Vi e gi G, Br usasc o V et al. I nt er pretati v e 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.
1 7. S o u b a ni 
A O, 
U berti J P. Br o n c hi olitis o blitera ns f oll o wi n g hae mat o p oieti c 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.
1 8.
U K S m P C Ci cl os p ori n A ( Ne oral ® ).
1 9.
Wa n ger J, Cla use n J L, C o ates A et al. Sta n dar disati o n of t he me as ure m e 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.
2 0.
Wils o n E B. Pr o ba ble i nfere n ce, t he la w of s uccessi o n, a n d st atistical i nfere nce. J A S A
1 9 2 7; 2 2: 2 0 9- 2 1 2.


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Pa g e 8 0  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
2 4  A P P E N DI X I – C O R E I N F O R M E D C O N S E N T F O R M 
T he i nf or me d c o nse nt f or m m ust be a da pte d t o l ocal re q uire m e nts b ut m ust c o ntai n at least t he 
f oll o wi n g p oi nts: 

T hat t he trial i n v ol v es res earc h.

T he p ur p ose of t he trial.

T he trial treat me nt(s) a n d t he pr o ba bilit y f or ra n d o m assi g n me nt t o eac h treat m e nt.

T he trial pr oc e d ures t o b e f oll o we d, i ncl u di n g all i n vasi v e pr oce d ures.

T he p atie nt’s res p o nsi biliti es.

T h ose as p ects of t he tri al t h at are e x p eri me ntal.

T he reas o n a bl y f oreseea ble ris ks or i n c o n ve nie nces t o t h e p atie nt a n d, w he n a p plica ble, t o a n
e m br y o, fet us, or n ursi n g i nfa nt.

T he re as o na bl y e x p ecte d be nefits. W h e n t here is n o i nte n de d cli nical b e nefit t o t h e p atie nt,
t he patie nt s h o ul d be ma de a ware of t his.

T he alter nati ve pr oce d ure(s) or c o urse(s) of treat m e nt t hat ma y be a vaila bl e t o t he p atie nt, a n d
t heir i m p orta nt p ote ntial be nefits a n d ris ks.

T he c o m pe ns ati o n a n d/ or treat me nt a vaila ble t o t he patie nt i n t he e v e nt of trial relate d patie nt
i nj ur y.

T he a ntici pate d pr orate d pa y me nt, if a n y, t o t he p atie nt f or partici p ati n g i n t he trial.

T he a ntici pate d e x pe nses, if a n y, t o t h e patie nt f or p artici pati n g i n t he trial.

T hat t he p atie nt‘s partici pati o n i n t he tri al is v ol u ntar y a n d t h at t he pati e nt ma y ref us e t o
partici pate or wit h dra w fr o m t he trial, at a n y ti me, wit h o ut p e nalt y or l oss of b e nefits t o w hi c h
t he patie nt is ot h er wise e ntitle d.

T hat t h e m o nit or(s), t h e a u dit or(s), t h e E C, a n d t he re g ulat or y a ut h orit y(ies) will be gra nt e d
direct access t o t he p atie nt‘s ori gi nal me dical rec or ds f or v erificati o n of cli nical trial
pr oce d ures a n d/ or d ata, wit h o ut vi ol ati n g t he c o nfi d e ntialit y of t h e patie nt, t o t h e e xte nt
per mitt e d b y t he a p pli ca ble la ws a n d re g ulati o ns a n d t h at, b y si g ni n g a writte n i nf or me d
c o nse nt f or m, t h e p atie nt or t he p atie nt‘s le gall y acce pta bl e re prese ntati ve is a ut h orizi n g s u c h
access.

T hat rec or ds i de ntif yi n g t he patie nt will be k e pt c o nfi d e ntial a n d, t o t he e xt e nt per mitte d b y
t he a p plica bl e l a ws a n d/ or re g ul ati o ns, will n ot b e ma de p u blicl y a vail a bl e. If t he res ults of
t he trial are p u blis he d, t h e patie nt’s i de ntit y will re mai n c o nfi d e nti al.

T hat t he patie nt or t he p atie nt‘s le gall y acce pta ble re pres e ntati v e will b e i nf or me d i n a ti mel y


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 8 1  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
ma n ner if i nf or mati o n bec o mes a vail a ble t hat ma y b e rele va nt t o t h e p atie nt‘s willi n g n ess t o 
c o nti n ue p arti ci pati o n i n t he trial. 

T he pers o n(s) t o c o nt act f or f urt her i nf or m ati o n re gar di n g t h e trial a n d t h e ri g hts of trial
patie nts, a n d w h o m t o c o ntact i n t he e ve nt of trial-rel at e d i nj ur y.

T he f oreseea ble cir c u msta nces a n d/ or reas o ns u n d er w hi c h t he pati e nt‘s parti ci pati o n i n t he
trial m a y b e ter mi nate d.

T he e x pect e d d urati o n of t h e p atie nt‘s partici p ati o n i n t h e trial.

T he a p pr o xi m ate n u m b er of patie nts i n v ol v e d i n t h e trial.

I nf or mati o n re gar di n g t h e trial ca n b e f o u n d o n cli ni caltrials. g o v.


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 H S C T 
B T – L- Cs A – 2 0 1 – S C T 
Za m b o n S p A 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pa g e 8 2  of 8 2  
Cli nical Trial Pr ot o c ol B T – L- Cs A – 2 0 1 – S C T 
Versi o n 5. 0; 3 0 A pril 2 0 2 1 
 
2 5  A P P E N DI X II – A C C E P T A B L E M E T H O D S O F C O N T R A C E P TI O N 
A w o ma n is c o nsi dere d of c hil d beari n g p ote ntial, i.e. fertil e, f oll o wi n g me narc he a n d u ntil 
bec o mi n g p ost- me n o pa usal u nless per ma ne ntl y sterile. T he stat us of p ost- me n o pa usal is defi n e d 
as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical ca us e a n d/ or t h e a g e of 6 0 ye ars. 
Acc or di n g t o t he Cli nical Trial Facilit ati o n Gr o u p ( C T F G) d at e d 2 1/ S e p/ 2 0 2 0, t he f oll o wi n g 
met h o ds are all o w e d f or c o ntrace pti o n d uri n g t h e cli nical trial wit h a fail ure rat e of less t h a n 1 %: 

c o m bi n e d (estr o ge n a n d pr o g est o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h
i n hi biti o n of o v ulati o n 1:
o
oral
o
i ntra va gi nal
o
tra ns der mal

pr o g est o ge n- o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 1:
o
oral
o
i njecta ble
o
i m pla nta bl e 2

i ntra uteri ne d e vice (I U D) 2

i ntra uteri ne h or m o ne-releasi n g s yste m (I U S) 2

bilateral t u bal occl usi o n 2

vas ect o mise d part ner 2, 3

se x u al a bsti ne nce 4
Fr o m res ults of pre vi o us cli nical trials wit h aer os olize d L- Cs A p ote ntial i nteracti o ns bet w ee n t h e 
I M P a n d h or m o n al c o ntrace pti ves ha ve n ot b ee n i n vesti gate d.  It is rec o g ni ze d t h at h or m o n al 
c o ntrac e pti v es ca n i n cre ase ser u m le vels of s yste micall y d ose d c ycl os p ori n e, b ut c ycl os p ori ne 
d oes n ot alt er t he effic ac y of h or m o n al c o ntrace pti ves.  S u bjects i n t h e trial will be m o nit ore d f or 
s yste mic c ycl os p ori n e le vels.   
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
1 H or m o nal c o ntrace pti o n ma y be s usce pti ble t o i nteracti o n wit h t he I M P, w hic h ma y re d u ce t he efficac y of t he c o ntrace pti o n 
met h o d 
2 C o ntrace pti o n met h o ds t h at i n t h e c o nt e xt of t his g ui d a nce are c o nsi d ere d t o h a ve l o w user d e pe n de nc y. 
3V asect o mise d part n er is a hi g hl y effecti ve birt h c o ntr ol met h o d pr o vi d e d t h at p art ner is t h e s ol e s e x ual p art ner of t h e W O C B P 
trial p arti ci pa nt a n d t h at t h e vasect o mis e d p art ner h as recei v e d me di cal assess me nt of t he s ur gical s uccess. 
4 I n t h e c o nte xt of t his g ui d a n ce se x u al a bsti n e nce is c o nsi d ere d a hi g hl y effecti v e met h o d o nl y if defi n e d as refrai ni n g fr o m 
h eter ose x ual i nterc o urse d uri n g t he e ntire p eri o d of ris k ass o ciat e d wit h t h e st u d y treat me nts. T h e relia bilit y of se x ual a bsti n e n ce 
n ee ds t o be e val u at e d i n relati o n t o t h e d urati o n of t he cli ni cal trial a n d t he pref erre d a n d us u al lifest yle of t h e s u bj ect. 

SAP_001.pdf: 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
BOSTON-4: A Phase IIa Multi-Center, Randomized, Single-Blind Safety and Tolerability 
Study of inhaled Liposomal Cyclosporine A in Bronchiolitis Obliterans Syndrome Following 
Allogeneic Hematopoietic Stem Cell Transplantation 
 
 
Protocol No: BT – L-CsA – 201 – SCT 
(BOSTON-4) 
Version: 5.0 
Date: 30 April 2021 
Protocol Amendment No 4 
 
SPONSOR 
Zambon SpA 
Via Lillo del Duca 10, 
20091 Bresso (MI) 
Italy  
 
INVESTIGATIONAL MEDICINAL PRODUCT 
Liposomal Cyclosporine A (L-CsA) 
 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 2 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
1 SIGNATORIES 
SPONSOR 
Zambon SpA 
Via Lillo del Duca 10, 
20091 Bresso (MI) 
Italy  
 
  
 
 
 
_________________________________ 
 
 
 
Date 
 
Signature 
Phone: 
 
Email: 
 
 
 
 
 
 
 
_________________________________ 
 
 
 
 
Date 
 
Signature 
Phone: 
 
Email: 
  
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 3 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
2 TABLE OF CONTENTS 
1 SIGNATORIES .................................................................................................................2 
2 TABLE OF CONTENTS ......................................................................................................3 
3 ABBREVIATIONS .............................................................................................................6 
4 VERSION HISTORY ..........................................................................................................8 
5 INTRODUCTION ..............................................................................................................9 
6 CHANGES TO STUDY PROTOCOL .....................................................................................9 
7 TRIAL OBJECTIVES ..........................................................................................................9 
8 INVESTIGATIONAL PLAN ............................................................................................... 10 
8.1 TRIAL DESIGN ............................................................................................................... 10 
8.2 RANDOMIZATION AND STRATIFICATION................................................................................ 12 
8.3 PRIMARY ENDPOINTS ...................................................................................................... 12 
8.4 SECONDARY ENDPOINTS .................................................................................................. 12 
8.5 EXPLORATORY ENDPOINTS ................................................................................................ 13 
8.6 SAFETY ENDPOINTS......................................................................................................... 13 
9 STATISTICAL CONSIDERATIONS..................................................................................... 13 
9.1 GENERAL CONSIDERATIONS AND DESCRIPTIVE STATISTICS ......................................................... 13 
9.1.1 IMPUTATION OF MISSING DATA .............................................................................................. 14 
9.2 SAMPLE SIZE CONSIDERATIONS .......................................................................................... 14 
9.2.1 INTERIM ANALYSIS FOR SAMPLE SIZE RE-ESTIMATION ................................................................. 14 
9.3 TYPE I ERROR CONSIDERATIONS ......................................................................................... 14 
9.4 DATA MONITORING COMMITTEE AND CONFIDENTIALITY OF RESULTS ........................................... 15 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 4 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
10 DEFINITIONS ................................................................................................................ 15 
10.1 PROTOCOL DEVIATIONS ................................................................................................. 15 
10.2 ANALYSIS DATA SETS .................................................................................................... 16 
10.2.1 SAFETY ANALYSIS SET ......................................................................................................... 16 
10.2.2 FULL ANALYSIS SET ............................................................................................................ 16 
10.2.3 PER PROTOCOL SET ........................................................................................................... 17 
10.3 DEFINITIONS RELATED TO SAFETY DATA ............................................................................. 17 
10.3.1 TREATMENT-EMERGENT ADVERSE EVENTS ............................................................................. 17 
10.3.2 TREATMENT-RELATED ADVERSE EVENTS ................................................................................ 17 
10.4 STUDY DAY AND TIME FROM RANDOMIZATION .................................................................... 17 
11 DISPOSITION ................................................................................................................ 18 
12 BASELINE DEMOGRAPHICS AND DISEASE CHARACTERISTICS ......................................... 18 
13 PRIMARY ASSESSMENTS............................................................................................... 19 
13.1 ANALYSIS OF LOCAL TOLERABILITY .................................................................................... 19 
13.2 ANALYSIS OF OVERALL TOLERABILITY ................................................................................. 20 
13.3 ANALYSIS OF SAFETY ..................................................................................................... 20 
13.3.1 ADVERSE EVENTS (NON-SERIOUS OR SERIOUS) ......................................................................... 20 
13.3.2 LABORATORY MEASURES, VITAL SIGNS, PHYSICAL EXAMINATION .................................................. 22 
13.4 ANALYSIS POPULATION .................................................................................................. 23 
13.5 WORKING HYPOTHESIS .................................................................................................. 23 
13.6 ANALYSIS MODEL ......................................................................................................... 23 
13.7 SENSITIVITY ANALYSES FOR THE PRIMARY ENDPOINT ............................................................. 23 
14 SECONDARY ASSESSMENTS .......................................................................................... 23 
14.1 LOCAL AND OVERALL TOLERABILITY, AND SAFETY .................................................................. 23 
14.2 CSA PHARMACOKINETICS ............................................................................................... 23 
15 EXPLORATORY ASSESSMENTS ...................................................................................... 24 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 5 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
15.1 SPIROMETRY MEASURES ................................................................................................ 24 
15.2 SHORT FORM (36) HEALTH SURVEY (SF-36) ....................................................................... 25 
15.3 CORTICOSTEROIDS AND IMMUNOSUPPRESSIVE DRUGS ............................................................ 25 
16 SAFETY DATA ............................................................................................................... 26 
16.1 GENERAL CONSIDERATIONS ............................................................................................. 26 
16.2 EXTENT OF EXPOSURE .................................................................................................... 26 
16.3 COVID-19 SPECIFIC CONSIDERATIONS ............................................................................... 27 
17 REFERENCES ................................................................................................................. 27 
 
 
 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 6 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
3 ABBREVIATIONS  
AE 
Adverse Event 
allo-HSCT 
Allogeneic Hematopoietic Stem Cell Transplantation 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC0-4h 
Area Under the Curve, 0 – 4 hours after dosing 
BDRM 
Blind Data Review Meeting 
bid 
Bis in die, twice daily 
BOS 
Bronchiolitis Obliterans Syndrome 
CGI 
Clinical Global Impressions 
cGvHD 
Chronic Graft Versus Host Disease 
Cmax 
Maximum Plasma Concentration 
CsA 
Cyclosporin A 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
EoS 
End of Study 
EoT 
End of Treatment 
FAS 
Full Analysis Set 
FEF25-75 
Forced Midexpiratory Flow 
FEV1 
Forced Expiratory Volume in One Second 
FVC 
Forced Vital Capacity 
IMP 
Investigational Medicinal Product (study drug: L-CsA) 
IPD 
Important Protocol Deviation 
L-CsA 
Liposomal Cyclosporine A Inhalation Solution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model of Repeated Measures 
N-IPD 
Non-Important Protocol Deviation 
PD 
Protocol Deviation 
PK 
Pharmacokinetics 
PPS 
Per Protocol Set 
PT 
Preferred Term 
Q1 
1st quartile 
Q3 
3rd quartile 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 7 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SCT 
Stem Cell Transplantation 
SF-36 
Short Form (36) Health Survey 
SoC 
Standard of Care 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TFLs 
Tables, figures and listings 
tmax 
Time Between Dosing and Maximum Plasma Concentration 
WHO 
World Health Organization 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 8 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
4 VERSION HISTORY  
Date 
Version 
Brief Description of Changes 
25 FEB 2022 
Final v1 
No previous final version 
 
 
 
 
 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 9 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
5 INTRODUCTION 
This Statistical Analysis Plan (SAP) provides details of planned analyses to be performed on the 
data to be collected from clinical trial BT – L-CsA – 201 – SCT (BOSTON-4). It is based on the 
Clinical Trial Protocol, version 5.0 of 30 April 2021 (including Protocol Amendment 4). 
Modifications to this SAP will be subject to detailed documentation relating to timing and 
rationale, with a focus on identifying and providing a rationale for changes. Any deviations from 
the SAP will be fully described in the integrated clinical study report (CSR). 
This SAP is not intended to pre-specify all possible analyses that may be performed after 
completion of the clinical trial. The main purpose of this SAP is to pre-specify statistical analyses 
that relate to identified clinical trial objectives. Any supportive or exploratory analyses presented 
in the integrated CSR which are not described in the SAP will be identified as such. 
This SAP will be finalized before database lock or any unblinding for this study. The programming 
specifications including tables, figures and listings (TFLs) to support the analysis as described 
below will be presented as a separate document. 
6 CHANGES TO STUDY PROTOCOL 
The planned analysis will be performed according to the study protocol, its amendments and this 
statistical analysis plan. If there are contradictions between the study protocol or its amendments 
and this statistical analysis plan, the analysis will be performed according to this analysis plan. 
Any deviation from the planned analysis has to be described in the CSR. 
 
The differences between study protocol and statistical analysis plan are summarized in the 
following table: 
Change 
Clinical Study Protocol 
(CSP) 
In the Statistical Analysis Plan  
Will be changed to:  
Wording in CSP  
Major Protocol Deviation 
Minor Protocol Deviation 
Important Protocol Deviation  
Non-Important Protocol Deviation  
7 TRIAL OBJECTIVES 
The primary objective of this study is to assess the tolerability and safety of two dose levels of 
aerosolized, liposomal cyclosporine A (L-CsA) in comparison to placebo, applied in addition to 
standard of care (SoC) therapy, for Bronchiolitis Obliterans Syndrome (BOS) in adult allogeneic 
hematopoietic stem cell transplantation (allo-HSCT) recipients. The secondary objectives are to 
assess the pharmacokinetics (PK) and exploratory efficacy and quality of life ratings of two dose 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 10 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
levels of aerosolized L-CsA in comparison to placebo in addition to SoC therapy in the same 
indication and patient population. 
8 INVESTIGATIONAL PLAN 
8.1 Trial Design 
This is a Phase IIa, prospective, multicenter, randomized, single-blind, placebo-controlled clinical 
trial of L-CsA for the treatment of BOS in adults with confirmed BOS following allo-HSCT. 
Patients will receive either L-CsA 5 mg or L-CsA 10 mg or placebo via the 
 
System twice daily in addition to SoC treatment, for a period of 12 weeks (see Table 1). 
A total of the following visits will be performed during the clinical trial: 
• Screening 
• Week 0 (Randomization/Baseline) [Visit 1]  
• Week 2 [Visit 2]  
• Week 4 [Visit 3] 
• Week 8 [Visit 4] 
• Week 12 (End of Treatment (EoT) [Visit 5]  
• Week 14 (End of Study (EoS) [Visit 6] 
After informed consent has been obtained, a Screening Visit will be carried out in order to 
determine the eligibility for randomized treatment. At the Baseline Visit (V1, randomization visit), 
inclusion and exclusion criteria will be re-confirmed and baseline spirometry performed. During 
the 12-week treatment period, interim visits are scheduled at weeks 2, 4, and 8 (V2 – V4). Visit 5 
(End of Treatment, EoT) is scheduled to occur 12 weeks after Visit 1. Visit 6 (End of Study, EoS) 
is a safety follow-up visit performed 2 weeks after Visit 5/EoT. 
However, if one of the visits V3, V4 and V6 cannot be performed at site due to COVID-19, remote 
visits (e.g., by telephone) are possible. COVID-19 related Adverse Events will be reported as 
SAEs.  
 
COVID-19 specific consideration: the patients will be supplied during V1 with the full amount of 
study medication needed, to cover the total treatment period of 12 weeks. Patient has to bring all 
study medication back to the site at EoT Visit V5 for Drug Accountability. 
 
 
CCI


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 11 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
Table 1 Schedule of Activities 
Clinical Trial Period 
Screening 
Treatment 
 
Follow-Up 
Visit Number 
- 
V 1 
V 2 
V 3 
V 4 
V 5 / 
EOT 
Remote 
Visits 
V 6 / EoS 
Week & Window 
W -4 to 
W 0 
  
W 1 
 Day 
1  
W 2 
± 3 
Days 
W 4 
± 3 
Days 
W 8 
± 7 
Days 
W 12 
± 7 
Days 
V3, V4 and 
V6 can be 
performed 
remotely 
W 14 
± 3 Days 
Informed Consent1 
X 
 
 
 
 
 
 
 
Demographics/Medical History 
X 
- 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
Serum/Urine Pregnancy Test 
X 
X 
X 
X 
X 
X 
 
X 
Physical Examination2 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
 
X 
Clinical Laboratory Tests4 
X 
X 
X 
X 
X 
X 
 
X 
PK Blood Sampling5 
 
X 
X 
X 
X 
X 
 
 
Spirometry7 
X 
X6 
X6 
X6 
X6 
X6 
 
 
Randomization 
 
X 
 
 
 
 
 
 
SF-36 
 
X 
X 
X 
X 
X 
X8 
 
CGI Questionnaire 
 
X 
X 
X 
X 
X 
 
 
Investigator’s Tolerability Assessment 
 
 
 
X 
 
X 
 
 
Local IMP Tolerability 
 
X 
X 
X 
X 
X 
 
 
IMP Administration 
 
Twice daily administration 
X 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
Permanent assessment throughout the complete clinical trial period 
Drug Accountability/IMP availability check 
 
 
X 
X 
X 
X 
X 
 
1 
Conduct prior to any screening activities. 
2 
Including body weight and height (at Screening visit only), cardiovascular, respiratory, nervous, gastrointestinal, hepatic, renal, 
dermatological, musculoskeletal, extremities, eyes, ears, nose, throat, and lymphatic. 
3 
Including systolic and diastolic blood pressure (sitting, after minimum 5 minutes of rest), pulse rate (sitting, after min. 5 minutes of rest), 
body temperature (the same method should be used for each patient and throughout the clinical trial), and respiratory rate. 
4 
According to Section 12.1.6. of the protocol 
5 
Day 1 blood samples at pre-dose, directly after end of inhalation, 15, 30, 45 min (+/- 5 minutes), and 1, 1.5, 2, 4 h (+/- 15 minutes), after end 
of inhalation. Other visits are a trough (pre-dose – 15 min before inhalation) sample only.  
6 
According to Section 12.1.1. of the protocol 
7 
Spirometry results at screening visit are required to confirm BOS diagnosis. The assessment is allowed to be peformed +/-2 days from 
screening visit date (but has to be performed after informed consent was given by the patient). 
8       applicable for remote Visits 3 and 4 only 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 12 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
8.2 Randomization and Stratification 
At the Baseline visit (V1), after all inclusion and exclusion criteria have been fully evaluated, 
eligible patients will be assigned to one of the three treatment groups at a ratio of 1:1:1 by means 
of block randomization. 
No stratification will be performed. 
8.3 Primary Endpoints 
• Investigational medicinal product (IMP) tolerability and safety during the first 4 weeks of 
treatment. IMP tolerability will be assessed using the following outcomes: 
o Local Tolerability: 
- Cough 
- Wheezing 
- Bronchospasm 
- Throat irritation 
- Change in FEV1 
o Overall Tolerability: 
- Clinical Global Impressions (CGI) scale 
- Investigator’s tolerability assessment  
o Safety 
- Adverse events (AEs) 
- Serious adverse events (SAEs) 
- Clinical laboratory values 
- Vital signs 
- Physical examination 
8.4 Secondary Endpoints 
• IMP tolerability and safety during the first 12 weeks of treatment (using the outcomes listed 
in Section 8.3) 
• CsA PK, using the following parameters: 
- Week 0, at pre-dose; directly after end of inhalation; 15, 30, and 45 minutes, 
and 1, 1.5, 2, and 4 hours after end of inhalation: Cmax, tmax, AUC0-4h 
• Whole blood trough levels parameter (Cyclosporine A Concentration) at week 2, 4, 8, and 
12 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 13 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
8.5 Exploratory Endpoints 
The following measures of treatment efficacy will be analyzed as exploratory assessments: 
• FEV1 % predicted, FEV1/FVC at randomization compared to Week 2, Week 4, Week 8, 
and Week 12 
• SF-36 Quality of Life Questionnaire at Week 2, Week 4, Week 8, and Week 12 
• Changes in the dose of corticosteroids and immunosuppressive therapy 
administered throughout trial duration 
For efficacy assessments determined at post-baseline visits, measured values as well as change 
from baseline will be analyzed. 
8.6 Safety Endpoints 
See Sections 8.3 and 8.4. 
9 STATISTICAL CONSIDERATIONS 
9.1 General Considerations and Descriptive Statistics 
Analyses and outputs will be produced using SAS® software 
, 
version 9.4 or later, or other suitable, commercially or publicly available statistical software, in a 
secure and validated environment. All tables, figures and data listings to be included in the report 
will be independently checked for consistency and integrity. 
The data recorded in the eCRF will be summarized as appropriate, per treatment group and for the 
applicable total analysis population, 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 using frequency counts and 
percentages.  
• Discrete ordinal or higher-level data will be summarized as continuous data, but a 
tabulation of categories may also be included, depending on the number of categories. 
• “Missing” category should be added for a categorical variable if there is at least one subject 
with missing data for that categorical variable unless the following evaluation requires 
otherwise. 
For all measures analyzed, tabulations comparing the treatment groups will be prepared. For 
outcomes measured more than once, the analyses will include tabulations of the measured values 
PPD


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 14 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
by visit, as well as change from baseline. Where provided, all confidence intervals will be two-
sided 95% intervals. 
All data recorded in the eCRF will be listed in subject data listings. 
9.1.1 Imputation of Missing data 
There will be no imputation of data for efficacy analysis. All data will be analyzed as they appear 
in the database. Missing data will be displayed in subject data listings and will be declared in tables 
as appropriate. 
The following imputation rules will apply only for AE data: 
• Imputed data should be flagged and properly footnoted as “imputed”. 
• AEs with unknown onset date/time will be counted as treatment emergent AEs (TEAEs). 
• AEs/TEAEs with unknown end date/time will be counted as an ongoing AEs/TEAEs, unless 
ongoing was ticked on the CRF. 
• TEAEs will be considered potentially IMP related if the investigator’s rating of the causal 
relationship is anything other than ‘not related’ or missing. 
• If for the calculation of a time period the full date format ddmmmyyyy is needed, missing 
entries will be imputed as follows:  
o Missing day in start date of a time period is imputed by the first day of the month; 
o Missing day in stop date of a time period is imputed by the last day of the month; 
o Missing month in start date of a time period is imputed by January of the year; 
o Missing month in stop date of a time period is imputed by December of the year; 
o Missing year is not imputed. 
9.2 Sample Size Considerations 
This is a Phase IIa study in a rare indication, with very limited availability of eligible patients and 
a purely descriptive statistical concept. Accordingly, the sample size for the study was established 
based on considerations of feasibility rather than on power calculations. 
A total of 24 patients (3 arms with 8 patients in each) are planned to be randomized. 
9.2.1 Interim Analysis for Sample Size Re-estimation 
Not applicable. 
9.3 Type I Error Considerations 
Not applicable. 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 15 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
9.4 Data Monitoring Committee and Confidentiality of Results 
An independent Data Monitoring Committee (DMC) will be established to monitor the safety of 
the IMP throughout the conduct of the study. The statistical analysis to be prepared for the 
meetings of the DMC are described in a separate SAP. 
10 DEFINITIONS 
10.1 Protocol Deviations 
According to the Protocol Deviation Management Plan, PDs are classified as either Important PDs 
(IPDs) or Non-important PDs (N-IPDs). IPDs are a subset of PDs that may significantly impact 
the completeness, accuracy, and/or reliability of the trial data or that may significantly affect a 
subject's rights, safety, or well-being. Additionally, PD related to Covid-19 will be classified. 
IPDs for which a significant influence on the assessment of treatment efficacy cannot be excluded 
will lead to the exclusion of a subject from an efficacy analysis data set (see Section 10.2 below). 
The impact of PDs on the efficacy endpoint results will be investigated by assessing the robustness 
of the efficacy results and conclusions to the choice of analysis population, both including and 
excluding data potentially affected by such PDs (see Sections 10.2.2 and 10.2.3 below). 
The relevant PDs have to be defined by a systematic data review prior to database closure. For this 
purpose, PDs that occurred during the study such as deviations of inclusion/exclusion criteria or 
forbidden concomitant medications or subject non-compliance will be assessed as ‘important’ or 
‘non-important’ depending on their potential to interfere with the objectives of the study. Listings 
will be prepared to show the eligibility of all subjects. Comprehensive justification for the 
classification of a protocol deviation as “important” will be given in the integrated clinical study 
report. 
Important protocol deviations and the assessment of analysis sets will be defined during the data 
review before data base closure. All definitions given in the Minutes of the Final Data Review will 
be taken into account in the analysis.  
The list of protocol deviations will be reviewed by the sponsor and finalized before locking the 
database. The sponsor will identify important PDs which will lead to exclusion of subjects from 
PP population. Important PDs leading to the exclusion of patients from the analyses sets will be 
flagged in the protocol deviation listing. 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 16 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
10.2 Analysis Data Sets 
The term ‘analysis data set’ is used to define the set of patients to be included in a class of analyses. 
The analysis data set is described in terms of the specific criteria for patient inclusion. 
Eligibility for the analysis data sets will be determined in a Blind Data Review Meeting (BDRM) 
held after closing the database but before unblinding the random code. To maintain the blinding 
of the meeting participants in this single-blind study, information on protocol deviation as well as 
any other subject data will be presented during the BDRM in a format that assures that the actual 
treatment assignment of the subjects will not be revealed.  
Detailed justification for the classification of a protocol deviation as having an important influence 
on the assessment of treatment efficacy will be given in the BDRM minutes as well as in the 
integrated CSR.  
10.2.1 Safety Analysis Set 
The Safety Analysis Set (SAF) is defined as all randomized patients who have received a partial 
dose of IMP at least once. All data collected after baseline to the end of clinical trial participation 
will be included in the safety summaries. Patients will be analyzed according to the treatment they 
actually received. 
All safety and tolerability data will be summarized and analyzed using the SAF. 
10.2.2 Full Analysis Set 
The Full Analysis Set (FAS) is defined as all randomized patients for whom a baseline and at least 
one post-baseline measurement of an efficacy outcome measure, i.e., for spirometry or quality of 
life measures (Section 8.5), is available. For spirometry measures, baseline will correspond to the 
assessment at randomization visit (Visit 1) prior to inhalation of IMP. Patients will be analyzed 
according to the treatment group to which they were randomized. 
A BDRM will determine if patients should be excluded from the FAS in cases of significant 
protocol deviations that preclude an assessment of treatment efficacy (e.g., randomized patients 
not suffering from the condition under investigation). Any exclusion of patients from the FAS will 
require individual justification. 
The primary analysis of all efficacy endpoints will be performed using the FAS. 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 17 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
10.2.3 Per Protocol Set 
The Per Protocol Set (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 IPD leading to exclusion from PPS was identified during the data review 
meeting. The IPD criteria will be defined in the protocol deviation (PD) list and reviewed 
before database closure. The reviewed PD list will be included into the CSR. 
Patients with one or more AE related to IMP will be discussed during the BDRM to decide if there 
is a lack of tolerability.  
Patients with “AE (including SAE/Death)”, “Investigator's withdrawal of subject in the best 
interest of the patient” or with free text “Lack of efficacy” as primary reason for non-completion 
of the study will be discussed during the BDRM to decide if there is a lack of efficacy. 
For selected efficacy endpoints, the PPS may be used as a sensitivity analysis to assess the impact 
of important protocol deviations on the results. 
Patients will be analyzed according to the treatment they were randomly assigned. 
10.3 Definitions Related to Safety Data 
10.3.1 Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as AEs with onset on or after the IMP 
intake or pre-existing and worsening after IMP intake. 
10.3.2 Treatment-related Adverse Events 
The Investigator will assess the relationship (unrelated, possible, definite) of each AE to the 
investigational treatment (L-CsA (10 mg bid or 5 mg bid) plus SoC or SoC alone). Treatment-
related AEs are defined as events with any causal relationship other than ‘not related’ according 
to the assessment of the Investigator.  Patients who experience the same event multiple times will 
be included in the most related category for summarization. 
10.4 Study Day and Time from Randomization 
Baseline is defined to be the day of the randomization visit (visit 1, week 0). Time from baseline 
(days) for subsequent visits is defined to be visit date – date of randomization visit + 1. 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 18 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
11 DISPOSITION  
The number of patients screened, who failed screening, randomized, treated with clinical trial 
treatment and completing the clinical trial (and reason for not completing) as scheduled will be 
presented in frequency tables by treatment group.  
The number of randomized patients in each analysis population (SAF, FAS and PPS) will be 
summarized by treatment group. A by-patient listing of disposition will be provided. 
All important protocol deviations will be presented as a frequency table by treatment group. All 
protocol deviations will be presented in a by-patient listing, which will include the category of the 
deviation, the deviation text, if it was an important protocol deviation and if the PD led to the 
exclusion from FAS and/or PP.  
A separate listing will be provided for covid-19 related protocol deviations. 
12 BASELINE 
DEMOGRAPHICS 
AND 
DISEASE 
CHARACTERISTICS 
All baseline demographic, anthropometric, medical data will be summarized by treatment group 
for the SAF, FAS, and PPS analysis populations. For summary purposes, the most recent, non-
missing result obtained on or prior to the baseline visit will be used. 
Prior and concomitant medication will be summarized and tabulated according to the 1st and 2nd 
levels of the WHO ATC system. The version will be provided in Data Management related 
document “DM-AD-089-Study-specific Dictionary Coding Conventions and Specifications”. 
Non-IMP medication will be assessed as prior treatment when the start of the treatment lies before 
the baseline visit, and as concomitant medication for any treatment started or ongoing after 
baseline. The definition implies that medication started before the baseline visit but continued into 
the randomized treatment phase will be both prior and concomitant. 
In case of incomplete information for start of non-IMP medication, the earliest possible date will 
be assumed for determining whether treatment is prior and/ or concomitant (e.g., ‘2019’ will be 
assumed to indicate ’01-Jan-2019’). For incomplete information on treatment end, the latest 
possible date will be assumed unless it lies in the future (e.g., ’09-2017’ will be assumed to indicate 
’30-Sep-2017’). Medication with an entirely missing start date will be assumed to be prior 
treatment. Similarly, medication with an entirely missing stop date will be assumed to be ongoing 
during randomized treatment. 
Time from Transplantation to BOS Score 1 Diagnosis (days) will be summarized and is derived 
as: Date of BOS Score 1 Diagnosis – Date of Transplantation + 1.   


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 19 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
By-patient listings will be provided for all baseline demographic and disease characteristics. 
13 PRIMARY ASSESSMENTS 
The primary assessments will be measures of safety and local tolerability listed in Section 8.3 and 
covering the first 4 weeks of treatment, defined as data collected until Visit 3. AEs will be included 
into this analysis if their date of onset lies on or before Visit 3 or, in case of an incomplete or 
missing date of onset, if they could have started on or before Visit 3 in accordance with all available 
information, using the procedure for incomplete data information already described in Section 12 
above.  
Outcomes assessed during study visits will be included into the primary analysis up until Visit 3 
scheduled to be performed at Week 4 after baseline, or until the EoT visit if it was performed on 
or before Visit 3. 
All analyses described in this chapter will be performed on the SAF. 
13.1 Analysis of Local Tolerability 
In accordance with the study protocol, local tolerability events of interest (i.e., cough, wheezing, 
bronchospasm, throat irritation, and change in FEV1) will be documented in the eCRF as AEs. 
During data analysis local tolerability events of interest thus have to be identified from the CRF 
form of AEs as follows: 
• MedDRA (version 23.1) Preferred Terms (PTs): 
o Cough (MedDRA code 10011224) 
o Wheezing (MedDRA code 10047924) 
o Bronchospasm (MedDRA codes 10006482, 10072338) 
o Throat irritation (MedDRA code 10043521) 
o Change in FEV1 (MedDRA codes 10016987, 10016989, 10016985) 
The version of the utilized dictionary will be presented either in the title or footnote of the 
provided tables and listings. 
• The event must have newly appeared within 1 hour after the end of an IMP inhalation. 
• They must have occurred within on or before Visit 3. 
• Events meeting the criteria above will be selected independently of the causality 
assessment of the investigator. 
For each local tolerability event, pairwise treatment group comparisons of the proportion of 
patients with at least one local tolerability event will be performed based on Wilson score 95% 
confidence intervals (Wilson, 1927).  


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 20 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
Moreover, incidence densities of events per patient treatment day starting with the first IMP 
administration will be determined separately for each local tolerability event. In accordance with 
the visit schedule, incidence densities will be provided for the periods between every two adjacent 
visits starting with the first IMP administration for the entire randomized treatment period up until 
Visit 3, and for entire randomized treatment period (as secondary assessment, please refer to 
section 8.4). Events will be assigned to their period of onset.  
In addition to the pairwise treatment group comparisons, all analyses specified above in this section 
will also be performed for the comparison between all patients treated with L-CsA (2 x 5 mg/day 
or 2 x 10 mg/day) and those treated with placebo. 
13.2 Analysis of Overall Tolerability 
The CGI is a 3-item observer-rated scale that measures illness severity, global improvement or 
change and therapeutic response. A modified version of the CGI will be used in this trial to assess 
“illness” instead of “mental” illness. For CGI Items 1 and 2, a table of frequencies as well as a 
table of summary statistics will be produced, broken down by treatment group and visit. Item 3 
will only be tabulated in frequency tables. The two dimensions of the item, ‘Therapeutic effect’ 
and ‘Side effects’, will be tabulated separately and overall. 
For all CGI Items, a score of 0 (‘Not assessed’) will be treated as missing data and will thus be 
excluded from the computation of summary statistics. The scale does not support the computation 
of a summary (total) score. 
A table of frequencies will be prepared for the Investigator’s Tolerability Assessment at Visit 3. 
Pairwise treatment group comparisons will be performed for CGI Items 1 and 2, for the dimensions 
of Item 3 assessed separately as well as for the Investigator’s Tolerability Assessment using 
Wilcoxon-Mann-Whitney U-tests. Comparisons for CGI between treatment groups will be 
provided for Visit 3 and for Visit5/EOT. 
13.3 Analysis of Safety 
13.3.1 Adverse events (non-serious or serious) 
AEs will be coded using the MedDRA. The version of the utilized dictionary will be presented 
either in the title or footnote of the provided tables and by-patient listings. Events will be identified 
as treatment-emergent (TEAE) and non-treatment-emergent (Non-TEAE) on the basis of the date 
of onset relative to the date of the first IMP dose. Events with an onset date before the date of the 
first IMP dose will be defined as Non-TEAE. Events with an onset date on or after the first IMP 
dose or pre-existing and worsening after IMP intake will be defined as TEAE. 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 21 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
For all TEAEs occurring during the first 4 weeks of treatment (on or before Visit 3), and separately 
for all TEAEs (i.e. events with onset at any time during randomized treatment, as secondary 
assessment, please refer to section 8.4), a summary containing the following counts and 
percentages of subjects will be presented by treatment group and overall: 
• 
Overview table, including the number (percent) of patients with 
o Any TEAEs 
o Mild TEAEs 
o Moderate TEAE 
o Severe TEAEs, 
o Serious TEAEs 
o Treatment-related TEAEs, 
o Serious Treatment-related TEAEs, 
o COVID-19 related TEAEs; 
o TEAEs leading to discontinuation of study, 
o TEAEs leading to discontinuation of treatment, 
o TEAEs having an outcome of death. 
 
AEs leading to discontinuation of study are identified as AEs whose CRF field in AE form “Study 
discontinued due to this (S)AE” is flagged as “Yes”. 
AEs leading to discontinuation of treatment are identified as AEs whose CRF field in AE form 
“Action taken” is flagged as “Treatment stopped”. 
 
Patients who have multiple events will be counted only once but all events will be considered as 
occurred.  
Summaries (number of events as well as number and percentage of patients with any events of a 
particular type) of TEAEs will be provided by primary system organ class (SOC) and preferred 
term (PT) and will be ordered in terms of decreasing frequency for SOC, and PT within SOC, in 
the total column. Patients who have multiple events coding to the same PT or within the same SOC 
will be counted only once in the patient counts for the corresponding summaries, but all events 
will be considered and listed. Patients who experience the same event multiple times will be 
included in the most severe category where applicable. 
Summaries of TEAEs by primary system organ class (SOC) and preferred term (PT) will be 
presented for all TEAEs occurring during the first 4 weeks of treatment (on or before Visit 3), and 
separately for all TEAEs (as secondary assessment-please refer to section 8.4). 
Number of events and number (%) of patients experiencing TEAEs by maximum severity (mild, 
moderate, and severe), relationship to IMP, and action taken with regard to IMP will be 
summarized.  


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 22 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
 
Number (%) of events and of patients with TEAEs leading to discontinuation of clinical trial 
participation as well as treatment discontinuation will also be summarized.  
 
Tables will be provided also for TEAEs related to COVID-19 (as described in section 16.3), for 
related TEAEs, for serious TEAEs, for serious TEAEs by seriousness criteria, for serious TEAE 
by relationship and for serious -related TEAEs. 
 
Treatment group comparisons of the proportion of patients with TEAEs will be based on Wilson 
score confidence intervals (Wilson, 1927). Pairwise comparisons between all treatment groups will 
be provided at the SOC level for TEAEs occurring on or before Visit 3, and for all TEAEs (as 
secondary assessment-please refer to section 8.4). 
Incidence densities of events per patient day starting with the first IMP administration will be 
determined for all TEAEs. In accordance with the visit schedule, incidence densities will be 
provided for the periods between every two adjacent visits starting with the first IMP 
administration. Additionally, the overall of all incidence densities and the sum of the incidence 
densities during the first 4 weeks of treatment (on or before Visit 3) will be presented. 
 In addition to the pairwise treatment group comparisons, all analyses specified above in this 
section will also be performed for the comparison between all patients treated with L-CsA (2 x 5 
mg/day or 2 x 10 mg/day) and those treated with placebo in order to increase the chance of 
identifying TEAEs potentially related to L-CsA. 
13.3.2 Laboratory measures, vital signs, physical examination 
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 
for the following parameters: 
Hematology 
(Basophils, 
Basophils/Leukocytes, 
Eosinophils, 
Eosinophils/Leukocytes, 
Lymphocytes, Lymphocytes/Leukocytes, Monocytes, Monocytes/Leukocytes, Neutrophils, 
Neutrophils/Leukocytes, Platelets, Erythrocytes, Leukocytes) 
Chemistry (Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, 
Bilirubin, Creatinine, Gamma Glutamyl Transferase, Urea Nitrogen) 
Vital Signs (Systolic and diastolic blood pressure, Heart Rate, Body Temperature, Respiratory 
Rate.) 
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 V3 and at EoT. 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 23 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
For physical examination results, tables of frequencies will be prepared, broken down by treatment 
group and visit. 
13.4 Analysis Population 
In this trial whose primary measures are safety and tolerability related outcomes, the applicable 
analysis population will be the SAF. See Sections 10.2.1 and 10.3 for further details. 
13.5 Working Hypothesis 
Not applicable. 
13.6 Analysis Model 
Not applicable. 
13.7 Sensitivity Analyses for the Primary Endpoint 
Not applicable. 
14 SECONDARY ASSESSMENTS 
14.1 Local and Overall Tolerability, and Safety 
In the context of secondary assessments i.e. IMP tolerability and safety during the first 12 weeks 
of treatment, all analyses described in Section 13 will be performed for the entire randomized 
treatment period. 
For all tabulations broken down by visit, no separate tabulations for primary and secondary 
assessments are required as the results for the period up until Visit 3 are a subset of those for the 
entire period of observation and can thus be taken from the same table. 
All analyses will be carried out in the SAF set. 
14.2 CsA Pharmacokinetics 
PK analyses will be carried out using SAS® software, Version 9.4 or later. Descriptive statistics 
(N, arithmetic means, standard deviation, geometric means, geometric coefficient of variation, 
medians, minimum and maximum) will be presented for all PK parameters indicated in section 8.4 
including Whole blood trough level parameter (Cyclosporine A Concentration) at Weeks 2, 4, 8, 
and 12, separately for each treatment group. A figure with overlaying individual pharmacokinetic 
concentration-time profiles will be presented for plasma concentrations after end of inhalation per 
treatment group. 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 24 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
The statistical analysis will be carried out on a log scale for AUC0-4 h and Cmax-values, while tmax 
and trough levels will be evaluated on a linear scale.  
Analyses of variance will be performed to compare the treatment groups with regards to  
AUC0-4 h and Cmax. This will include the computation of 95% confidence intervals for the between-
group differences. 
The statistical analysis will be performed as a valid case analysis including all patients of the FAS. 
15 EXPLORATORY ASSESSMENTS 
Exploratory analyses of efficacy will including accepted spirometry values performed as per 
protocol and be based on the FAS, and on the PPS analysis populations (as sensitivity analysis) 
15.1 Spirometry Measures 
For the spirometry measures (FEV1 % predicted, FEV1/FVC, FEV1 absolute, FVC absolute, FVC 
% predicted), the observed values and corresponding changes from baseline will be summarized 
using descriptive statistics by parameter and visit. Different methods of measuring will not 
distinguished in the descriptive statistics and the statistical model. Baseline spirometry 
measurement is the last post-bronchodilator assessment at randomization visit (Visit 1) prior to 
inhalation of IMP which is the following measurement in the eCRF: Before inhalation of IMP 
(“Before inhalation of 2-4 puffs of salbutamol” if “Before inhalation of IMP” is not available). 
For each spirometry measure identified in Section 8.5, treatment group comparisons will be carried 
out using a mixed model for repeated measures (MMRM), using all available measurements of the 
outcome of interest. The dependent variables will be the absolute change from baseline of the 
outcome of interest at the visits scheduled for Weeks 2 through 12, using fixed effects for 
treatment, visit, and the treatment x visit interaction and the baseline value as a fixed effect 
covariate. Treatment group comparisons at each visit will be estimated by differences between the 
marginal (adjusted) means from the treatment x visit interaction, with accompanying p-values and 
95% confidence intervals. The analyses will include pairwise treatment group comparisons for 
each post-baseline visit via contrasts. 
For the covariance model of the MMRM analyses, an unstructured covariance matrix should 
preferably be used. If the model does not converge (e.g., due to the small sample size), a 
Heterogeneous Toeplitz matrix will be used and, if this model does not converge either, a 
compound symmetry matrix will be used. If all models fail to converge, patients treated with 
L-CsA 2 x 5 mg/day or 2 x 10 mg/day will be merged into one group that will be compared to 
placebo, and the models for the covariance matrix will be applied as before, starting with an 
unstructured matrix, until the model converges. If none of the models converge, treatment group 


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 25 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
comparisons of change versus baseline will be performed for each visit using pairwise, 
independent samples t-tests on the observed data. Note that the covariance model to be used may 
be different for different spirometry parameters, depending on whether and when convergence is 
achieved. 
Descriptive summary measures will be provided based on all observed values as well as based on 
the marginal means determined via MMRM analyses (if convergence can be achieved). 
15.2 Short Form (36) Health Survey (SF-36) 
The SF-36 is a multi-purpose, short-form health survey with 36 questions yielding 8 health domain 
scales and 2 psychometrically based physical and mental component summary measures. 
The standard form of the SF-36 Version 1 will be used and the raw data (questions), the scoring 
of health domains and the summary scores will be provided in SAS Format to Biostats by Data 
Management. The calculation of the derived scores will be done by validated 
 
 System.1 
 
The 8 health domain scales are referred to as the ‘Physical Functioning (PF)’, ‘Role- Physical 
(RP)’, ‘Bodily Pain (BP)’, ‘General Health (GH)’, ‘Vitality (VT)’, ‘Social Functioning (SF)’, 
‘Role-Emotional (RE)’, and ‘Mental Health (MH)’ scales. The two summary measures are referred 
to as the physical component score (PCS) and mental component score (MCS). 
 
For the scales and summary scores of the SF-36, the numeric values and corresponding changes 
from baseline will be summarized using descriptive statistics by parameter and time point. 
The analysis will be carried out using a mixed model for repeated measures (MMRM), using all 
available measurements of the outcome of interest. The dependent variables will be the absolute 
change from baseline of the outcome of interest at the visits scheduled for Weeks 2 through 12, 
using fixed effects for treatment, visit, and the treatment x visit interaction and the baseline value 
as a fixed effect covariate. Treatment group comparisons in the change versus baseline at each 
visit will be estimated by differences between the marginal (adjusted) means from the treatment x 
visit interaction, with accompanying p-values and 95% confidence intervals.  
Descriptive summary measures will be provided based on all observed values as well as based on 
the marginal means determined via MMRM analyses. 
15.3 Corticosteroids and immunosuppressive drugs 
Corticosteroid medications and immunosuppressive therapy will be identified through an ongoing 
medical review of the concomitant medications collected in the study, using an ad-hoc excel 
spreadsheet, including column “Immunosuppressant Yes/No” to flag corticosteroid medications 
                                                 
 
1 
 
 
CCI
CCI
CCI


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 26 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
and immunosuppressive therapy. The process will be performed before database lock. This excel 
spreadsheet (approved by the sponsor and provided together with the database extract by data 
management) will be imported via SAS and included in SDTM datasets by the statistical 
programmer.  
Summary with counts and frequencies of patients with corticosteroid medications and 
immunosuppressive therapy presented at Baseline will be presented for Safety Analysis Set per 
study arm and overall.  
In addition, counts and frequencies of these patients will be presented for an increased, decreased 
or a stopped dose. This summary statistic will be repeated for patients started a new therapy after 
Baseline.  An increase (or decrease) of a dose is defined as a change in the average daily dose. 
Increase (or decrease) of dosing will be discussed and confirmed during the BDRM with the 
physician. 
A by-patient listing will present all different medications and doses per visit. 
16 SAFETY DATA 
16.1 General considerations 
Except for the analysis of extent of exposure and COVID-19 related AEs, analysis of safety has 
already been covered in Sections 13 and 14 above. 
16.2 Extent of exposure 
Exposure to the IMP (L-CsA or placebo) will be confirmed based on the difference between the 
number of IMP vials/ampoules dispensed and the number of unused vials/ampoules returned, and 
dosing recorded in the eCRF (this implies that IMP vials/ampoules not returned will be considered 
as having been used). Summary tables will be prepared including the following details about 
administration of L-CsA or placebo: 
• Descriptive statistics for the total number of doses received. 
• Descriptive statistics for the duration of treatment in days. For each patient, the treatment 
duration will be calculated as the difference between the dates of last and first 
administration of L-CsA (or placebo) plus 1. 
• Descriptive statistics for the number of exposure days. For each patient, the number of 
exposure days is the count of unique days on which the patient received at least one 
administration of L-CsA (or placebo). 
A by-patient listing will present all IMP administration data. This listing will include at least: date 
and time of L-CsA (or placebo) administration and L-CsA (or placebo) dose changed (yes, no, not 
applicable). If L-CsA (or placebo) dose changed, dose adjustment date and time and the reason for 
deviation will be displayed as well.  


L-CsA: 
Protocol Number: 
Sponsor: 
Treatment of BOS after HSCT 
BT – L-CsA – 201 – SCT 
Zambon Spa  
____________________________________________________________________________________________________ 
__________________________________________________________________________ 
Page 27 of 27 
Statistical Analysis Plan Protocol BT–L-CsA–201–SCT 
Version: Final 1.0 of 25 February 2022 
 
 
 
 
Moreover, a table of treatment compliance will be produced for the investigational treatment based 
on the ratio between the amount of IMP actually administered and the prescribed amount across 
the period between baseline and EoT. Treatment compliance will be categorized as <50%, 50-79%, 
80-120% as well as >120%. Besides using the safety analysis set, this table will also be produced 
using the Full Analysis Set and the Per Protocol set. 
16.3 COVID-19 specific considerations 
COVID-19 related AEs using COVID-19 (SMQ) available at https://www.meddra.org/COVID-
19-terms-and-MedDRA will be reported as SAEs. All confirmed cases of COVID-19, occurring 
after the patient has provided informed consent will be summarized in a table and flagged in the 
AE subject data listing.  
The seriousness criterion for COVID-19 hospitalized patients should be “hospitalization”; if the patient 
was not admitted to a hospital or the event is not resulting in prolonged hospitalization, the seriousness 
criterion “medically significant” will be used. 
  
In all cases, details of the patient's symptoms, treatment and any clinically relevant information, from 
the SAE CRF-form will be presented in a separate subject data listing. 
17 REFERENCES 
Quanjer, P. H., Stanojevic, S., Cole, T. J., Baur, X., Hall, G. L., Culver, B. H., . . . E. R. S. Global 
Lung Function Initiative. (2012). Multi-ethnic reference values for spirometry for the 3-
95-yr age range: the global lung function 2012 equations. European Respiratory Journal, 
40(6), 1324-1343. doi:10.1183/09031936.00080312 
Wilson, E. B. (1927). Probable inference, the Law of Succession, and statistical inference. Journal 
of the American Statistical Association, 22, 209-212.