Conditions: MRSA Cystic Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 188
Healthy volunteers: no

Brief summary:
This is a multi-center, randomized phase III study to evaluate the clinical effectiveness of AeroVanc in persistent methicillin-resistant Staphylococcus aureus (MRSA) infection in patients with cystic fibrosis (CF).

Detailed description:
This is a phase III, randomized, multicenter, double-blind, placebo-controlled, parallel-group study to examine the safety and efficacy of AeroVanc in the treatment of persistent MRSA lung infection in patients diagnosed with CF. After the Screening period to confirm study eligibility, participants are randomly assigned in a blinded fashion to receive either AeroVanc 30 mg twice daily (BID), or placebo BID (1:1 active to placebo) by inhalation for 24 weeks or 3 dosing cycles (Period 1). Upon completion of Period 1, participants receive open-label AeroVanc 30 mg BID for an additional 24 weeks or 3 dosing cycles (Period 2), to evaluate long-term safety of AeroVanc. A dosing cycle is defined as 28 days of treatment followed by 28 days of observation.

Participants on a 28-day cyclical on/off anti-Pseudomonal antibiotic regimen enter the Screening period at a time such that the Baseline visit coincide with the end of their anti-Pseudomonas antibiotic cycle. Study drug is thereby administered during the off-cycle, and participants can then resume anti-Pseudomonal therapy during the 28-day observation period. Participants continuing alternating anti-Pseudomonal therapy can continue their treatment during the study drug administration, and observation period.

The primary and secondary analyses are conducted in participants ≤21 years old. Subjects \>21 years old are analyzed separately as supportive analyses.

Arms:
arm 1: Vancomycin inhalation powder 30 mg is administered twice daily (BID) during the 24-week double-blind period (Period 1) by inhalation during three dosing cycles, each cycle being 28 days of treatment followed by 28 days of observation. arm 2: Matching placebo is administered BID during the 24-week double-blind period (Period 1) by inhalation during three dosing cycles, each cycle being 28 days of treatment followed by 28 days of observation. arm 3: In the 24-week Period 2, all participants receive AeroVanc 30 mg BID by inhalation during three dosing cycles, each cycle being 28 days of treatment followed by 28 days of observation.

Interventions: intervention 1: Vancomycin inhalation powder intervention 2: Placebo inhalation powder intervention 3: Vancomycin inhalation powder
Intervention descriptions: intervention 1: 100 participants are to be treated with double-blind vancomycin inhalation powder (75 subjects ≤21 years old, 25 subjects \>21 years old) for 24 weeks during Period 1. intervention 2: 100 participants are to be treated with double-blind placebo (75 subjects ≤21 years old, 25 subjects \>21 years old) for 24 weeks during Period 1. intervention 3: In the 24-week Period 2, all participants are to be treated with open-label vancomycin inhalation powder.

Protocol document:
Prot_000.pdf: 
 
S A V 0 0 5 -0 4  
A P h as e III, r a n d o miz e d, d o u bl e -bli n d, pl ac e b o -
c o ntr oll e d st u d y of A er o V a nc f or t h e tr e at m e nt of 
p ersist e nt m et hicilli n -r esist a nt St a p hyl oc occ us 
a ur e us  l u n g i nf ecti o n i n c ystic fi br osis p ati e nts 
 
N C T 0 3 1 8 1 9 3 2  
 
1 8 A pril 2 0 1 8  


 
 
Cli ni c al  St u d y  P r ot o c ol  
S A V 0 0 5- 0 4 
A  P h as e III,  r a n d o mi z e d,  d o u bl e -bli n d,  pl a c e b o -c o nt r oll e d st u d y  of  A e r o V a n c  f o r t h e t r e at m e nt  of 
p e rsi st e nt  m et hi cilli n -r esi st a nt  St a p h yl o c o c c us  a ur e us  l u n g i nf e cti o n i n  c ysti c fi b r osis  p ati e nts 
 
P r o d u ct  N a m e:  
A e r o V a n c ( v a n c o m y ci n  h y d r o c hl o ri d e 
i n h al ati o n  p o w d e r), 3 0  m g  t wi c e  d ail y ( B I D) 
I n di c ati o n:  
M et hi cilli n -r esi st a nt  St a p h yl o c o c c us  a ur e us  
l u n g i nf e cti o n i n  p ati e nts  wit h  c ysti c fi b r osis 
P h as e:  
III  
S p o ns o r:  
S a v a r a I n c.  
6 8 3 6  B e e  C a v es  R d.,  B uil di n g III  
S uit e  2 0 0 
A usti n,  T X  7 8 7 4 6  
D at e  of  P r ot o c ol : 
1 8 -A p r -2 0 1 8  
S a v a r a  D o c u m e nt  N u m b e r:  
D -0 2 7  
V e rsi o n : 
2  
 
 
 
T his  c o nfi d e nti al i nf o r m ati o n  a b o ut  a n i n v esti g ati o n al  p r o d u ct is  p r o vi d e d f o r t h e  e x cl usi v e  us e  of 
In v esti g at o rs  of t his  p r o d u ct  a n d is s u bj e ct t o  r e c all  at  a n y ti m e.  T h e i nf o r m ati o n i n t his  d o c u m e nt 
m a y  n ot  b e  dis cl os e d  u nl ess f e d e r al  o r st at e l a w  o r  r e g ul ati o ns  r e q ui r e s u c h  dis cl os u r e.  S u bj e ct t o t h e 
f o r e g oi n g, t his i nf o r m ati o n  m a y  b e  dis cl os e d  o nl y t o t h os e  p e rs o ns i n v ol v e d i n t h e st u d y  w h o  h a v e  a 
n e e d t o  k n o w,  wit h t h e  o bli g ati o n  n ot t o f u rt h e r  diss e mi n at e t his i nf o r m ati o n.  
 
 


Jessica Jackson 
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2018.05.03 16:11:50 -05'00'
Cecilia Ganslandt 
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2018.05.04 07:25:37 +02'00'
Taneli Jouhikainen 
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2018.05.04 14:55:31 -05'00'
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S a v ar a  P h ar m a c e uti c al s  
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
3 
P R O T O C O L  A G R E E M E N T  
A m e n d m e nt  # 1  
 
I  h a v e r e a d t h e  pr ot o c ol s p e cifi e d  b el o w. I n  m y f or m al  c a p a cit y  as I n v esti g at or,  m y  d uti es i n cl u d e 
e ns uri n g t h e  s af et y  of t h e st u d y  s u bj e ct s e nr oll e d  u n d er  m y s u p er visi o n  a n d  pr o vi di n g  S a v ar a  wit h 
c o m pl et e  a n d ti m el y i nf or m ati o n,  as  o utli n e d i n t h e  pr ot o c ol.  It i s  u n d erst o o d t h at  all i nf or m ati o n 
p ert ai ni n g t o t h e  st u d y  will  b e  h el d stri ctl y  c o nfi d e nti al  a n d t h at t his  c o nfi d e nti alit y r e q uir e m e nt  a p pli es t o 
all st u d y st aff  at t his sit e.  F urt h er m or e,  o n  b e h alf  of t h e st u d y  st aff  a n d  m ys elf, I  a gr e e t o  m ai nt ai n t h e 
pr o c e d ur es r e q uir e d t o  c arr y  o ut t h e  st u d y i n  a c c or d a n c e  wit h  a c c e pt e d  G C P  pri n ci pl es  a n d t o  a bi d e  b y t h e 
t er ms  of t his  pr ot o c ol. 
P r ot o c ol  N u m b e r:   S A V 0 0 5 -0 4  
P r ot o c ol  Titl e:   A  P h as e III, r a n d o mi z e d,  d o u bl e -bli n d,  pl a c e b o -c o ntr oll e d st u d y  of  A er o V a n c f or t h e 
tr e at m e nt  of  p ersist e nt  m et hi cilli n-r esist a nt St a p h yl o c o c c us  a ur e us  l u n g i nf e cti o n i n  c ysti c fi br osis 
p ati e nts  
Pr ot o c ol  D at e:   1 8 -A pr -2 0 1 8  
 
 
  
 
I n v esti g at or  Si g n at ur e  
  
D at e  
 
Pri nt  N a m e  a n d  Titl e  
 
Sit e  #  
 
 
PI  N a m e   
 
Sit e  N a m e   
 
A d dr ess   
 
 
 
 
 
 
 
P h o n e  N u m b er   
 
 
 
 


S a v ar a  P h ar m a c e uti c al s  
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
4 
S Y N O P SI S  
Titl e:  
A  P h as e III, r a n d o mi z e d,  d o u bl e -bli n d,  pl a c e b o -c o ntr oll e d st u d y  of  A er o V a n c 
f or t h e tr e at m e nt  of  p ersist e nt  m et hi cilli n-r esi st a nt St a p h yl o c o c c us  a ur e us  l u n g 
i nf e cti o n i n  c ysti c fi br osis  p ati e nt s 
St u d y  D r u g:   
A er o V a n c ( v a n c o m y ci n  h y dr o c hl ori d e i n h al ati o n  p o w d er),  3 0  m g  BI D  
N u m b e r  of  St u d y 
C e nt e rs:  
A p pr o xi m at el y  8 5  
P h as e:  
III 
N u m b e r  of  S u bj e cts:    2 0 0 s u bj e cts ( 1 5 0 s u bj e cts  ≤  2 1  y e ars  ol d,  5 0 s u bj e ct s  >  2 1  y e ars  ol d)  
 
C o o r di n ati n g 
I n v esti g at o r: 
P atri c k  Fl u m e,  M D  
St u d y  D esi g n:   
R a n d o mi z e d,  m ulti c e nt er,  d o u bl e -bli n d,  pl a c e b o -c o ntr oll e d,  p ar all el -gr o u p 
st u d y t o  e x a mi n e t h e s af et y  a n d  effi c a c y  of  A er o V a n c i n t h e tr e at m e nt  of 
p ersist e nt  M et hi cilli n r esi st a nt  St a p h yl o c o c c us  a ur e us  (M R S A ) l u n g i nf e cti o n 
i n  p ati e nt s  di a g n os e d  wit h  c ysti c fi br osis ( C F). 
Aft er  t h e  Scr e e ni n g  p eri o d ( u p t o  4 2  d a ys)  t o  c o nfir m st u d y  eli gi bilit y, s u bj e cts 
will  b e  r a n d o ml y  assi g n e d i n  a  bli n d e d f as hi o n t o r e c ei v e  eit h er  A er o V a n c  30 
m g t wi c e  d ail y ( BI D ),  or  pl a c e b o BI D  ( 1: 1  a cti v e t o  pl a c e b o)  b y i n h al ati o n f or 
2 4  w e e ks  or  3  d osi n g  c y cl es ( P eri o d  1).  U p o n  c o m pl eti o n  of  P eri o d  1, s u bj e cts 
will r e c ei v e  o p e n -l a b el  A er o V a n c  30  m g  BI D  f or  a n  a d diti o n al  2 4  w e e ks  or 
3  d osi n g  c y cl es ( P eri o d  2), t o  e v al u at e l o n g -t er m s af et y  of  A er o V a n c.  
A  d osi n g  c y cl e is  d efi n e d  as  2 8  d a ys  of tr e at m e nt f oll o w e d  b y  2 8  d a ys  of 
o bs er v ati o n.  S u bj e cts  m e eti n g t h e i n cl usi o n /  e x cl usi o n  crit eri a  will  b e str atifi e d 
u p o n r a n d o mi z ati o n  o n t h e  b asi s  of  ( a) a g e ( 6 – 2 1 ; >  2 1 ), ( b) B as eli n e  F E V 1 
( ≥ 6 0 %;  < 6 0 %), (c)  pri or  e x a c er b ati o ns tr e at e d  wit h  a nti bi oti cs  d uri n g t h e 
pr e vi o us  1 2  m o nt hs ( 1 -2;  ≥  3)  a n d ( d)  P.  a er u gi n os a  tr e at m e nt (n ot tr e at e d; 
tr e at e d).  
S u bj e cts  o n  a  2 8 -d a y  c y cli c al  o n/ off  a nti -Ps e u d o m o n al  a nti bi oti c r e gi m e n  will 
e nt er t h e  S cr e e ni n g  p eri o d  at  a ti m e s u c h t h at t h e  B as eli n e  visit  c oi n ci d es  wit h 
t h e  e n d  of t h eir  a nti-Ps e u d o m o n as  a nti bi oti c  c y cl e.  St u d y  dr u g  will t h er e b y  b e 
a d mi nist er e d  d uri n g t h e  off -c y cl e,  a n d s u bj e ct s  c a n t h e n r es u m e  a nti -
Ps e u d o m o n al t h er a p y  d uri n g t h e  2 8 -d a y  o bs er v ati o n  p eri o d ( W e e k  5 t hr o u g h 
W e e k  8).  S u bj e ct s  c o nti n ui n g  alt er n ati n g  a nti -Ps e u d o m o n al t h er a p y  c a n 
c o nti n u e t h eir tr e at m e nt  d uri n g t h e st u d y  dr u g  a d mi nistr ati o n,  a n d  o bs er v ati o n 
p eri o d.   


S a v ar a  P h ar m a c e uti c al s  
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
5 
 
2 0 0 s u bj e cts ( 1 5 0 s u bj e cts  ≤  2 1  y e ars  ol d,  5 0 s u bj e ct s  >  2 1  y e ars  ol d)  
T r e at m e nt:   
A er o V a n c  is  a  p o w d er f or m  of  v a n c o m y ci n,  d eli v er e d  usi n g  a r el o a d a bl e 
c a ps ul e i n h al er.  T h e i n h al ati o n  p o w d er is  p a c k a g e d i nt o  c a ps ul es  wit h  e a c h 
c a ps ul e  c o nt ai ni n g  1 5  m g  of  v a n c o m y ci n.  T h e  d os e is  A er o V a n c  3 0  m g 
( 2 c a ps ul es)  BI D .  Alt er n ati v el y,  a s u bj e ct  m a y  b e r a n d o mi z e d t o r e c ei v e  a 
m at c hi n g  pl a c e b o,  wit h  e q ui v al e nt  n u m b ers  of  c a ps ul es.   
St u d y  D u r ati o n:  
T h e  d ur ati o n  of st u d y  p arti ci p ati o n f or  e a c h s u bj e ct is  5 0 -5 4  w e e ks:  
-  S cr e e ni n g  p eri o d,  u p t o  4 2  d a ys  
-  P eri o d  1,  D o u bl e -bli n d ( 3 0  m g  A er o V a n c  or  pl a c e b o  BI D) f or  3  c y cl es 
or  2 4  w e e ks   
-  P eri o d  2,  O p e n -l a b el ( 3 0  m g  A er o V a n c  BI D) f or  3  c y cl es  or  2 4  w e e ks 
St u d y  P o p ul ati o n:  
I n cl usi o n  C rit e ri a  
1.   S u bj e cts  ≥  6  y e ars  of  a g e  at ti m e  of I nf or m e d  C o ns e nt  F or m (I C F)  or 
Ass e nt  F or m si g ni n g.   
2.   C o nfir m e d  di a g n osis  of  C F,  d et er mi n e d  b y  h a vi n g  cli ni c al f e at ur es 
c o nsi st e nt  wit h t h e  C F  p h e n ot y p e,  pl us  o n e  of t h e f oll o wi n g:  
a.   P ositi v e s w e at  c hl ori d e t est ( v al u e  ≥   60  m E q/ L),   
b.   G e n ot y p e  wit h  2  m ut ati o ns  c o nsi st e nt  wit h  C F (i . e.,  a  m ut ati o n 
i n  e a c h  of t h e  c ysti c fi br osis tr a ns m e m br a n e  c o n d u ct a n c e 
r e g ul at or [ C F T R]  g e n es). 
3.   P ositi v e s p ut u m  c ult ur e  or  a t hr o at s w a b  c ult ur e f or  M R S A  at 
S cr e e ni n g.   
4.   I n  a d diti o n t o t h e  S cr e e ni ng s a m pl e,  h a v e  at l e ast  2  pri or s p ut u m  or 
t hr o at s w a b  c ult ur es  p ositi v e f or  M R S A,  of  w hi c h  at l e ast  1 s a m pl e is 
m or e t h a n  6  m o nt hs  pri or t o  S cr e e ni n g.  At l e ast  5 0 %  of  all  M R S A 
c ult ur es (s p ut u m  or t hr o at s w a b  c ult ur e)  c oll e ct e d  fr o m t h e ti m e  of t h e 
first  p ositi v e c ult ur e  (i n t h e  pr e vi o us  1  y e ar) m ust  h a v e t est e d  p ositi v e 
f or  M R S A. ( N ot e:  S cr e e ni n g  s a m pl e  m a y  c o u nt t o w ar ds  5 0 %  p ositi v e 
c o u nt)  
5.   F or c e d  e x pir at or y  v ol u m e i n  1 s e c o n d ( F E V 1)  ≥ 3 0 %  a n d  ≤  9 0 %  of 
pr e di ct e d t h at is  n or m al f or  a g e,  g e n d er, r a c e,  a n d  h ei g ht,  usi n g t h e 
Gl o b al  L u n g  F u n cti o n I niti ati v e ( G LI)  e q u ati o n.  
6.   At l e ast  1  e pis o d e  of  a c ut e  p ul m o n ar y i nf e cti o n tr e at e d  wit h  n o n -
m ai nt e n a n c e  a nti bi oti cs  wit hi n  1 2  m o nt hs  pri or t o t h e  B as eli n e  vi sit. 
(I niti ati o n  of tr e at m e nt  wit h i nt er mitt e nt i n h al e d a nti -Ps e u d o m o n al 
t h er a p y  will  n ot  q u alif y  as tr e at m e nt  wit h  n o n-m ai nt e n a n c e  a nti bi oti cs).  


S a v ar a  P h ar m a c e uti c al s  
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
6 
St u d y  P o p ul ati o n:   
I n cl usi o n  C rit e ri a  ( c o nt) 
7.   If f e m al e  of  c hil d b e ari n g  p ot e nti al,  a n  a c c e pt a bl e  m et h o d  of 
c o ntr a c e pti o n  m ust  b e  us e d  d uri n g  t h e st u d y  a n d  m ust  b e  c o m bi n e d 
wit h  a  n e g ati v e  pr e g n a n c y t est  o bt ai n e d  d uri n g  S cr e e ni n g;  s e xu all y 
a cti v e  m al e s u bj e ct s  of r e pr o d u cti v e  p ot e nti al  w h o  ar e  n o n -st eril e (i. e., 
m al e  w h o  h as  n ot  b e e n st erili z e d  b y  v as e ct o m y f or  at l e ast  6  m o nt hs , 
a n d  w er e  n ot  di a g n os e d  wit h  i nf ertilit y t hr o u g h  d e m onstr ati o n  of 
a z o os p er mi a i n  a s e m e n s a m pl e  a n d/ or  a bs e n c e  of  v as  d ef er e ns t hr o u g h 
ultr as o u n d )  m ust  b e  willi n g t o  us e  a b arri er  m et h o d  of  c o ntr a c e pti o n ,  or 
t h eir f e m al e p art n er  m ust  us e  a n  a c c e pt a bl e  m et h o d  of  c o ntr a c e pti o n , 
d uri n g  t h e st u d y. 
F or  p ur p os es  of t his  st u d y, t h e  S p o ns or  d efi n es  “ a c c e pt a bl e  m et h o ds  of 
c o ntr a c e pti o n ”  as:  
a.   Or al  birt h  c o ntr ol  pills  a d mi nist er e d f or  at l e ast  1  m o nt hl y  c y cl e 
pri or t o  a d mi nistr ati o n  of t h e st u d y  dr u g . 
b.   A  s y nt h eti c  pr o g esti n i m pl a nt e d r o d ( e g, I m pl a n o n ® ) f or  at l e ast 
1  m o nt hl y  c y cl e  pri or t o t h e  st u d y  dr u g  a d mi nistr ati o n  b ut  n ot 
b e y o n d t h e  4 t h s u c c essi v e  y e ar f oll o wi n g i ns erti o n . 
c.   I ntr a ut eri n e  d e vi c es (I U Ds), i ns ert e d  b y  a  q u alifi e d  cli ni ci a n f or 
at l e ast  1  m o nt hl y  c y cl e  pri or t o st u d y  dr u g  a d mi nistr ati o n.  
d.   M e dr o x y pr o g est er o n e a c et at e ( e g,  D e p o -Pr o v er a ® ) a d mi nist er e d 
f or  a  mi ni m u m  of  1  m o nt hl y  c y cl e  pri or t o  a d mi nistr ati o n  of t h e 
st u d y  dr u g  a n d  c o nti n ui n g  t hr o u g h  1    m o nt h  f oll o wi n g  st u d y 
c o m pl eti o n.  
e.   H yst er e ct o m y  or s ur gi c al st erili z ati o n.  
f.  A bsti n e n c e.  
g.   D o u bl e  b arri er  m et h o d ( di a p hr a g m  wit h s p er mi ci d al  g el  or 
c o n d o ms  wit h  c o ntr a c e pti v e f o a m).  
N O T E :  F or s u bj e cts  pr es cri b e d  Or k a m bi:  Or k a m bi  m a y s u bst a nti all y 
d e cr e as e  h or m o n al  c o ntr a c e pti v e  e x p os ur e, r e d u ci n g t h e  eff e cti v e n ess 
a n d i n cr e asi n g t h e i n ci d e n c e  of  m e nstr u ati o n -ass o ci at e d  a d v ers e 
r e a cti o ns.  H or m o n al  c o ntr a c e pti v es, i n cl u di n g  or al, i nj e ct a bl e, 
tr a ns d er m al,  a n d i m pl a nt a bl e, s h o ul d  n ot  b e r eli e d  u p o n  as  a n  eff e cti v e 
m et h o d  of  c o ntr a c e pti o n  w h e n  c o -a d m i ni st er e d  wit h  Or k a m bi. 
 
8.   A bl e  a n d  willi n g t o  c o m pl y  wit h t h e  pr ot o c ol, i n cl u di n g  a v ail a bilit y f or 
all s c h e d ul e d st u d y  vi sits  a n d  a bl e t o  p erf or m  all t e c h ni q u es  n e c ess ar y 
t o  us e t h e  A er o V a n c i n h al er  a n d  m e as ur e l u n g f u n cti o n. 
9.   A gr e e  n ot t o s m o k e  d uri n g  a n y  p art  of t h e  cli ni c al tri al ( S cr e e ni n g  vi sit 
t hr o u g h  e n d  of st u d y). 
1 0.  S u bj e cts  wit h  a  P.  a er u gi n os a  c o -i nf e cti o n  m ust  eit h er  b e st a bl e  o n  a 
r e g ul ar s u p pr essi o n r e gi m e n  of i n h al e d  a nti bi oti cs  or  m ust  b e, i n t h e 
o pi ni o n  of t h e I n v esti g at or, st a bl e  d es pit e t h e l a c k  of s u c h tr e at m e nt.  


S a v ar a  P h ar m a c e uti c al s  
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
7 
 
E x cl usi o n  C rit e ri a  
1.   Us e  of  a nti -M R S A tr e at m e nts  pr es cri b e d  as  m ai nt e n a n c e t h er a p y 
(i ntr a v e n o us [I V]  or i n h al e d tr e at m e nt  wit hi n  2 8  d a ys;  or al tr e at m e nt 
wit hi n  1 4  d a ys)  pri or t o t h e  B as eli n e  visit.     
2.   Us e  of  n o n -m ai nt e n a n c e  a nti bi oti c  f or  p ul m o n ar y i nf e cti o n  or 
e xtr a p ul m o n ar y  M R S A i nf e cti o n  (I V  or i n h al e d  a nti bi oti c  wit hi n  2 8 
d a ys;  or al  a nti bi oti c  wit hi n  1 4  d a ys)  pri or t o t h e  B as eli n e  visit.     
3.   Hist or y  of  pr e vi o us  all er gi es  or s e nsiti vit y t o  v a n c o m y ci n,  or  ot h er 
c o m p o n e nt(s)  of t h e st u d y  dr u g  or  pl a c e b o  e x c e pt f or  a  hist or y  of r e d -
m a n s y n dr o m e.  
4.   I n a bilit y t o t ol er at e i n h al e d  pr o d u cts. 
5.   First ti m e  s p ut u m  c ult ur e  or t hr o at s w a b  c ult ur e  yi el di n g  B.  c e p a ci a ,  or 
n o nt u b er c ul o us  M y c o b a ct eri a i n t h e  pr e vi o us  6  m o nt hs  t o  S cr e e ni n g.  
6.   Hist or y  of l u n g  or  ot h er  s oli d  or g a n tr a ns pl a nt ati o n  or  c urr e ntl y  o n t h e 
list t o r e c ei v e l u n g  or  ot h er s oli d  or g a n tr a ns pl a nt ati o n. 
7.   R esist a n c e t o  v a n c o m y ci n  at  S cr e e ni n g ( v a n c o m y ci n r esi st a nt 
St a p h yl o c o c c us  a ur e us  [ V R S A],  or  v a n c o m y ci n i nt er m e di at e r esist a nt 
St a p h yl o c o c c us  a ur e us  [ VI S A],  wit h  mi ni m u m i n hi bit or y  c o n c e ntr ati o n 
[ MI C]  ≥ 8  µ g/ m L).  
8.   Or al  c orti c ost er oi ds i n  d os es  e x c e e di n g  1 0  m g  pr e d nis o n e  p er  d a y  or 
2 0  m g  pr e d nis o n e  e v er y  ot h er  d a y,  or  e q ui p ot e nt  d os e s  of ot h er 
c orti c ost er oi d s. 
9.   C h a n g es i n  a nti mi cr o bi al,  br o n c h o dil at or,  a nti -i nfl a m m at or y  or 
c orti c ost er oi d  m e di c ati o ns  wit hi n  1 4  d a ys , or  c h a n g es i n  C F T R 
m o d ul at ors  wit hi n  2 8  d a ys,  pri or t o t h e  B as eli n e  vi sit.  
1 0.  A b n or m al l a b or at or y fi n di n gs  or  ot h er fi n di n gs  or  m e di c al  hi st or y  at 
S cr e e ni n g t h at, i n t h e I n v esti g at or's  o pi ni o n,  w o ul d  c o m pr o mis e t h e 
s af et y  of t h e s u bj e ct  or t h e  q u alit y  of t h e st u d y  d at a.  
1 1.  I n a bilit y t o t ol er at e i n h al ati o n  of  a s h ort  a cti n g  b et a 2  a g o ni st 
1 2.  S p O 2 < 9 0 %  at  S cr e e ni n g.  
1 3.  C h a n g es i n  p h ysi ot h er a p y t e c h ni q u e  or  p h ysi ot h er a p y s c h e d ul e d  wit hi n 
1  w e e k  of t h e  B as eli n e  vi sit.  
1 4.  A d mi nistr ati o n  of  a n y i n v esti g ati o n al  dr u g  or  d e vi c e  wit hi n  4  w e e ks 
pri or t o t h e  S cr e e ni n g  visit  a n d  d uri n g t h e st u d y  
1 5.  F e m al e  wit h  p ositi v e  pr e g n a n c y t est r es ult  d uri n g  S cr e e ni n g,  pr e g n a nt 
( or i nt e n ds t o  b e c o m e  pr e g n a nt), l a ct ati n g  or i nt e n ds t o  br e astf e e d 
d uri n g t h e st u d y.  
1 6.  R e n al i ns uffi ci e n c y,  d efi n e d  as  cr e ati ni n e  cl e ar a n c e  <  5 0  m L/ mi n  usi n g 
t h e  C o c k cr oft-G a ult  e q u ati o n f or  a d ults  or  S c h w art z  e q u ati o n f or 
c hil dr e n  at t h e  S cr e e ni n g  visit.  
1 7.  A b n or m al li v er f u n cti o n,  d efi n e d  as  ≥  4 x  u p p er li mit  of  n or m al ( U L N), 
of s er u m  as p art at e  a mi n otr a nsf er as e ( A S T)  or s er u m  al a ni n e 
a mi n otr a nsf er as e ( A L T),  or  k n o w n  cirr h osi s  at  S cr e e ni n g.  
 


S a v ar a  P h ar m a c e uti c al s  
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
8 
 
E x cl usi o n  C rit e ri a  ( C o nt.) 
1 8.  Di a g n os e d  wit h  cli ni c all y  si g nifi c a nt  h e ari n g l oss.  
1 9.  Hist or y  of  p ositi v e r es ult  f or  h u m a n i m m u n o d efi ci e n c y  vir us ( HI V), 
h e p atitis  B  vir us ( H B V)  or  h e p atiti s  C  vir us ( H C V).  
2 0.  Pl a n n e d  h os pit ali z ati o ns f or  pr o p h yl a xis  a nti bi oti c tr e at m e nt  wit hi n  2 8 
d a ys  pri or t o  B as eli n e  visit  or  d uri n g t h e  d o u bl e -bli n d  p eri o d ( P eri o d 
1).  
P ri m a r y  Effi c a c y 
E n d p oi nt:  
T h e  pri m ar y  effi c a c y  e n d p oi nt is t h e  m e a n  a bs ol ut e  c h a n g e fr o m  b as eli n e i n 
F E V 1 p er c e nt  pr e di ct e d.  T h e  e n d p oi nt  will  b e  a n al y z e d s e q u e nti all y  at  W e e k  4 
( e n d  of  C y cl e  1),  W e e k  1 2 ( e n d  of  C y cl e  2), a n d  at  W e e k  2 0 ( e n d  of  C y cl e  3) . 
•   If  A er o V a n c i s s u p eri or t o  pl a c e b o  aft er  C y cl e  1, t h e n t h e  m e a n  c h a n g e i n 
t h e  F E V1 p er c e nt  pr e di ct e d  aft er  C y cl e  2  will  b e  a n al y z e d  a n d if  A er o V a n c 
is s u p eri or t o  pl a c e b o  aft er  C y cl e  2, t h e n t h e  m e a n  c h a n g e i n t h e  F E V1 
p er c e nt  pr e di ct e d  aft er  C y cl e  3  will  b e  a n al y z e d.  
•   T h e  pri m ar y  a n al ysis  will  b e  b as e d  o n t h e  I T T  p o p ul ati o n  of all  r a n d o mi z e d 
s u bj e cts ≤  2 1  y e ars  of  a g e .  
S e c o n d a r y  Effi c a c y 
E n d p oi nt s: 
T h e f oll o wi n g  p ar a m et ers  will  b e  a n al y z e d  as  s e c o n d ar y  effi c a c y  e n d p oi nts:  
•   T i m e t o first p ul m o n ar y  e x a c er b ati o n  r e q uiri n g us e  of  a n ot h er  a nti bi oti c 
m e di c ati o n ( or al,  I V, a n d/ or i n h al e d) .  
•   C h a n g e fr o m  B as eli n e i n t h e  C ysti c  Fi br osi s  Q u esti o n n air e -R e vis e d ( C F Q -
R) s c or es  at  W e e ks  4 ,  1 2, a n d  2 0.   
•   C h a n g e fr o m  B as eli n e i n t h e  C ysti c  Fi br osi s  R es pir at or y  S y m pt o m  Di ar y -
C hr o ni c  R es pir at or y  S y m pt o m  S c or e ( C F R S D -C RI S S)  s c or es  at  W e e ks  4,  
1 2,  a n d  2 0.  
•   R el ati v e  c h a n g e fr o m  B as eli n e i n  F E V 1 p er c e nt  pr e di ct e d  at  W e e ks  4 ,  1 2, 
a n d  2 0.  
•   T h e  n u m b er  of s u c c essf ul r es p o ns e  c y cl es  a s u bj e ct  a c hi e v es  o v er  P eri o d  1  
( W e e ks 4,  1 2 , a n d  2 0) .  
If  a s u bj e ct  e x p eri e n c es a n  e x a c er b ati o n  a n d  c o n c o mit a nt  a nti bi oti c 
t h er a p y is  gi v e n, t h e s u bj e ct is  c o nsi d er e d  a f ail ur e i n t h at  c y cl e, b ut t h e 
f ail ur e  d o es  n ot  pr e cl u d e s u c c ess i n f ut ur e  c y cl es. 
N ot e:  A r es p o ns e i n  a  c y cl e i s  d efi n e d  b y  at l e ast  a  5  % r el ati v e 
i m pr o v e m e nt i n  F E V1 p er c e nt  pr e di ct e d  at t h e  e n d  of t h e r es p e cti v e 
c y cl e ( W e e k  4,  W e e k  1 2,  a n d  W e e k  2 0). If t h e r el ati v e  F E V 1 
i m pr o v e m e nt i s l ess t h a n  5  %, t h e s u bj e ct i s  c o nsi d er e d  a f ail ur e i n t h at 
c y cl e,  b ut t h e f ail ur e  d o es  n ot  pr e cl u d e s u c c ess i n f ut ur e  c y cl es.  
•   Fr e q u e n c y  of  p ul m o n ar y  e x a c er b ati o ns . 
•   Ar e a  u n d er t h e  F E V 1 –  ti m e  pr ofil e, i. e. t h e m e a n tr e at m e nt  diff er e n c e i n 
F E V 1 a cr oss  all  p ost -b as eli n e  visits.  
 


S a v ar a  P h ar m a c e uti c al s  
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
9 
E x pl o r at o r y 
Effi c a c y  E n d p oi nts:  
•   C h a n g es fr o m  B as eli n e i n  E Q -5 D -5 L/ E Q -5 D y s c or es  at  W e e ks  4 ,  1 2, a n d 
2 0 . 
•   C h a n g e fr o m  B as eli n e i n  M R S A s p ut u m  d e nsit y  at  W e e ks  4 ,  1 2, a n d  2 0.  
•   C h a n g e fr o m  B as eli n e i n  b o d y  w ei g ht  at  W e e ks  8 ,  1 6, a n d  2 4.  
•   C h a n g e fr o m  B as eli n e i n  MI C f or  V a n c o m y ci n  a t  W e e ks  4,  1 2  a n d  2 0. 
•   E m er g e n c e  of  a d diti o n al  p at h o g e ns  i n s p ut u m. 
P h a r m a c o ki n eti cs:   
P h ar m a c o ki n eti cs  will  b e st u di e d  as  a s u b -st u d y  of  a p pr o xi m at el y  1 0 0 s u bj e cts, 
wit h tr o u g h  pl as m a  a n d  s p ut u m s a m pl es c oll e ct e d  as  p er t h e  S c h e d ul e  of 
E v e nt s . 
S af et y:  
S af et y  ass ess m e nts  will  b e  c o n d u ct e d  o n t h e s af et y  p o p ul ati o n (t h os e r e c ei vi n g 
at l e ast  1  d os e  of  dr u g)  i n cl u d e  a n al ysis  of  all  a d v ers e  e v e nts ( A Es),  as  w ell  as 
st a n d ar d  h e m at ol o g y,  bi o c h e mistr y,  a n d  uri n e  a n al ys es,  vit al si g ns,  p h ysi c al 
e x a mi n ati o n, s pir o m etr y,  p ul m o n ar y f u n cti o n t est s ( P F T)  a n d 
el e ctr o c ar di o gr a m ( E C G).  P ot e nti al  e m er g e n c e  of  a d diti o n al  p a t h o g e ns i n 
s p ut u m will  b e  ass ess e d . 
S a m pl e  Si z e   
A t ot al  of  2 0 0 s u bj e cts  will  b e  e nr oll e d i nt o t h e st u d y ( 1 5 0 s u bj e ct s  ≤  2 1  y e ars 
ol d,  5 0 s u bj e cts  >  2 1  y e ars  ol d).  
T h e  pri m ar y  a n al ysis  p o p ul ati o n  will  b e t h e s u bj e cts  ≤  2 1  y e ars  of  a g e. I n t h e 
si n gl e  c y cl e  P h as e II  st u d y,  wit h  missi n g  d at a i m p ut e d  usi n g  c o ns er v ati v e r ul es 
a d o pt e d  b y t h e  U nit e d  St at es  F o o d  a n d  Dr u g  A d mi nistr ati o n ( F D A ),  a 
diff er e n c e i n t h e  m e a n  a bs ol ut e  c h a n g e i n  F E V 1 p er c e nt  pr e di ct e d  of  4. 3  %  a n d 
a r o ot  m e a n s q u ar e  d e vi ati o n  of  6. 3  %  w er e  o bs er v e d  b et w e e n t h e tr e at m e nt 
ar ms i n  s u bj e cts  <  2 1  y e ars  of  a g e.  B as e d  o n t h es e  n u m b ers,  a s a m pl e si z e  of  4 5 
s u bj e cts  p er  ar m  w o ul d  pr o vi d e  8 9  %  p o w er t o  d et e ct  a st ati sti c all y si g nifi c a nt 
diff er e n c e  at  al p h a l e v el  of  0. 0 5.  T o  a c c o u nt f or  p ot e nti al  dr o p  o uts  a n d/ or 
s m all er eff e ct si z e i n  a  3- c y cl e st u d y,  a s a m pl e si z e  of  7 5  s u bj e cts p er  ar m  will 
b e  e nr oll e d  w hi c h , if  all  c o m pl et e d, w o ul d  pr o vi d e  9 0 %  p o w er t o  d et e ct  a 
diff er e n c e  of  3. 4 %  at  2 0  w e e ks  ass u mi n g t h e s a m e st a n d ar d  d e vi ati o n  of  6. 3 %. 
I n a d diti o n,  a p pr o xi m at el y  2 5  p ati e nt s  p er  ar m i n t h e  o v er  2 1 -y e ar  a g e  gr o u p 
will  b e i n cl u d e d.  
St atisti c al 
M et h o ds/ A n al ysis:   
All st atisti c al  t esti n g  will  b e t w o-si d e d  a n d  will  b e  p erf or m e d  at t h e  0. 0 5 
si g nifi c a n c e l e v el.   D es cri pti v e st atisti cs  will  b e  pr o vi d e d  b y tr e at m e nt  gr o u p  at 
b as eli n e  a n d  at  e a c h  criti c al ti m e  p oi nt.   C at e g ori c al  v ari a bl es  will  b e 
s u m m ari z e d  b y  c o u nt s  a n d  b y  p er c e nt a g e  of s u bj e ct s i n  c orr es p o n di n g 
c at e g ori es.  C o nti n u o us  v ari a bl es  will  b e s u m m ari z e d  wit h  m e a ns, st a n d ar d 
d e vi ati o ns,  m e di a ns,  mi ni m u m s,  a n d  m a xi m u ms.  
 T h e f oll o wi n g  p o p ul ati o ns  will  b e  us e d f or  effi c a c y  a n al ys es:   
- T h e  I T T  p o p ul ati o n  will i n cl u d e  all r a n d o mi z e d s u bj e cts ≤  2 1  y e ars  of  a g e . 
- T h e  P er -Pr ot o c ol ( P P)  p o p ul ati o n  will i n cl u d e  s u bj e cts  ≤  2 1  y e ars  of  a g e  w h o 
a d h er e t o  all  k e y  pr ot o c ol  pr o c e d ur es, t o  b e s p e cifi e d i n  a s e p ar at e  St atisti c al 
A n al ysi s  Pl a n ( S A P).  


S a v ar a  P h ar m a c e uti c al s  
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
1 0 
Effi c a c y  A n al ysis :  
A n al ysis  of  P ri m a r y  a n d  S e c o n d a r y  E n d p oi nts   
Pri m ar y  a n d s e c o n d ar y  effi c a c y  a n al ys es, f or  w hi c h f ull  c o ntr ol  of  T y p e I  err or 
will  b e i m pl e m e nt e d,  will  b e  i n t h e gr o u p  of  p ati e nt s  w h o  ar e  ≤  2 1  y e ars  of  a g e.  
T h e  pri m ar y  effi c a c y  e n d p oi nt is t h e  m e a n  a bs ol ut e  c h a n g e fr o m  b as eli n e i n 
F E V 1 p er c e nt  pr e di ct e d.  T h e  e n d p oi nt  will  b e  a n al y z e d s e q u e nti all y  at  W e e k  4 
( e n d  of  C y cl e  1),  W e e k  1 2 ( e n d  of  C y cl e  2) a n d  at  W e e k  2 0 ( e n d  of  C y cl e  3). If 
a st atisti c all y si g nifi c a nt  diff er e n c e i s  o bs er v e d i n f a v or  of  A er o V a n c  c o m p ar e d 
t o  pl a c e b o  aft er  C y cl e  1, t h e n t h e  m e a n  c h a n g e i n t h e  F E V1 p er c e nt  pr e di ct e d 
fr o m  B as eli n e t o  e n d  of  C y cl e  2 will  b e  a n al y z e d . Si mil arl y, if t h e  eff e ct  aft er 
C y cl e  2 is st ati sti c all y si g nifi c a nt, t h e n t h e  a n al ysi s  of  B as eli n e t o  e n d  of  C y cl e 
3  will  b e r e p ort e d.  T h e  d at a  will  b e  a n al y z e d  usi n g  a n  a n al ysis  of  c o v ari a n c e 
m o d el  wit h  b as eli n e  F E V 1 p er c e nt  pr e di ct e d  as  a  c o v ari at e  a n d t h e str atifi c ati o n 
f a ct ors  as fi x e d  eff e cts. 
F or  c o nfir m ati o n  of t h e  pri m ar y  e n d p oi n t, s e nsiti vit y  a n al ys es  will  b e 
c o n d u ct e d  w h er e  missi n g  d at a  will  b e i m p ut e d i n  diff er e nt  w a ys.   
 
Of t h e s e c o n d ar y  e n d p oi nts,  th e  dist ri b uti o ns  of ti m e t o first p ul m o n ar y 
e x a c er b ati o n  will  b e  c o m p ar e d  b et w e e n t h e tr e at m e nt  ar ms  usi n g  a  C o x 
pr o p orti o n al  h a z ar ds r e gr essi o n  m o d el i n cl u di n g t h e  eff e cts  of tr e at m e nt  gr o u p  
a n d t h e  str a tifi c ati o n f a ct ors. T h e  n u m b er  of  d a ys fr o m  r a n d o mi z ati o n u ntil t h e 
d at e  of first  e x a c er b ati o n  will  b e  c al c ul at e d  a n d s u m m ari z e d  usi n g  a  K a pl a n -
M ei er lif e t a bl e  pr es e nt ati o n.  S u bj e ct s  w h o  d o  n ot e x p eri e n c e  a  p ul m o n ar y 
e x a c er b ati o n  pri or t o  dis c o nti n u ati o n fr o m t h e st u d y  will  b e  c e ns or e d  at t h e  d at e 
of  dis c o nti n u ati o n  of t h e  st u d y. 
C h a n g es i n  C F Q - R a n d  C F R S D -C RI S S s c or e,  a n d r el ati v e  c h a n g e fr o m 
b as eli n e i n  F E V 1 p er c e nt  pr e di ct e d , will  all  b e  a n al y z e d si mil arl y  at  W e e k  4 , 
1 2,  a n d  2 0  usi n g  a n  a n al ysis  of  c o v ari a n c e i n cl u di n g  b as eli n e  c o v ari at e  a n d 
str atifi c ati o n f a ct ors.   
T h e  n u m b er  of s u c c essf ul r es p o ns e  c y cl es  e a c h s u bj e ct  a c hi e v es  o v er t h e  3 
c y cl es  of t h er a p y ( 0,  1,  2  or  3)  will  b e  c o m p ar e d  usi n g  a  pr o p orti o n al  o d ds 
m o d el f o r  or d er e d  c at e g ori es. 
Fr e q u e n c y  of  p ul m o n ar y  e x a c er b ati o ns  will  b e  c o m p ar e d  b et w e e n t h e  gr o u ps 
usi n g  a  n e g ati v e  bi n o mi al  m o d el f or  c o u nt  d at a,  a dj usti n g f or  e a c h  s u bj e ct’s 
l e n gt h  of f oll o w-u p.   T h e r a n d o mi z ati o n str atifi c ati o n f a ct ors  will  b e i n cl u d e d 
i n t h e  m o d el  as fi x e d  eff e cts. 
Ar e a  u n d er t h e  F E V 1– ti m e  pr ofil e  will  b e  a n al y z e d  usi n g  a n al ysi s  of  c o v ari a n c e 
i n cl u di n g t h e  p ati e nt’s  b as eli n e  F E V1 a n d t h e  str atifi c ati o n f a ct ors.  
T y p e I  err or r at e  will  b e  c o ntr oll e d  b y  a s e q u e nti al t esti n g  pr o c e d ur e.  
F or  p ati e nts  w h o  ar e  > 2 1  y e ars  of  a g e, t h e  a b o v e  a n al ys es  will  b e r e p e at e d  b ut 
wit h  a n  e m p h asi s  o n  esti m ati o n  of t h e tr e at m e nt  eff e ct, r at h er t h a n st ati sti c al 
si g nifi c a n c e t esti n g.   N o  T y p e I  err or  c o ntr ol  will  b e  us e d f or t h e  a n al ys es  of 
t h es e s u bj e cts. 
N o i nt eri m  a n al ys es  ar e  pl a n n e d.  


S a v ar a  P h ar m a c e uti c al s  
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
1 1 
S af et y  A n al ysis   
E xt e nt  of  e x p os ur e  a n d  d osi n g  c o m pli a n c e  will  b e s u m m ari z e d  b y tr e at m e nt 
gr o u p.  
A d v ers e  e v e nt s  will  b e  m a p p e d t o  pr ef err e d t er ms  a n d s yst e m  or g a n  cl ass es 
usi n g t h e  M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es ( M e d D R A).  T h e 
i n ci d e n c e  of  A Es ( e v er  h a vi n g)  a n d t h e fr e q u e n c y  of  A Es (t ot al  n u m b er) a n d 
9 5 %  c o nfi d e n c e i nt er v al s will  b e t a b ul at e d  b y tr e at m e nt  gr o u p, s yst e m  or g a n 
cl ass,  a n d  pr ef err e d t er m.  S eri o us  a d v ers e  e v e nts ( S A Es)  will  b e s u m m ari z e d i n 
a si mil ar f as hi o n.  A d v ers e  e v e nt s u m m ari es  b y s e v erit y  a n d r el ati o ns hi p t o 
st u d y  dr u g  will  als o  b e  pr o vi d e d.  T h e  A E s u m m ari es  will  b e  pr es e nt e d f or  all 
s u bj e cts  a n d  b y  t h e t w o a g e  gr o u p s. 
L a b or at or y  p ar a m et ers  will  b e s u m m ari z e d  usi n g  d es cri pti v e st atisti cs  at 
B as eli n e  a n d  at  e a c h  p ost - Bas eli n e  vi sit.  C h a n g es fr o m  B as eli n e  will  als o  b e 
s u m m ari z e d. I n  a d diti o n, s hift t a bl es ( i. e., l o w-n or m al -hi g h  at  B as eli n e  v ers us 
l o w-n or m al -hi g h  at  e a c h  p ost -b as eli n e  vi sit i n  a  3 -b y -3  c o nti n g e n c y t a bl e)  will 
b e  pr o vi d e d t o  ass ess  c h a n g es fr o m  B as eli n e i n l a b or at or y  v al u es.  
Vit al si g ns  will  b e s u m m ari z e d  usi n g  d es cri pti v e st ati sti cs  at  B as eli n e  a n d  at 
e a c h  p ost -B as eli n e  vi sit.  C h a n g es fr o m  B as eli n e  will  als o  b e s u m m ari z e d.  
El e ctr o c ar di o gr a m  p ar a m et ers  will  b e s u m m ari z e d  usi n g  d es cri pti v e st atisti cs  at 
B as eli n e  a n d  at  e a c h  p ost - Bas eli n e  vi sit  w h er e  a n  E C G  ass ess m e nt  w as  m a d e. 
C h a n g es fr o m  B as eli n e  will  als o  b e s u m m ari z e d. I n  a d diti o n, s hift t a bl es ( i. e., 
n or m al,  n ot  cli ni c all y si g nifi c a nt [ N C S],  cli ni c all y si g nifi c a nt [ C S])  at  B as eli n e 
v ers us  n or m al,  N C S,  C S  at  e a c h  p ost -b as eli n e  visit i n  a  3 -b y -3  c o nti n g e n c y 
t a bl e)  will  b e  pr o vi d e d t o  ass ess  c h a n g es fr o m  B as eli n e.  
 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
1 2 
T A B L E  O F  C O N T E N T S 
 
A P P R O V A L  SI G N A T U R E S  
2  
S Y N O P SI S  
4  
LI S T I N G  O F  T A B L E S  
1 5  
LI S T I N G  O F  F I G U R E S  
1 5  
LI S T  O F  A B B R E VI A T I O N S 
1 6  
1   B A C K G R O U N D  
1 9  
2   
O v er vi e w  of  N o n -Cli ni c al  St u di es  ................................................................................... 2 0  
3   
O v er vi e w  of  Cli ni c al  St u di es  ........................................................................................... 2 1  
3. 1   P h as e I .............................................................................................................................. 2 1  
3. 2   P h as e II  ............................................................................................................................ 2 2  
3. 2. 1   D e m o gr a p hi cs  .................................................................................................................. 2 2  
3. 2. 2   M R S A  D e nsit y  ................................................................................................................. 2 3  
3. 2. 3   Pl as m a  a n d  S p ut u m  P h ar m a c o ki n eti cs  ............................................................................. 2 4  
3. 2. 3. 1   
P h ar m a c o ki n eti c  A n al ys es  ........................................................................................ 2 5  
3. 2. 4   S af et y  ............................................................................................................................... 2 7  
3. 2. 4. 1   
S eri o us  A d v ers e  E v e nts  ............................................................................................ 3 0  
3. 2. 5   Effi c a c y  R es ults  ............................................................................................................... 3 0  
3. 2. 5. 1   
S u bj e cts l ess t h a n  2 1  y e ars  of  a g e  ............................................................................. 3 0  
4   S T U D Y  R A TI O N A L E  
3 3  
5   S T U D Y  O B J E C TI V E S  
3 3  
5. 1   Pri m ar y  O bj e cti v e  ............................................................................................................ 3 3  
5. 2   S e c o n d ar y  O bj e cti v es  ....................................................................................................... 3 4  
6   I NV E S TI G A T I O N A L  P L A N  
3 4  
6. 1   St u d y  P o p ul ati o n  .............................................................................................................. 3 4  
6. 2   St u d y  D esi g n  .................................................................................................................... 3 4  
6. 3   Effi c a c y  a n d  S af et y  E v al u ati o ns  ...................................................................................... 3 5  
6. 4   I n cl usi o n  Crit eri a ............................................................................................................. 3 5  
6. 5   E x cl usi o n  Crit eri a  ............................................................................................................ 3 6  
6. 6   Crit eri a f or  T er mi n ati o n  of t h e  St u d y  ............................................................................... 3 7  
7   C O N C U R R E N T  M E DI C A TI O N S  
3 8  
7. 1   Pr o hi bit e d  M e di c ati o ns  a n d  Tr e at m e nts  ........................................................................... 3 8  
7. 2   A nti -Ps e u d o m o n as  A nti bi oti c  Tr e at m e nt  ......................................................................... 3 8  
8   S T U D Y  T R E A T M E N T  
3 8  
8. 1   A er o V a n c  F or m ul ati o n  .................................................................................................... 3 8  
8. 2   Pl a c e b o  F or m ul ati o n  ........................................................................................................ 3 9  
       8. 3      P a c k a gi n g  a n d  L a b eli n g  ................................................................................................... 3 9 
8. 4   S u p pl y  of  St u d y  Dr u g  at t h e  Sit e  ...................................................................................... 3 9  
       8. 5      D os a g e/ D os a g e  R e gi m e n  .................................................................................................4 0  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
1 3 
       8. 6      Dis p e nsi n g  ........................................................................................................................ 4 0 
8. 7   M et h o d  of  Assi g ni n g  S u bj e ct s t o  Tr e at m e nt  Gr o u ps  ........................................................ 4 0  
8. 8   Bli n di n g  a n d  U n bli n di n g  of  St u d y  M e di c ati o n  ................................................................ 4 0  
       8. 9       I n h al er  D e vi c e ................................................................................................................. 4 0 
       8. 1 0    A d mi nistr ati o n I nstr u cti o ns  .............................................................................................. 4 0 
       8. 1 1     St or a g e  ............................................................................................................................ 4 1 
8. 1 2   St u d y  Dr u g  A c c o u nt a bilit y  .............................................................................................. 4 1  
8. 1 3   Tr e at m e nt  C o m pli a n c e  ..................................................................................................... 4 1  
8. 1 4   D os e  A dj ust m e nt  .............................................................................................................. 4 1  
8. 1 5   A c c o u nt a bilit y  .................................................................................................................. 4 1  
9   S T U D Y  P R O C E D U R E S  A N D  G UI D E LI N E S  
4 1  
9. 1   Cli ni c al  Ass ess m e nts  ....................................................................................................... 4 2  
9. 1. 1   
C o n c o mit a nt  M e di c ati o ns  ......................................................................................... 4 2 
9. 1. 2   
D e m o gr a p hi cs ........................................................................................................... 4 2 
9. 1. 3   
M e di c al  Hist or y  ........................................................................................................ 4 2 
9. 1. 4   
P h ysi c al  E x a mi n ati o n  ............................................................................................... 4 2 
9. 1. 5   
Vit al  Si g ns  ................................................................................................................ 4 2 
9. 1. 6   
1 2 -l e a d  El e ctr o c ar di o gr a m ( E C G) ............................................................................ 4 2 
9. 1. 7   
C F R S D -C RI S S  ......................................................................................................... 4 2 
9. 1. 8   
C F Q - R ...................................................................................................................... 4 3 
9. 1. 9   
E Q -5 D -5 L  &  E Q -5 D y  .............................................................................................. 4 3 
9. 1. 1 0   
P ul m o n ar y  F u n cti o n  T est s ( P F T)  .............................................................................. 4 3 
9. 1. 1 1   
S p ut u m  Mi cr o bi ol o g y  ............................................................................................... 4 4 
9. 1. 1 2   
E m er g e n c e  of  A d diti o n al  P at h o g e ns  ......................................................................... 4 4 
9. 1. 1 3   
Ti m e t o  A nti bi oti c  Us e  a n d  E x a c er b ati o n  Ass ess m e n t ............................................. 4 4 
9. 2   Cli ni c al  L a b or at or y  M e as ur e m e nt s  .................................................................................. 4 4  
9. 2. 1   
H e m at ol o g y  a n d  Bl o o d  C h e mistr y  Pr ofil es  .............................................................. 4 4 
9. 2. 2   
Pr e g n a n c y  T est  ......................................................................................................... 4 5 
9. 2. 3   
Uri n al ysis  ................................................................................................................. 4 5 
9. 3   P h ar m a c o ki n eti c  M e as ur e m e nts  ....................................................................................... 4 5  
9. 4   U ns c h e d ul e d  Visit(s)  ........................................................................................................ 4 5  
1 0   P R E C A U TI O N  
4 5  
1 0. 1   Pr e g n a n c y  ........................................................................................................................ 4 5  
1 1   S A F E T Y  E V A L U A TI O N S  
4 6  
1 2   A D V E R S E  E V E N T  R E P O R T I N G  A N D  D O C U M E N T A TI O N 
4 6  
1 2. 1   A d v ers e  E v e nt s  ................................................................................................................ 4 6  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
1 4 
1 2. 2   S e v erit y  ............................................................................................................................ 4 7  
1 2. 3   R el ati o ns hi p t o  St u d y  Tr e at m e nt  ...................................................................................... 4 7  
1 2. 4   S eri o us  A d v ers e  E v e nts ( S A E)  ........................................................................................ 4 8  
1 2. 4. 1   
S eri o us  A d v ers e  E v e nt  R e p orti n g  ............................................................................. 4 8 
1 2. 5   S us p e ct e d  U n e x p e ct e d  S eri o us  A d v ers e  R e a cti o ns ( S U S A Rs)  ........................................ 4 9  
1 3   DI S C O N TI N U A TI O N  A N D  WI T H D R A W A L  O F  S U B J E C T S  
5 0  
1 3. 1   E arl y  Dis c o nti n u ati o n  a n d  Wit h dr a w al  of  St u d y  a n d  St u d y  Dr u g  .................................... 5 0  
1 3. 2   R e pl a c e m e nt  of  S u bj e ct s  .................................................................................................. 5 0  
1 4   P R O T O C O L  VI O L A TI O N S  
5 0  
1 5   D A T A  S A F E T Y  M O NI T O RI N G  
5 1  
1 6   S T A TI S TI C A L  M E T H O D S  A N D  C O N SI D E R A TI O N S  
5 1  
1 6. 1   D at a  S ets  A n al y z e d  .......................................................................................................... 5 1  
1 6. 2   D e m o gr a p hi c  a n d  B as eli n e  C h ar a ct eri sti cs  ...................................................................... 5 2  
1 6. 3   A n al ysi s  of  Pri m ar y  E n d p oi nt  .......................................................................................... 5 2  
1 6. 4   A n al ysi s  of  S e c o n d ar y  E n d p oi nts  .................................................................................... 5 2  
1 6. 5   M ulti pli cit y /  C o ntr ol  of  T y p e I  err or r at e  ........................................................................ 5 3  
1 6. 6   S af et y  A n al ysi s  ................................................................................................................ 5 4  
1 6. 7   I nt eri m  A n al ysis ............................................................................................................... 5 4  
1 6. 8   S a m pl e  Si z e  a n d  R a n d o mi z ati o n  ...................................................................................... 5 4  
1 7   D A T A  C O L L E C TI O N,  R E T E N TI O N  A N D  M O NI T O RI N G  
5 5  
1 7. 1   D at a  C oll e cti o n I nstr u m e nts  ............................................................................................. 5 5  
1 7. 2   D at a  M a n a g e m e nt  Pr o c e d ur es  .......................................................................................... 5 5  
1 7. 3   D at a  Q u alit y  C o ntr ol  a n d  R e p o rti n g ................................................................................ 5 5  
1 7. 4   Ar c hi v al  of  D at a ............................................................................................................... 5 5  
1 7. 5   A v ail a bilit y  a n d  R et e nti o n  of I n v esti g ati o n al  R e c or ds  ..................................................... 5 5  
1 7. 6   M o nit ori n g  ....................................................................................................................... 5 6  
1 7. 7   S u bj e ct  C o nfi d e nti alit y  .................................................................................................... 5 6  
1 8   A D MI N I S T R A TI V E,  E T HI C A L,  R E G U L A T O R Y  C O N S I D E R A TI O N S  
5 6  
1 8. 1   P rot o c ol  A m e n d m e nts  ...................................................................................................... 5 6  
1 8. 2   I nstit uti o n al  R e vi e w B o ar ds  a n d I n d e p e n d e nt  Et hi cs  C o m mitt e es  ................................... 5 6  
1 8. 3   I nf or m e d  C o ns e nt  F or m ................................................................................................... 5 7  
1 8. 4   P u bli c ati o ns ...................................................................................................................... 5 7  
1 8. 5   I n v esti g at or  R es p o nsi biliti es ............................................................................................ 5 7  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
1 5 
1 9.  R E F E R E N C E S  
5 9  
A P P E N DI X  1.  S C H E D U L E  O F  E V E N T S  
6 0  
A P P E N DI X  2.  B L O O D  V O L U M E  C A L C U L A TI O N  
6 1  
A P P E N DI X  3.  C Y S TI C  F I B R O SI S  R E S P I R A T O R Y  S Y M P T O M  DI A R Y ( C F R S D ©)  S E L F -R E P O R T  – 
W E E K L Y  V E R S I O N  2. 0 
6 2  
A P P E N DI X  4.  C Y S TI C  F I B R O SI S  Q U E S TI O N N AI R E  - R E VI S E D ( C F Q -R)  S E L F -R E P O R T  –  T W O 
W E E K  R E C A L L;  V E R SI O N   2 
6 9  
A P P E N DI X  5.  E Q -5 D -5 L  &  E Q -5 D Y  
7 6  
A P P E N DI X  6. I N S T R U C TI O N S  F O R  U S E  O F  A E R O V A N C I N H A L E R  
7 8  
 
 
 
LI S TI N G  O F  T A B L E S 
T a bl e  1:  P h as e II  D e m o gr a p hi cs  a n d  C h ar a ct eristi cs  at  B as eli n e ( B L). ..................................................................... 2 3  
T a bl e  2:  Pl as m a  P K  P ar a m et ers.  ............................................................................................................................... 2 6  
T a bl e  3:  S p ut u m  P K  P ar a m et ers.  .............................................................................................................................. 2 7  
T a bl e  4: I n ci d e n c e  of  a d v ers e  e v e nt s  o c c urri n g i n  ≥ 2 s u bj e cts i n  at l e ast  o n e tr e at m e nt  gr o u p  a n d  wit h  a n  o ns et 
d uri n g t h e tr e at m e nt  p eri o d.  ...................................................................................................................................... 2 9  
T a bl e  5:  S u bj e ct  E arl y  Dis c o nti n u ati o ns.  .................................................................................................................. 3 0  
T a bl e  6:  F or m ul ati o n  of  A er o V a n c.  .......................................................................................................................... 3 9  
T a bl e  7:  F or m ul ati o n  of  Pl a c e b o.  .............................................................................................................................. 3 9  
T a bl e  8:  A E  S e v erit y  Gr a di n g.  .................................................................................................................................. 4 7  
T a bl e  9:  R el at e d n ess.  ................................................................................................................................................ 4 7  
 
LI S TI N G  O F  FI G U R E S  
Fi g ur e  1:  S ur vi v al  a c c or di n g t o  M R S A i nf e cti o n st at us i n  C F  p ati e nts ( D as e n br o o k,  et  al.,  2 0 1 0, r e pri nt e d  wit h 
p er missi o n,  C o p yri g ht  © ( 2 0 1 0) J A M A). .................................................................................................................. 1 9  
Fi g ur e  2:  A er o V a n c  a n d i ntr a v e n o us  v a n c o m y ci n  pl as m a  c o n c e ntr ati o n  as  a f u n cti o n  of ti m e (s e mi -l o g)  aft er  a 
si n gl e  d os e  a d mi ni str ati o n.  ........................................................................................................................................ 2 1  
Fi g ur e  3: C h a n g e i n  M R S A  D e nsit y i n  S p ut u m i n  3 2  m g  a n d  6 4  m g  D os e  C o h orts  P o ol e d.  ..................................... 2 4  
Fi g ur e  4:  M e a n  S p ut u m  C o n c e ntr ati o ns  of  V a n c o m y ci n  F oll o wi n g  A er o V a n c  A d mi ni str ati o n  wit h  Visits  O v erl ai d 
a n d  S e p ar at e d  b y  Tr e at m e nt ( S e mi -l o g  S c al e). ......................................................................................................... 2 5  
Fi g ur e  5:  C h a n g e i n  M R S A  D e nsit y i n  S p ut u m i n  S u bj e cts l ess t h a n  2 1  Y e ars  of  A g e.  ........................................... 3 1  
Fi g ur e  6:  A bs ol ut e  C h a n g e fr o m  B as eli n e i n  F E V 1 P er c e nt  Pr e di ct e d i n  S u bj e ct s l ess t h a n  2 1  Y e ars  of  A g e.  ......... 3 2  
Fi g ur e  7:  Ti m e t o  Us e  of  Ot h er  A nti bi oti cs f or  R es pir at or y I nf e cti o n i n  S u bj e cts l ess t h a n  2 1  Y e ars  of  A g e.  .......... 3 3  
Fi g ur e  8:  St u d y  D esi g n.  ............................................................................................................................................ 3 5  
 
 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
1 6 
LI S T  O F  A B B R E VI A TI O N S 
ß -h C G   
H u m a n  c h ori o ni c  g o n a d otr o pi n  b et a -s u b u nit  
A E  
A d v ers e  e v e nt  
A L T  
A l a ni n e  a mi n otr a nsf er as e 
A N C O V A   
A n al ysi s  of  c o v ari a n c e  
A PI  
A cti v e  p h ar m a c e uti c al i n gr e di e nt  
A S T  
A s p art at e  a mi n otr a nsf er as e  
A T S  
A m eri c a n  T h or a ci c  S o ci et y  
A U C   
A r e a  u n d er t h e  c ur v e 
B.  c e p a ci a   
B ur k h ol d eri a  c e p a ci a  
B I D 
B is i n  di e/t wi c e  d ail y 
B L  
B as eli n e  
B MI  
B o d y  m ass i n d e x  
B P  
B l o o d  pr ess ur e 
B U N   
B l o o d  ur e a  nitr o g e n 
C A T  
C o nti n ui n g  alt er n ati n g  a nti -Ps e u d o m o n al t h er a p y  
C F  
C ysti c fi br osis  
C F R S D -C RI S S   C ysti c  Fi br osi s  R es pir at or y  S y m pt o m  Di ar y -C hr o ni c  R es pir at or y  S y m pt o m  S c or e  
C F T R   
C ysti c fi br osis tr a ns m e m br a n e  c o n d u ct a n c e r e g ul at or  
C F U  
C ol o n y f or mi n g  u nit s  
C F U/ g   
C ol o n y f or mi n g  u nit s  p er  gr a m  
CI  
C o nfi d e n c e i nt er v al  
° C  
D e gr e es  C el si us  
C m a x  
M a xi m u m  c o n c e ntr ati o n  
C N S  
C e ntr al  n er v o us s yst e m  
C P M P   
C o m mitt e e f or  Pr o pri et ar y  M e di ci n al  Pr o d u ct s  
C R F  
C as e r e p ort f or m  
C R O   
C o ntr a ct r es e ar c h  or g a ni z ati o n  
C V  
C o effi ci e nt  of  v ari ati o n  
D L T  
D os e  Li miti n g  T o xi cit y  
D M C   
D at a  M o nit ori n g  C o m mitt e e  
D S M B   
D at a  S af et y  M o nit ori n g  B o ar d  
E C G  
E l e ctr o c ar di o gr a m 
E D C  
El e ctr o ni c  D at a  C a pt ur e  
e -Di ar y   
E l e ctr o ni c  di ar y 
E D T A   
E t h yl e n e  di a mi n et etr a-a c eti c  a ci d  
E L F  
E pit h eli al li ni n g fl ui d  
E T  
E arl y t er mi n ati o n  
F D A  
F o o d  a n d  Dr u g  A d mi nistr ati o n  
F E F  
F or c e d  e x pir at or y fl o w  
F E V 1  
F or c e d  e x pir at or y  v ol u m e i n  1  s e c o n d  
F V C  
F or c e d  vit al  c a p a cit y  
G C P  
G o o d  Cli ni c al  Pr a cti c e  
G G T   
G a m m a  gl ut a m yltr a nsf er as e  
GI  
G astr oi nt esti n al  
G LI  
Gl o b al  L u n g  F u n cti o n I niti ati v e  
G L P  
G o o d  L a b or at or y  Pr a cti c es  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
1 7 
c G M P   
C urr e nt  G o o d  M a n uf a ct uri n g  Pr a cti c e  
h r 
H o ur(s)  
H B S  A g   
H e p atiti s  B s urf a c e  a nti g e n  
H C V  A b   
H e p atiti s  C  a nti b o d y  
H E E N T   
H e a d,  e y es,  e ars,  n os e,  a n d t hr o at  
HI P A A   
H e alt h I ns ur a n c e  P ort a bilit y  a n d  A c c o u nt a bilit y  A ct  
HI V  
H u m a n  i m m u n o d efi ci e n c y  vir us 
H P L C   
H i g h-p erf or m a n c e li q ui d  c hr o m at o gr a p h y  
H P M C   
( H y dr o x y pr o p yl) m et h yl  c ell ul os e 
I C F 
Inf or m e d  c o ns e nt f or m  
I C H 
I nt er n ati o n al  C o nf er e n c e  o n  H ar m o ni s ati o n 
I E C 
I n d e p e n d e nt  Et hi cs  C o m mitt e e 
I R B 
I nstit uti o n al  R e vi e w  B o ar d 
I T T 
I nt e nt t o  Tr e at 
I U D 
Intr a ut eri n e  d e vi c e  
I V 
Intr a v e n o us  
I W R 
I nt er a cti v e  W e b  R es p o ns e 
k g  
K il o gr a m 
L D H   
L a ct at e  d e h y dr o g e n as e  
M C H   
M e a n  c ell  h e m o gl o bi n  
M C H C   
M e a n  c ell  h e m o gl o bi n  c o n c e ntr ati o n  
M C V   
M e a n  c ell  v ol u m e  
M D  
M e di c al  D o ct or  
M e d D R A   
M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es  
m g  
M illi gr a m 
MI C  
M e a n i n hi bit or y  c o n c e ntr ati o n  
µ g   
M i cr o gr a m 
mi n  
M i n ut e(s) 
mI T T   
M o difi e d I nt e nt -t o-Tr e at  
m m H g   
M illi m et er(s)  of  m er c ur y 
M R S A   
M et hi cilli n  r esist a nt- St a p h yl o c o c c us  a ur e us  
n  
N u m b er  of  s u bj e cts wit h  a n  o bs er v ati o n  
N  
N u m b er  of  s u bj e cts i n t h e  d at as et  or  p o p ul ati o n  
n g  
N a n o gr a m  
N O A E L   
N o  o bs er v e d  a d v ers e  eff e ct  l e v el 
P A  
P s e u d o m o n as A er u gi n os a  
P E F  
P e a k  e x pir at or y fl o w  
P E F R   
P e a k  e x pir at or y fl o w r at e  
P F R D   
P e a k  Fl o w  R e c or di n g  D e vi c e  
P F T  
P ul m o n ar y f u n cti o n t est  
P K  
P h ar m a c o ki n eti c(s)  
P P  
P er  pr ot o c ol  
R B C  
R e d  bl o o d  c ell  
R E B  
R es e ar c h  Et hi cs  B o ar d  
s 
S e c o n d(s)  
S.  a ur e us   
St a p h yl o c o c c us  a ur e us  
S A E  
S eri o us  a d v ers e  e v e nt  
S A P  
St atisti c al  A n al ysis  Pl a n  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
1 8 
S D  
S t a n d ar d  d e vi ati o n 
S D V  
S o ur c e  d at a  v erifi e d  
S O P  
St a n d ar d  O p er ati n g  Pr o c e d ur e  
S U S A R   
S us p e ct e d  u n e x p e ct e d s eri o us  a d v ers e r e a cti o n  
T D N  
T h er a p e uti cs  D e v el o p m e nt  N et w or k  
T E A E   
T r e at m e nt-e m er g e nt  a d v ers e  e v e nt(s)  
T O BI   
T o br a m y ci n i n h al ati o n  s ol uti o n  
U L N   
U p p er li mit  of  n or m al  
U S  
U nit e d  St at es  
U S P  
U S  P h ar m a c o p ei al  C o n v e nti o n  
VI S A   
V a n c o m y ci n i nt er m e di at e r esist a nt  St a p h yl o c o c c us  a ur e us  
V R S A   
V a n c o m y ci n r esi st a nt  St a p h yl o c o c c us  a ur e us  
W B C   
W hit e  bl o o d  c ell  
W M A   
W orl d  M e di c al  Ass o ci ati o n  
 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
1 9 
1   B A C K G R O U N D  
C ysti c fi br osis ( C F) is  a  g e n eti c  dis e as e  c h ar a ct eri z e d, i n  p art,  b y t h e  pr e v al e n c e  of t hi c k, sti c k y  m u c us  pr o d u c e d i n 
t h e l u n g, fr e q u e nt l u n g i nf e cti o ns,  a n d  a r es ult a nt  d e cli n e i n  p ul m o n ar y f u n cti o n.  T h e  c hr o ni c l u n g i nf e cti o ns 
e x p e dit e t h e str u ct ur al  d a m a g e  of t h e l u n gs  c o ntri b uti n g t o t h e  pr e m at ur e  d e at h  of t h e  p ati e nts. I n t h e  p ast  d e c a d e, 
p ersist e nt  M R S A l u n g i nf e cti o n  h as  b e c o m e i n cr e asi n gl y  c o m m o n i n  p ati e nts  wit h  C F,  wit h  a  pr e v al e n c e  of  a b o ut 
2 6 % ( a p pr o x.  8, 0 0 0  p ati e nt s) i n t h e  U nit e d  St at es  ( C F F  P ati e nt  R e gistr y,  2 0 1 4).  P ersist e nt  M R S A i nf e cti o n i n 
p ati e nts  wit h  C F  h as  b e e n  ass o ci at e d  wit h i n cr e as e d  us e  of i ntr a v e n o us (I V)  a nti bi oti cs  ( Mi all  L S,  2 0 0 1) ( Eli z ur  A, 
2 0 0 7) , i n cr e as e d  h os pit ali z ati o ns ( V a n d er h elst  E,  2 0 1 2),  a f ast er  d e cli n e  of l u n g f u n cti o n ( V a n d er h el st  E,  2 0 1 2) 
( D as e n br o o k  E C  M.  C.-W.,  2 0 0 8) ,  as w ell  as  s h ort e n e d lif e- e x p e ct a n c y,  ( D as e n br o o k  E C  C.  W.,  2 0 1 0).  
 
Fi g u r e  1 : S u r vi v al  a c c o r di n g t o  M R S A i nf e cti o n st at us i n  C F  p ati e nts ( D as e n b r o o k,  et  al.,  2 0 1 0,  r e p ri nt e d  wit h 
p e r missi o n,  C o p y ri g ht  © ( 2 0 1 0)  J A M A).  
P ersist e nt  M R S A l u n g i nf e cti o n i n  C F  p ati e nt s is  diffi c ult t o  er a di c at e  or  m a n a g e  usi n g  or al  or I V  a nti bi oti cs,  a n d 
t h er e is  n o st a n d ar d  of  c ar e t o  m a n a g e t h e i nf e cti o n i n  C F  p ati e nts ( Z o b ell J T,  2 0 1 5) d es pit e t h e  hi g h  n e e d. I n  
c o ntr ast t o t h e  est a blis h e d tr e at m e nt  of  P.  a er u gi n os a  i nf e cti o n  wit h i n h al e d  a nti bi oti cs, t h er e is  n o  F D A-a p pr o v e d 
i n h al e d  a nti bi oti c tr e at m e nt  a v ail a bl e f or  M R S A i nf e cti o n. V a n c o m y ci n is t h e  dr u g  of  c h oi c e f or t h e tr e at m e nt  of 
M R S A i nf e cti o n,  b ut it i s  o nl y  a v ail a bl e i n I V f or m.  W hil e  hi g hl y  eff e cti v e  a g ai nst  gr a m  p ositi v e  b a ct eri a,  c hr o ni c 
us e  of I V  v a n c o m y ci n  m a y  b e  ass o ci at e d  wit h s yst e mi c t o xi cit y,  es p e ci all y r e n al t o xi cit y  a n d  ot ot o xi cit y.  D u e t o  its 
I V  us e  a n d  p ot e nti al f or t o xi cit y, I V  v a n c o m y ci n us e i s  g e n er all y li mit e d t o  h os pit al s etti n gs.  As  o bs er v e d  wit h 
i n h al e d  a nti-Ps e u d o m o n al  dr u gs, t h er e  m a y  b e  si g nifi c a nt  cli ni c al  a d v a nt a g e i n  d eli v eri n g  v a n c o m y ci n  dir e ctl y t o 
t h e sit e  of i nf e cti o n i n  or d er t o  m a xi mi z e t h e  cli ni c al  effi c a c y, r e d u c e s yst e mi c  e x p os ur e  a n d t h e ri s k  of  a d v ers e 
eff e cts,  a n d t o  e n a bl e  c o n v e ni e nt  us e  of t h e  pr o d u ct  o utsi d e  of t h e  h os pit al s etti n g.  
S a v ar a  h as  d e v el o p e d  a  hi g h -p erf or m a n c e i n h al ati o n  p o w d er f or m ul ati o n  of  v a n c o m y ci n  h y dr o c hl ori d e,  A er o V a n c, 
utili zi n g  a  c o n v e nti o n al  c a ps ul e i n h al er.  V a n c o m y ci n is  a  gl y c o p e pti d e  a nti bi oti c  eff e cti v e  a g ai nst  m ost  g r a m-
p ositi v e  b a ct eri a,  a n d  h as  b e e n  e xt e nsi v el y  us e d f or t h e tr e at m e nt  of  M R S A i nf e cti o ns f or  o v er fi v e  d e c a d es.  T h e 
pr o p os e d i n di c ati o n  of  A er o V a n c is tr e at m e nt  of  C F  p ati e nts  wit h  p ersist e nt  M R S A i nf e cti o n  of t h e l u n gs.  T h e  ai m  
of  A er o V a n c tr e at m e nt is i nf e cti o n s u p pr essi o n i n  or d er t o i m pr o v e  p ati e nts’ r es pir at or y s y m pt o ms,  a n d l u n g 
f u n cti o n,  a n d t o  pr ol o n g t h e ti m e t o  n e e d  of  ot h er  a nti bi oti cs  a n d  p ul m o n ar y  e x a c er b ati o n.  A er o V a n c  w as  gr a nt e d 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
2 0 
Or p h a n  Dr u g  d esi g n ati o n i n  S e pt e m b er  2 0 1 2  a n d  Q u alifi e d I nf e cti o us  Dis e as e  Pr o d u ct/ F ast  Tr a c k  D esi g n ati o n i n 
N o v e m b er  2 0 1 3  b y t h e  F D A . 
2   O v e r vi e w  of  N o n- Cli ni c al  St u di es  
T h e  n o n cli ni c al t o xi c ol o g y  pr ofil e f or  A er o V a n c  h as  b e e n  w ell -c h ar a ct eri z e d i n  a s eri es  of  a c ut e  a n d r e p e at e d  d os e 
i n h al ati o n t o xi cit y st u di es i n r ats  a n d  d o gs,  as  w ell  as i n t h e I C H/ F D A  pr es cri b e d s af et y  p h ar m a c ol o g y st u di es 
i n v ol vi n g t h e  c ar di o v as c ul ar s yst e m,  p ul m o n ar y s yst e m  a n d  c e ntr al  n er v o us s yst e m ( C N S). A er o V a n c  di d  n ot r es ult 
i n  a n y  a d v ers e  eff e cts i n f u n cti o n alit y  of t h e  c ar di o v as c ul ar s yst e m  a n d  p ul m o n ar y s yst e m  at  a n y  d os e l e v el  u p t o 
3 0  m g/ k g i n  b e a gl e  d o gs,  a n d  C N S  at  a n y  d os e l e v el  u p t o  1 0 0  m g/ k g i n  S pr a g u e -D a wl e y r ats.   
T h e  pi v ot al  G o o d  L a b or at or y  Pr a cti c e  ( G L P) t o xi c ol o g y st u di es  c o nsi st e d  of t w o  2 8 - da y i n h al ati o n t o xi cit y  st u di es 
wit h  a  2 8 -d a y r e c o v er y  p eri o d i n  d o gs  a n d r ats,  a n d  a  1 3 -w e e k i n h al ati o n t o xi cit y st u d y i n r ats.  
F oll o wi n g  2 8  d a ys  of i n h al ati o n  e x p os ur e, t h er e  w er e  n o i n di c ati o ns  of s yst e mi c t o xi cit y  n ot e d i n  eit h er t h e r ats  or 
d o gs.  Cli ni c al  p at h ol o g y i n di c es f or t o xi cit y i n t h e  m aj or  or g a n  s yst e ms r e v e al e d  c o m p ar a bl e  v al u es  b et w e e n  air  a n d 
v e hi cl e  c o ntr ol  a ni m als  a n d  v a n c o m y ci n -e x p os e d r ats  a n d  d o gs.  T h er e  w er e  a  n u m b er  of  mi cr os c o pi c  c h a n g es  n ot e d 
al o n g t h e r es pir at or y tr a ct  a n d i n t h e l u n gs t h at r e pr es e nt e d l o c al irrit ati v e  eff e ct s,  a d a pti v e  c h a n g es,  a n d  n or m al 
p h ysi ol o gi c al r es p o ns es t o t h e i m p a cti o n  of  p arti cl es  al o n g t h e r es pir at or y tr a ct  a n d  d e p ositi o n  of  p arti cl es i n t h e 
l u n gs.  A  2 8-d a y r e c o v er y  p eri o d s h o w e d  c o m pl et e t o  p arti al r e v ersi bilit y  of t h e fi n di n gs,  wit h  n o  n ot a bl e  diff er e n c e 
b et w e e n t h e  a cti v e  d os e  gr o u ps  a n d t h e  v e hi cl e  c o ntr ol  gr o u p  w h e n  c o m p ar e d t o t h e  air  c o ntr ol.  B as e d  o n t h e r es ults 
of t h es e  2 8 -d a y st u di es, t h e  N o  O bs er v e d  A d v ers e  Eff e ct  L e v el  (N O A E L ) i n t h e r ats  w as  1 8. 6  m g/ k g/ d a y  a n d t h e 
N O A E L i n t h e  d o gs  w as  1 1. 5  m g/ k g/ d a y,  b ot h  N O A E L’s r e pr es e nti n g t h e  mi d  d os e l e v el s  us e d i n t h e r es p e cti v e 
st u di es.  
F oll o wi n g  1 3  w e e ks  of i n h al ati o n  e x p os ur e,  t h er e  w er e  n o  a p p ar e nt i n di c ati o ns  of s yst e mi c  c h a n g es  n ot e d i n  a n y 
tiss u es  o utsi d e t h e r es pir at or y tr a ct.  Cli ni c al  p at h ol o g y i n di c es  w er e  c o m p ar a bl e  b et w e e n tr e at e d  gr o u ps  a n d 
r es p e cti v e  air  a n d  v e hi cl e  c o ntr ol  v al u es.  A d mi nistr ati o n  of t h e  v e hi cl e ( L-L e u ci n e: Tr e h al os e)  a n d t h e t est it e m, 
A er o V a n c, r es ult e d i n  v e hi cl e -r el at e d  a n d t est it e m-r el at e d  mi cr os c o pi c  c h a n g es i n t h e  n as al  c a vit y,  u p p er 
r es pir at or y tr a ct  a n d l u n gs  of  a ni m als fr o m t h e tr e at e d  gr o u ps,  a n d i n t h e  n as al  c a vit y i n t h e  v e hi cl e tr e at e d  gr o u p. 
T h e  d os e -r el at e d fi n di n gs i n t h e tr e at e d  gr o u p s i n t h e  n as al  c a vit y i n cl u d e d  d e g e n er ati o n  of t h e  olf a ct or y  e pit h eli al 
c ell/i n cr e as e d  e osi n o p hili c  dr o pl ets . T h e  n as al  c a vit y  of t h e  v e hi cl e tr e at e d  g r o u p s h o w e d  v a c u ol ar  d e g e n er ati o n  of 
t h e  olf a ct or y  e pit h eli u m.  T h e irrit ati o n/ a d a pti v e  c h a n g es  of t h e  u p p er r es pir at or y tr a ct ( c ari n a, l ar y n x,  n as al  c a vit y 
a n d  n as o p h ar y n x)  a n d l u n gs  o bs er v e d i n cl u d e d  c h a n g es  s u c h  as s q u a m o us  m et a pl asi a  of t h e r es pir at or y  e pit h eli u m 
i n t h e  c ari n a  a n d l ar y n x,  er osi o n/ atr o p h y  of t h e  olf a ct or y  e pit h eli u m  a n d  m at eri al/ e x u d at e/ c ell  d e bris i n l u m e n  of t h e 
n as al  c a vit y  a n d  g o bl et  c ell  h y p er pl asi a  of t h e r es pir at or y  e pit h eli u m  of  n as al  c a v it y/ n as o p h ar y n x, 
e nl ar g e d/i n cr e as e d  al v e ol ar  histi o c yt es/ al v e ol ar  hi sti o c yt osi s ( c orr el at e d  wit h  d os e -d e p e n d e nt i n cr e as es i n l u n g 
w ei g hts  a n d  m a cr os c o pi c fi n di n g  of  p al e  ar e a/f o c u s i n t h e l u n gs)  a n d  g o bl et  c ell  h y p er pl asi a/ m et a pl asi a 
wit h/ wit h o ut  c ell  d e bris/ e osi n o p hili c  m at eri al i n  al v e ol ar  d u ct/ b r o n c hi ol ar l u m e n  a n d  p eri v as c ul ar/ p eri br o n c hi ol ar 
c ell i nfiltr at e i n t h e l u n gs.  A  hi g h er i n ci d e n c e/ s e v erit y  of t h es e fi n di n gs  w as  n ot e d i n t h e  hi g h  d os e  gr o u p  a ni m als.  
Aft er t h e  4 -w e e k r e c o v er y  p eri o d, t h e t est it e m -r el at e d  c h a n g es ( d e g e n er ati o n  of t h e  olfa ct or y  e pit h eli al 
c ell/i n cr e as e d  e osi n o p hili c  dr o pl ets)  as  w ell  as t h e  v e hi cl e -r el at e d  c h a n g e ( v a c u ol ar  d e g e n er ati o n  of t h e  olf a ct or y 
e pit h eli u m)  w er e still  pr es e nt i n t h e  n as al  c a vit y  of t h e r e c o v er y  a ni m als i n  t h e  hi g h-d os e  gr o u p  a ni m als ,  b ut  wit h  a 
l o w er s e v erit y, s u g g esti n g  a n  o n g oi n g r e c o v er y  pr o c ess (r e g e n er ati o n  of t h e  olf a ct or y  e pit h eli u m).  T h e 
irrit ati o n/ a d a pti v e  c h a n g es  of t h e  u p p er r es pir at or y tr a ct ( c ari n a, l ar y n x,  n as al  c a vit y  a n d  n as o p h ar y n x)  a n d l u n gs 
s h o w e d i n di c ati o ns  of r e c o v er y  at  v ari o us  l e v els, s u g g esti n g  a n  o n g oi n g r e c o v er y  pr o c ess. 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
2 1 
B as e d  o n t h e r es ults  of t h e  1 3 -w e e k st u d y, t h e  N O A E L  w as  c o nsi d er e d t o  b e  at t h e  a c hi e v e d  d os e l e v el  of 
1 0. 5  m g/ k g/ d a y f or t h e r ats  w h e n  d os e d f or  9 1  c o ns e c uti v e  d a ys  b y  n os e -o nl y i n h al ati o n.   
I n  c o n cl usi o n, t h e  n o n cli ni c al  c h ar a ct eri z ati o n  of  A er o V a n c  p o w d er f or i n h al ati o n  w as s u c c essf ull y  c arri e d  o ut i n  a 
s eri es  of  G L P r e p e at  d os e i n h al ati o n t o xi cit y st u di es i n r ats  a n d  d o gs. I n  a d diti o n t o  d et er mi ni n g  a  N O A E L i n  b ot h 
n o n cli ni c al  s p e ci es, it  w as  d et er mi n e d t h at,  u n d er t h e  c o n diti o ns  of t h es e  st u di es, t h e  p ul m o n ar y  d eli v er y  of 
A er o V a n c  w as  n ot  ass o ci at e d  wit h  a n y  a p p ar e nt  a d v ers e  s yst e mi c fi n di n gs  as  d et er mi n e d  b y  cli ni c al  a n d 
hist o p at h ol o gi c  e x a mi n ati o ns.  T h e  c h a n g es t h at  w er e  n ot e d  w er e  pri m aril y li mit e d t o  t h e r es pir at or y tr a ct  a n d l u n gs 
a n d r e pr es e nt e d l o c al irrit ati v e/ a d a pti v e  c h a n g es  e x p e ct e d f oll o wi n g t h e  e x p os ur e t o  hi g h l e v el  of t h e t est  arti cl e.   
3   O v e r vi e w  of  Cli ni c al  St u di es  
3. 1   P h as e  I 
O n e  P h as e I  cli ni c al  st u d y  h as  b e e n  c o n d u ct e d  wit h  A er o V a n c.  W h e n  a d mi nist er e d t o  1 8  h e alt h y  v ol u nt e ers  a n d  7 
s u bj e cts wit h  c ysti c fi br osis i n  a si n gl e  es c al ati n g  d os e st u d y,  A er o V a n c  w as  w ell t ol er at e d  at t h e  hi g h est  d os e 
a d mi nist er e d,  8 0  m g.  A er o V a n c s h o w e d  a f a v or a bl e  p h ar m a c o ki n eti c  ( P K) pr ofil e,  wit h  a r el ati v el y sl o w  p ul m o n ar y 
a bs or pti o n  p h as e (t m a x  of  1. 3 3  h r –2. 0 8  h r), f oll o w e d  b y  distri b uti o n  a n d  eli mi n ati o n  c o m p ar a bl e t o t h e i ntr a v e n o us 
a d mi nistr ati o n  (Fi g ur e  2 ) T h e  m e a n  a bs ol ut e  bi o a v ail a bilit y  a cr oss  all  A er o V a n c  d os es  w as  4 9 % ( st a n d ar d 
d e vi ati o n [ S D ] 8 %),  wit h  n o  a p p ar e nt  diff er e n c e  o bs er v e d  b et w e e n t h e  d os es.  T h e  a bs ol ut e  bi o a v ail a bilit y  cl os el y 
c orr es p o n ds  wit h t h e  p ul m o n ar y  a bs or pti o n  of  v a n c o m y ci n,  c o nsi d eri n g t h at  v a n c o m y ci n i s  n ot  a bs or b e d fr o m t h e 
g astr oi nt esti n al ( GI ) tr a ct.  T h e  m e a n  Cm a x  of  A er o V a n c  aft er  a n  8 0  m g  d os e  w as  6 1 8  n g/ m L,  c orr es p o n di n g t o 
a p pr o xi m at el y  1/ 5 t h of t h e  d os e  a dj ust e d  C m a x  aft er  a  2 5 0  m g  d os e  of I V  v a n c o m y ci n.  T h e  d os e li n e arit y  of 
A er o V a n c i n t er ms  of  C m a x  a n d  ar e a  u n d er t h e  c ur v e ( A U C ) v al u es  w as  e x c ell e nt ( R 2 >  0. 9 9). I n t h e  C F  c o h orts ,  all 
s u bj e cts  h a d s p ut u m  v a n c o m y ci n  c o n c e ntr ati o ns i n  hi g h  e x c ess  of t h e  m e a n i n hi bit or y  c o n c e ntr ati o n  (MI C ) of 
v a n c o m y ci n f or  M R S A  ( 2 µ g/ m L)  at  1  h r aft er t h e  a d mi nistr ati o n  of  A er o V a n c  wit h  b ot h t h e l o w  a n d t h e  hi g h  d os e 
( m e a n  of  1 0 6  μ g/ m L,  a n d  2 6 1  μ g/ m L, r es p e cti v el y).  At l at er ti m e  p oi nt s, t h e  c o n c e ntr ati o ns  d e cr e as e d,  b ut  o n 
a v er a g e r e m ai n e d  a b o v e t h e  MI C  v al u es f or  u p t o  2 4  h o urs.  V ari a bilit y i n s p ut u m  c o n c e ntr ati o ns  w as  hi g h,  as 
e x p e ct e d ( S D f or  C m a x  1 7 9 -1 9 0 %).    
 
 
Fi g u r e  2 : A e r o V a n c  a n d i nt r a v e n o us  v a n c o m y ci n  pl as m a  c o n c e nt r ati o n  as  a f u n cti o n  of ti m e (s e mi -l o g)  aft e r  a si n gl e 
d os e  a d mi nist r ati o n . 
 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
2 2 
T h e r el ati v el y sl o w  a bs or pti o n  of  v a n c o m y ci n  aft er  A er o V a n c  a d mi nistr ati o n,  as  w ell  as t h e r el ati v el y sl o w 
eli mi n ati o n fr o m t h e s p ut u m  o bs er v e d i n t h e st u d y  ar e i n  k e e pi n g  wit h t h e l ar g e  m ol e c ul ar  w ei g ht  of  v a n c o m y ci n, 
t h e  v a n c o m y ci n l u n g  c o n c e ntr ati o ns  o bs er v e d  aft er  n e b uli z e d  v a n c o m y ci n  a d mi ni str ati o n ( S hir ai  et  al.,  1 9 9 5), t h e 
a ni m al  P K  i nf or m ati o n ( V all e,  2 0 0 7),  as  w ell  as t h e  p o or  p e n etr ati o n  of  v a n c o m y ci n t o t h e  e pit h eli al li ni n g fl ui d 
( E L F) fr o m t h e  bl o o d  o bs er v e d i n  h u m an st u di es ( Cr u ci a ni  et  al,  1 9 9 6;  L a m er  et  al,  1 9 9 3).    
All  t h e  a d v ers e  e v e nts i n t h e  h e alt h y  v ol u nt e ers  w er e  cl assifi e d  as  mil d,  a n d  all  of t h e  e v e nts t h at  w er e  c o nsi d er e d 
pr o b a bl y  dr u g -r el at e d i n v ol v e d l o c al irrit ati o n  eff e cts  a n d r es ol v e d s p o nt a n e o usl y  a n d r a pi dl y ( 1 5  mi n  –  6 0  mi n). 
S m all r e d u cti o n i n t h e  p ost -d os e  F E V 1 ( 7 % –  1 1 %)  w as  o bs er v e d i n  3  s u bj e cts  aft er t h e  8 0  m g  d os e.  N o n e  of t h e  
s u bj e cts r e q uir e d  br o n c h o dil at or tr e at m e nt,  a n d t h e  c h a n g es  w er e  c o nsi d er e d  b y  t h e D at a  S af et y  M o nit ori n g  B o ar d  
(D S M B ) t o  b e n ot  cli ni c all y si g nifi c a nt. I n  C F  s u bj e cts,  c h est  c o n g esti o n  a n d  c h est ti g ht n ess  w er e r e p ort e d  b y 4  of 
t h e 7  s u bj e cts,  a n d t h er e  ap p e ar e d t o  b e  a sli g ht tr e n d t o w ar ds  m or e  a d v ers e  e v e nt s  at t h e  hi g h er  d os e ( 8 0  m g).  All 
r e p ort e d r es pir at or y  e v e nts  w er e  mil d,  n o n e  of t h e s u bj e ct s f elt  distr ess e d,  a n d t h e  e v e nt s  eit h er  di d  n ot r e q uir e 
tr e at m e nt  or r es ol v e d  aft er  air w a y  cl e ar a n c e  a n d/ or al b ut er ol i n h al ati o n.  B as e d  o n t h e r es ult s,  br o n c h o dil at or  pr e -
tr e at m e nt w as  i m pl e m e nt e d i n s u bs e q u e nt cli ni c al tri als .  S h ort-a cti n g  br o n c h o dil at ors  h a v e  b e e n r o uti n el y  us e d  as 
pr e -tr e at m e nt i n t h e  p u blis h e d  a n d  u n p u bli s h e d st u di es  of  a er os oli z e d I V  v a n c o m y ci n  as  w ell  as i n h al e d t o br a m y ci n 
a n d  a ztr e o n a m st u di es.  S y m pt o m ati c  br o n c h o c o nstri cti o n is r ar e  w h e n  s u bj e cts ar e  pr e -tr e at e d  wit h  a 
br o n c h o dil at or.   
3. 2   P h as e II   
T h e  A er o V a n c  P h as e II  cli ni c al st u d y  w as  a r a n d o mi z e d,  d o u bl e -bli n d,  pl a c e b o -c o ntr oll e d st u d y  of  a  2 8 -d a y  3 2  m g 
BI D  or  6 4  m g  BI D  A er o V a n c tr e at m e nt i n  8 7  C F  s u bj e cts wit h  p ersi st e nt  M R S A l u n g i nf e cti o n,  c o n d u ct e d  at 
4 0  sit es i n t h e  U S.  T h e  C o or di n ati n g I n v esti g at ors i n t h e st u d y  w er e  Dr.  Elli ott  D as e n br o o k ( C as e  W est er n  R es er v e 
U ni v ersit y ,  Cl e v el a n d,  O H),  a n d  Dr.  P atri c k  Fl u m e ( Me di c al  U ni v ersit y  of  S o ut h  C ar oli n a ,  C h arl est o n,  S C). I n 
s u m m ar y,  A er o V a n c r e d u c e d  M R S A  d e nsit y i n s p ut u m  a n d s h o w e d  e n c o ur a gi n g t r e n ds  of i m pr o v e m e nt i n 
r es pir at or y s y m pt o ms, l u n g f u n cti o n,  a n d  pr ol o n g ati o n  of t h e ti m e t o  n e e d  of  ot h er  a nti bi oti cs,  a n d ti m e t o 
p ul m o n ar y  e x a c er b ati o n,  wit h  b est r es p o ns es  o bs er v e d i n  s u bj e cts <  2 1  y e ars  of  a g e.  V a n c o m y ci n  p e a k  a n d tr o u g h 
c o n c e ntr ati o n s i n s p ut u m  w er e i n  hi g h  e x c ess  o v er  MI Cs  aft er  m ulti pl e  d osi n g i n  all  s u bj e ct s at  b ot h  d os e l e v els. 
T h e st u d y  d at a f a v ors t h e s el e cti o n  of t h e  l o w d os e f or f urt h er  d e v el o p m e nt,  a n d s el e cti o n  of  F E V 1 b as e d  e n d p oi nts 
as t h e  pri m ar y  e n d p oi nts f or  t his P h as e  III  cli ni c al  st u d y. 
3. 2. 1   D e m o g r a p hi cs  
D e m o gr a p hi cs  of t h e  P h as e II  st u d y is  d e m o nstr at e d i n T a bl e  1 : 
 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
2 3 
T a bl e  1 : P h as e II  D e m o g r a p hi cs  a n d  C h a r a ct e risti cs  at  B as eli n e ( B L) . 
T r e at m e nt  
A e r o V a n c  3 2  m g  C o h o rt   1  
A e r o V a n c  6 4  m g  C o h o rt   2  
P o ol e d  C o h o rts  
Pl a c e b o   
A e r o V a n c   
  Pl a c e b o   
A e r o V a n c   
  Pl a c e b o   
A e r o V a n c  
N 
2 0  
2 0   
  
2 3   
2 4   
  
4 3   
4 4  
A g e ( m e a n)  
2 4. 6   
2 2. 4   
  
2 7. 8   
2 7. 8   
  
2 6. 3   
2 5. 3  
A g e ( <  2 1/ ≥  2 1  y e a rs)   
1 0/ 1 0   
1 0/ 1 0   
  
5/ 1 8   
4/ 2 0   
  
1 5/ 2 8   
1 4/ 3 0  
S e x ( m/f)  
1 1/ 9   
7/ 1 3   
  
1 5/ 8   
1 5/ 9   
  
2 6/ 1 7   
2 2/ 2 2  
P.  a e r u gi n os a ( +/ −)   
1 2/ 8   
1 3/ 7   
  
1 3/ 1 0   
1 4/ 1 0   
  
2 5/ 1 8   
2 7/ 1 7  
M R S A (l o g
1 0 
C F U/ m L)  
6. 7 8   
7. 3 1   
  
7. 5 4   
7. 2 4   
7. 1 8   
7. 2 7  
C F R S D -C RI S S   
3 1. 6   
2 9. 1   
  
3 0. 4   
2 7. 6   
3 1. 0   
2 8. 3  
F E V 1 p e r c e nt  p r e d. 
( %) 
5 5. 8   
6 1. 1   
  
6 6. 5   
5 6. 9   
6 1. 5   
5 8. 8  
3. 2. 2   M R S A  D e nsit y  
I n t h e  P h as e II  cli ni c al st u d y,  q u a ntit ati v e  M R S A  c ult ur es fr o m s p o nt a n e o usl y  e x p e ct or at e d  s p ut u m s a m pl es  w er e 
us e d i n t h e  pri m ar y  e n d p oi nt  of t h e st u d y.  T h e  a v er a g e  b as eli n e  v al u es i n  b ot h  a cti v e  dr u g  c o h orts,  as  w ell  as t h e 
pl a c e b o  c o h orts  w er e  hi g h, r a n gi n g fr o m  6. 7 8 t o  7. 5 4  l o g1 0 C F U/ m L,  d e p e n di n g  o n t h e  gr o u p ( T a bl e  1 ). A 
r e d u cti o n fr o m  b as eli n e i n  M R S A c ol o n y f or mi n g  u nit s ( C F U ) w as  o bs er v e d i n  b ot h  3 2  m g  a n d  6 4  m g  d os e  c o h orts 
i n t h e I T T  p o p ul ati o n (Fi g ur e  3 ), wit h  m e a ns  of  -0. 4 2 l o g  1 0 C F U/ m L ( 3 2  m g)  a n d  -0. 6 0 l o g  1 0 C F U/ m L ( 6 4  m g). 
T h e r e d u cti o ns i n t h e  6 4  m g  a cti v e  dr u g  c o h ort  a n d t h e  p o ol e d  a cti v e  dr u g  c o h orts  w er e st ati sti c all y si g nifi c a nt 
(l e ast s q u ar es  m e a ns -0. 6 3  v ers us  0. 1 6 l o g  1 0 C F U/ m L;  p = 0. 0 1 4 5,  a n d  -0. 5 2  v ers us  -0. 0 6 l o g  1 0 C F U/ m L;  p = 0. 0 3 1 2, 
r es p e cti v el y). N o l asti n g  er a di c ati o n s  of  M R S A  w er e  o bs er v e d.   


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
2 4 
 
Fi g u r e  3: C h a n g e i n  M R S A  D e nsit y i n  S p ut u m i n  3 2  m g  a n d  6 4  m g  D os e  C o h o rts  P o ol e d . 
3. 2. 3   Pl as m a  a n d  S p ut u m  P h a r m a c o ki n eti cs 
V a n c o m y ci n  p e a k  a n d tr o u g h  c o n c e ntr ati o ns  at  D a y  8  a n d  D a y  2 9 i n s p ut u m  w er e i n  v er y  hi g h  e x c ess  o v er  MI Cs 
( m e a n  Ctr o u g h/ MI C r ati o >  3 5 )  aft er  m ulti pl e  d osi n g i n  all s u bj e cts at  b ot h  d os e l e v els , wit h  a p p ar e nt  d os e -
d e p e n d e n c y,  b ut  n o  n ot a bl e  diff er e n c e i n  C  tr o u g h b et w e e n t h e t w o ti m e  p oi nts  (Fi g ur e  4 ). T h e  g e n er all y  a c c e pt e d 
MI C  of  v a n c o m y ci n f or  M R S A is ill ustr at e d  b y t h e  d ott e d li n e,  at  2  µ g/ m L.  
 
p  =  N /A
p  <  0 .0 1
p  <  0 .0 0 0 1
p  =  0 .0 3
-1 .4
-1 .2
-1 .0
-0 .8
-0 .6
-0 .4
-0 .2
0 .0
0 .2
0 .4
0 .6
B a s eli n e
D a y  8
D a y  1 5
D a y  2 9
C h a n g e i n  M R S A  D e n sit y i n  S p ut u m  ( lo g 1 0 C F U /m L )
A er o Va n c 
Pl a c e b o
v al u e s
-
a n d  p
, 
c o nf i d e n c e i nt er v al s
% 
9 5 
, 
L e a st  s q u ar e  m e a n s
.
ar e f r o m  a r e p e at e d  m e a s ur e s li n e ar  mi x e d  m o d el
.
4 3
= 
n 
: 
Pl a c e b o
, 
4 4 
= 
n 
: 
A er o V a n c
, 
MI T T


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
2 5 
 
Fi g u r e  4 : M e a n  S p ut u m  C o n c e nt r ati o ns  of  V a n c o m y ci n  F oll o wi n g  A e r o V a n c  A d mi nist r ati o n  wit h  Visits  O v e rl ai d  a n d 
S e p a r at e d  b y  T r e at m e nt ( S e mi -l o g  S c al e). 
3. 2. 3. 1   P h a r m a c o ki n eti c  A n al y s es  
S u bj e ct  pl as m a  a n d s p ut u m  P K s a m pl es  w er e  o bt ai n e d f or t h e  m e as ur e m e nt  of  v a n c o m y ci n l e v els i n  a s u bs et  of 
2 4  s u bj e cts (1 2  of t h e first  a d ult  s u bj e ct s tr e at e d  at  e a c h  d os e l e v el).  T h e  pr e d os e s a m pl es  w er e  c oll e ct e d  wit hi n 
6 0  mi n ut es  pri or t o t h e st art  of  d osi n g  o n  D a ys  1,  8,  a n d  2 9.  P ost d os e  pl as m a  a n d s p ut u m  P K s a m pl es  w er e 
c oll e ct e d  0. 2 5,  1,  2,  a n d  4  h o urs ( all  ± 1 0  mi n ut e s) P ost d os e  o n  D a ys  1,  8,  a n d  2 9  (T a bl e  2 ). 
 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
2 6 
T a bl e  2 : Pl a s m a  P K  P a r a m et e rs . 
M e a n ( C V  %)  Pl as m a  P K  P a r a m et e rs f o r  A e r o V a n c  
P K  P ar a m et er  
Visit  2 ( D a y  1)  
Visit  3 ( D a y  7 -8)  
Visit  6 ( D a y  2 8 -2 9)  
3 2  m g  BI D   
6 4  m g  BI D   
3 2  m g  BI D   
6 4  m g  BI D   
3 2  m g  BI D   
6 4  m g  BI D  
N u m b er  of 
S u bj e ct s  
6 
6 
6 
3 
2 
2 
C m a x  ( µ g/ m L)  
0. 2 8 3 ( 6 8. 7)   
0. 5 8 9 ( 3 7. 8)   
0. 3 1 5 ( 7 0. 5)   
0. 4 3 5 ( 1 9. 5)   
0. 2 6 6 ( N C b)  
0. 6 9 4 ( N C b) 
C m a x / D o s e 
( µ g/ m L/ m g) 
0. 0 0 8 8 4 ( 6 8. 7)   0. 0 0 9 2 0 ( 3 7. 8)   0. 0 0 9 8 5 ( 7 0. 5)   0. 0 0 6 7 9 ( 1 9. 5)   0. 0 0 8 3 3  ( N Cb)  0. 0 1 0 8 ( N C b) 
T m a x a ( h)  
1. 0 0 ( 1. 0 0 -2. 0 0)  1. 0 0 ( 1. 0 0 - 2. 0 0) 1. 0 0 ( 0. 2 5 -2. 0 0)  1. 0 0 ( 1. 0 0 - 4. 0 0) 1. 0 0 ( 1. 0 0 -1. 0 0)   1. 5 ( 1. 0 0 - 2. 0 0) 
C tr o u g h 
( µ g/ m L) 
- 
-  
0. 1 4 6 ( 1 3 3)   
0. 0 5 6 8 ( 4 6. 1) e  0. 0 9 2 0 ( 1 1. 4)   
0. 2 1 3 ( N C b) 
A U C 0- 4 
( h•  µ g/ m L) 
0. 9 1 4  ( 78 . 7)  
1. 7 3 ( 3 3. 4)   
1. 0 4 ( 8 0. 2)  
1. 3 4 ( 2 1. 4)   
0. 8 8 0 ( N C b)  
2. 1 3 ( N C b) 
A U C 0- 4/ D o s e 
( h• 
µ g/ m L/ m g) 
0. 0 2 8 6  ( 78. 7 )  
0. 0 2 7 1 ( 3 3. 4)   0. 0 3 2 6 ( 8 0. 2)   0. 0 2 1 0 ( 2 1. 4)   
0. 0 2 7 5 ( N C b)  
0. 0 3 3 3 ( N C b) 
C m a x _ A c c c   
- 
-  
1. 1 3 ( 1 6. 7)   
0. 6 3 6 ( N C b)d  
1. 2 2 ( N C b)  
0. 9 3 7 ( N C b) 
A U C _ A c c c   
- 
-  
1. 1 5 ( 2 2. 8 )  
0. 6 9 5 ( N C b)d  
1. 3 8 ( N C b)  
0. 9 9 1 ( N C b) 
A b br e vi ati o ns:  A c c:  a c c u m ul ati o n r ati o;  A U C:  ar e a  u n d er t h e  c o n c e ntr ati o n -ti m e  c ur v e;  BI D: t wi c e  d ail y;  Cm a x :  m a xi m u m 
c o n c e ntr ati o n;  C tr o u g h:  c o n c e ntr ati o n  at t h e  e n d  of t h e  d osi n g i nt er v al;  h:  h o ur;  P K:  p h ar m a c o ki n eti c(s);  Tm a x : tim e  of  m a xi m u m 
c o n c e ntr ati o n.  
a  Tm a x  w as r e pr es e nt e d  as  M e di a n ( R a n g e)  
b N C  =  St atisti cs  n ot  c al c ul at e d  w h e n  N < 3  
c  Cm a x _ A c c  a n d  A U C _ A c c  ar e  a c c u m ul ati o n r ati os,  c al c ul at e d  usi n g  P K  p ar a m et ers ( C m a x  a n d  A U C 0- 4)  of  Visit  3  or  Visit  6 
di vi d e d  b y t h at  of  Visit  2 fr o m t h e s a m e  s u bj e ct  
d  N u m b er  of  S u bj e cts  =  3  
 
T h e  pl as m a  v a n c o m y ci n  e x p os ur e ( C m a x  a n d  A U C 0- 4)  w as  g e n er all y  d os e-pr o p orti o n al f or t h e  A er o V a n c  3 2  m g  a n d 
6 4  m g  d os es,  b ot h f or si n gl e -d os e  a n d  m ulti pl e -d os e  a d mi nistr ati o n.  M e a n  a c c u m ul ati o n r ati os  of  C m a x  a n d  A U C 0- 4 
r a n g e d fr o m  1. 1 3 t o  1. 3 8 f or t h e  3 2  m g  bi d  gr o u p a n d r a n g e d fr o m  0. 6 3 6 t o  0. 9 9 1 f or t h e  6 4  m g  bi d  gr o u p, 
i n di c ati n g  n o  n ot a bl e  dr u g  a c c u m ul ati o n i n  pl as m a  o v er ti m e.  
T h e  a v er a g e s p ut u m  p h ar m a c o ki n eti c  p ar a m et ers f oll o wi n g  3 2  m g  BI D  a n d  6 4  m g  BI D  A er o V a n c  a d mi nistr ati o n 
ar e  pr es e nt e d  b el o w  i n T a bl e  3 , s e p ar at e d  b y  visit.  T h e  m e a n  C m a x  a n d  A U C 0- 4 v al u es i n cr e as e d  o v er  pr o gr essi v e 
visits.  T h e  m e a n  a c c u m ul ati o n r ati os  of  C m a x  a n d  A U C 0- 4 r a n g e d fr o m  3. 6 0 t o  6. 4 7 f or t h e  3 2  m g  BI D  gr o u p a n d 
ra n g e d fr o m  2. 0 9 t o  3. 1 4 f or t h e  6 4  m g  BI D  gr o u p, i n di c ati n g  dr u g  a c c u m ul ati o n  o c c urr e d i n s p ut u m. I n  g e n er al, 
t h er e  w as  a  pr o p orti o n al i n cr e as e i n  v a n c o m y ci n  e x p os ur e ( Cm a x  a n d  A U C 0- 4)  wit h i n cr e asi n g  d os e  of  A er o V a n c f or 
si n gl e -d os e ( Visit  2,  B as eli n e,  D a y  1)  a n d  m ulti pl e -d os e  a d mi ni str ati o ns  o n  Visit  3 ( D a y  8).  T h e  e x p os ur e  a p p e ar e d 
s o m e w h at l ess t h a n  d os e-pr o p orti o n al  o n  Visit  6 ( D a y  2 9),  b ut t h es e  esti m at es  ar e l ess r eli a bl e  b e c a us e  o nl y  2 
s u bj e cts  w er e i n cl u d e d i n t h e  esti m at es f or  e a c h  d os e  gr o u p.  
St e a d y st at e i n s p ut u m  a p p e ar e d t o  h a v e  b e e n r e a c h e d  aft er  o n e  w e e k  of  a d mi nistr ati o n,  b ut  b e c a us e  of t h e s m all 
s a m pl e si z e  es p e ci all y  at t h e  6 4 -m g  d os e  aft er  2 8  d a ys  of  d osi n g,  ass ess m e nt  of st e a d y st at e  s h o ul d  b e  m a d e  wit h 
c a uti o n.  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
2 7 
T a bl e  3 : S p ut u m  P K  P a r a m et e rs . 
M e a n ( C V  %)  S p ut u m  P K  P a r a m et e rs f o r  A e r o V a n c  
P K  P ar a m et er   
Visit  2 ( D a y  1)  
Visit  3 ( D a y  7 - 8) 
Visit  6 ( D a y  2 8 - 2 9) 
3 2  m g  BI D   
6 4  m g  BI D   
3 2  m g  BI D   
6 4  m g  BI D   
3 2  m g  BI D   
6 4  m g  BI D  
N u m b er  of 
S u bj e ct s  
6 
5 
6 
3 
2 
2 
C m a x  ( µ g/ g)  
3 1 6 ( 6 7. 5)   
5 3 1 ( 4 8. 4)   
7 6 7 ( 6 0. 7)   
1 7 9 0 ( 8 4. 1)   
1 2 7 0 ( N C b)  
1 4 0 0 ( N C b) 
C m a x / D o s e 
( µ g/ g/ m g) 
9. 8 9 ( 6 7. 5)   
8. 2 9 ( 4 8. 4)   
2 4. 0 ( 6 0. 7)   
2 7. 9 ( 8 4. 1)   
3 9. 5 ( N C b)  
2 1. 8 ( N C b) 
T m a x a ( h)  
0. 2 5 ( 0. 2 5 - 0. 2 5) 0. 2 5 ( 0. 2 5 -0. 2 5)  0. 2 5 ( 0. 2 5 - 0. 2 5) 0. 2 5 ( 0. 2 5 -0. 2 5)  0. 2 5  ( 0. 2 5- 0. 2 5) 0. 2 5 ( 0. 2 5 -0. 2 5)  
C tr o u g h ( µ g/ g)  
- 
-  
7 4. 5 ( 1 6 5)   
1 1 9 ( 8 0. 8)   
8 1. 4 ( 1 1 4) g  
9 9. 0 ( N C b) 
C tr o u g h / MI C 
(( µ g/ g)/  
( µ g/ m L))f 
- 
-  
3 7. 3 ( 1 6 5)    
5 9. 3 ( 8 0. 8)   
4 0. 7 ( 1 1 4) g  
4 9. 5 ( N C b) 
A U C 0- 4 
( h•  µ g/ g) 
1 9 4 ( 4 6. 9)   
2 8 4 ( 2 6. 1)   
6 4 7 ( 6 7. 6)   
1 4 3 0 ( 9 1. 3)   
8 2 2 ( N C b)  
9 8 8  ( N Cb) 
A U C 0 -
4/ D o s e  
( h•  µ g/ g/ m g) 
6. 0 5 ( 4 6. 9)   
4. 4 4 ( 2 6. 1)   
2 0. 2 ( 6 7. 6)   
2 2. 4 ( 9 1. 3)   
2 5. 7 ( N C b)  
1 5. 4 ( N C b) 
A U C 0- 1 2 
( h•  µ g/ g)e 
- 
-  
1 1 0 0 ( 8 0. 3)   
2 4 6 0 ( 9 1. 9)   
1 4 8 0 ( N C b)   
1 6 6 0 ( N C b) 
A U C 0- 1 2/ MI C 
(( h• µ g/ g)/ 
( µ g/ m L))f 
- 
-  
5 4 9 ( 8 0. 3)   
1 2 3 0 ( 9 1. 9)   
7 4 1 ( N C b)  
8 2 9 ( N C b) 
C a v g 0- 4 c 
( µ g/ g) 
4 8. 4 ( 4 6. 9)   
7 1. 0 ( 2 6. 1)   
1 6 2 ( 6 7. 6)   
3 5 8 ( 9 1. 3)   
2 0 6 ( N C b)  
2 4 7 ( N C b) 
C m a x _ A c c d   
- 
-  
3. 6 0 ( 9 4. 6)   
2. 0 9 ( N C b)  
5. 9 6 ( N C b)  
3. 1 4 ( N C b) 
A U C _ A c c d   
- 
-  
3. 8 6 ( 8 2. 2)   
2. 2 1  ( N Cb)  
6. 4 7 ( N C b)  
3. 1 2 ( N C b) 
A b br e vi ati o ns:  A c c:  a c c u m ul ati o n r ati o;  A U C:  ar e a  u n d er t h e  c o n c e ntr ati o n -ti m e  c ur v e;  BI D: t wi c e  d ail y;  C a v g:  a v er a g e 
c o n c e ntr ati o n;  C m a x :  m a xi m u m  c o n c e ntr ati o n;  Ctr o u g h:  c o n c e ntr ati o n  at t h e  e n d  of t h e  d osi n g i nt er v al;  h:  h o ur;  MI C:  mi ni m u m 
i n hi bit or y  c o nc e ntr ati o n;  P K:  p h ar m a c o ki n eti c(s);  T m a x : ti m e  of  m a xi m u m  c o n c e ntr ati o n. 
a    Tm a x  w as r e pr es e nt e d  as  M e di a n ( R a n g e)  
b  N C  =  St atisti cs  n ot  c al c ul at e d  w h e n  N  <  3  
c  C a v g 0- 4 is t h e  a v er a g e  c o n c e ntr ati o n  of t h e 4- h o ur  s a m pli n g  p eri o d,  c al c ul at e d  b y  A U C 0- 4/ 4 
d    Cm a x _ A c c  a n d  A U C _ A c c  ar e  a c c u m ul ati o n r ati os,  c al c ul at e d  usi n g  P K  p ar a m et ers ( C m a x  a n d  A U C 0- 4)  of  Visit  3  or  Visit 6 
di vi d e d  b y t h at  of  Visit  2 fr o m t h e s a m e  s u bj e ct  
e  1 2 -h o ur  c o n c e ntr ati o n  w as i m p ut e d t o t h e  pr e -d os e  v al u e f or t h e  c al c ul ati o n  of  A U C 0- 1 2 of  m ulti pl e -d os e  a d mi nistr ati o n 
( Visits 3  a n d  6).  ( A U C 0- 1 2  v al u e  usi n g i m p ut e d  1 2 -h o ur  c o n c e ntr ati o n  v al u e is  a r e as o n a bl e  esti m at e if st e a d y -st at e  c a n  b e 
pr es u m e d,  ot h er wis e  A U C 0- 1 2 is  u n d er esti m at e d,  a n d t h er ef or e  A U C/ MI C is  a  c o ns er v ati v e  esti m at e) 
f  MI C  =  Mi ni m u m i n hi bit or y  c o n c e ntr ati o n ( MI C)  of  v a n c o m y ci n f or  m et hi cilli n -r esist a nt  St a p h yl o c o c c us  a ur e us ( M R S A) 
( 2 µ g/ m L)  
g  N u m b er  of  S u bj e cts  =  3  
3. 2. 4   S af et y 
T h e  P h as e  II cli ni c al st u d y  d e m o nstr at e d t h e  A er o V a n c  3 2  m g  d os e  w as  w ell t ol er at e d,  wit h  n o  n ot a bl e  diff er e n c e 
fr o m  pl a c e b o i n t h e  o c c urr e n c e, s e v erit y  or r el at e d n ess  of tr e at m e nt-e m er g e nt  a d v ers e  e v e nt s ( T E A Es ).  H o w e v er, 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
2 8 
t h e  A er o V a n c  6 4  m g  d os e  w as  ass o ci at e d  wit h  hi g h er s e v erit y,  a n d r el at e d n ess  of  T E A Es,  as  w ell  as  a  hi g h er 
fr e q u e n c y  of st u d y  dr u g  dis c o nti n u ati o ns, s u g g esti n g t h e  hi g h er  d os e is  n ot  w ell t ol er at e d. I n  s u bj e cts <  2 1  y e ars  of 
a g e, s af et y  a n d t ol er a bilit y  w as si mil ar t o  or  b ett er t h a n  pl a c e b o  at  b ot h  d os e l e v els.  
T h e i n ci d e n c e  of  T E A Es  wit h  o ns et  d uri n g t h e  Tr e at m e nt  P eri o d  w as si mil ar  b et w e e n tr e at m e nt  gr o u ps i n  e a c h 
c o h ort (r a n g e,  8 2. 6 % t o  9 0. 0 %).  T h e  m ost  c o m m o n  T E A E  w as  c o u g h,  wit h  n o  n ot a bl e  diff er e n c e  b et w e e n t h e  d os e 
c o h orts  or  b et w e e n  a cti v e  a n d  pl a c e b o.  Si g ns  a n d s y m pt o ms  c o nsi st e nt  wit h  p ot e nti al  br o n c h o c o nstri cti o n  w er e 
o bs er v e d sli g htl y  m or e  oft e n i n t h e  a cti v e tr e at m e nt  gr o u ps,  b ut  wit h  n o  n ot a bl e  diff er e n c e  b et w e e n t h e t w o  d os e 
c o h orts.  T h es e  e v e nts i n cl u d e d  d ys p n e a,  c h est  dis c o mf ort,  br o n c h o c o nstri cti o n,  a n d  F E V 1 d e cr e as e  (T a bl e  4 ). 
N o  d e at hs  w er e r e p ort e d  d uri n g t h e  st u d y.  S eri o us  a d v ers e  e v e nt s ( S A Es)  w er e  e x p eri e n c e d  b y  4  s u bj e cts a n d  1 
s u bj e ct i n t h e  A er o V a n c 3 2  m g  a n d  6 4  m g  gr o u ps, r es p e cti v el y,  a n d  b y  2  a n d  4  s u bj e cts i n t h e  C o h ort  1  a n d  C o h ort 
2  pl a c e b o  gr o u ps, r es p e cti v el y.   
T h e  m aj orit y  of  all  a d v ers e  e v e nt s  ( A Es) w er e  mil d  or  m o d er at e,  a n d t h er e  w as  a s hift fr o m  mil d t o  m o d er at e  A Es  i n 
t h e  6 4  m g  A er o V a n c  c oh ort  as  c o m p ar e d  wit h t h e  3 2  m g  A er o V a n c  c o h ort,  a n d t h e  pl a c e b o  gr o u ps.  T h er e  w as  n o 
n ot a bl e  diff er e n c e  b et w e e n t h e tr e at m e nt  gr o u ps i n t h e  o c c urr e n c e  of s e v er e  T E A Es.  T h e i n ci d e n c e  of tr e at m e nt -
r el at e d  T E A Es ( T E A Es  c o nsi d er e d  p ossi bl y,  pr o b a bl y,  or r el at e d t o st u d y  dr u g)  w as si mil ar ( 2 1. 7  % t o  2 5. 0  %) i n 
t h e  A er o V a n c  3 2  m g  c o h ort  a n d t h e  pl a c e b o  gr o u ps,  w h er e as it  w as  hi g h er ( 5 8. 3  %) i n t h e  A er o V a n c  6 4  m g  gr o u p. 
A t ot al  of  2 3  s u bj e cts dis c o nti n u e d st u d y  dr u g  pri or t o  D a y  2 9.  T hr e e  s u bj e cts dis c o nti n u e d i n t h e  3 2  m g  gr o u p,  6 
s u bj e cts i n t h e  C o h ort  1  pl a c e b o  gr o u p,  1 3 s u bj e ct s i n t h e 6 4  m g  gr o u p,  a n d  1  s u bj e ct i n t h e  C o h ort  2  pl a c e b o  gr o u p. 
T h e  m aj orit y  of  s u bj e cts, 1 9 / 2 3,  dis c o nti n u e d  d u e t o  eit h er  a  T E A E  or  dr u g i nt ol er a n c e.  T h e  pr o p orti o n of  s u bj e cts 
w h o  dis c o nti n u e d st u d y  dr u g  pri or t o  d a y  2 9  d u e t o  a  T E A E  w as  5. 0  %,  2 5. 0  %,  4 1. 7  %,  a n d  0  % i n t h e  A er o V a n c 
3 2  m g ,  C o h ort  1  pl a c e b o,  A er o V a n c 6 4  m g,  a n d  C o h ort  2  pl a c e b o  gr o u ps,  r es p e cti v el y (T a bl e  5 ). 
T h e r es ult s  of  p ost -h o c  a n al ys es s u g g est e d t h at  s u bj e cts <  2 1  y e ars  of  a g e tr e at e d  wit h  A er o V a n c  3 2  m g  a n d  6 4  m g  
e x p eri e n c e d  T E A Es  at  a n i n ci d e n c e l ess t h a n  or si mil ar t o t h at  of  pl a c e b o  s u bj e cts. I n s u bj e cts ≥  2 1  y e ars  of  a g e, t h e 
o bs er v e d  T E A E i n ci d e n c e r at es  w er e  hi g h er i n t h e  A er o V a n c  gr o u ps  c o m p ar e d t o t h e  c orr es p o n di n g  pl a c e b o  gr o u ps 
( 1. 56  a n d  1. 8 4 f or t h e  A er o V a n c  3 2  m g  a n d  A er o V a n c  6 4  m g  gr o u ps, r es p e cti v el y).  N o  c o nsist e nt  or tr e a t m e nt-
r el at e d  c h a n g es i n  a n y  h e m at ol o g y,  c h e mi str y,  or  uri n al ysis l a b or at or y  p ar a m et er  v al u es,  vit al si g ns  m e as ur e m e nt, 
or  E C G  p ar a m et er  v al u es  w er e  n ot e d.  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
2 9 
T a bl e  4 : I n ci d e n c e  of  a d v e rs e  e v e nts  o c c u r ri n g i n  ≥ 2 s u bj e cts i n  at l e ast  o n e t r e at m e nt  g r o u p  a n d  wit h  a n  o ns et  d u ri n g 
t h e t r e at m e nt  p e ri o d. 
 
S yst e m  O r g a n  Cl ass  
  
P r ef e r r e d  T e r m  
C o h o rt  1  
C o h o rt  2   
P o ol e d  C o h o rts  
A e r o V a n c  
3 2  m g  
( N = 2 0) 
Pl a c e b o  
 
( N = 2 0) 
A e r o V a n c  
6 4  m g  
( N = 2 4) 
Pl a c e b o  
 
( N = 2 3) 
A e r o V a n c  
3 2 & 6 4  m g  
( N = 4 4) 
Pl a c e b o  
 
( N = 4 3) 
 
n ( %)   
n ( %)   
n ( %)   
n ( %)   
n ( %)   
n ( %)  
S u bj e ct s r e p orti n g  ≥  1  T E A E  Wit h  O ns et 
D uri n g t h e  Tr e at m e nt  P eri o d  
1 8 ( 9 0. 0)   
1 8 ( 9 0. 0)   
2 0 ( 8 3. 3)   1 9 ( 8 2. 6)   3 8 ( 8 6. 4)   3 7 ( 8 6. 0)  
 C o u g h  
9 ( 4 5. 0)   
7 ( 3 5. 0)   
9 ( 3 7. 5)   1 0 ( 4 3. 5)   1 8 ( 4 0. 9)   1 7 ( 3 9. 5)  
 R es pir at or y tr a ct  c o n g esti o n  
8 ( 4 0. 0)   
4 ( 2 0. 0)   
7 ( 2 9. 2)   
7 ( 3 0. 4)   1 5 ( 3 4. 1)   1 1 ( 2 5. 6)  
 F ati g u e  
5 ( 2 5. 0)   
4 ( 2 0. 0)   
8 ( 3 3. 3)   
3 ( 1 3. 0)   1 3 ( 2 9. 5)   
7 ( 1 6. 3)  
 S p ut u m i n cr e as e d  
6 ( 3 0. 0)   
7 ( 3 5. 0)   
6 ( 2 5. 0)   
5 ( 2 1. 7)   1 2 ( 2 7. 3)   1 2 ( 2 7. 9)  
 P ar a n as al si n us  h y p ers e cr eti o n  
6 ( 3 0. 0)   
3 ( 1 5. 0)   
4 ( 1 6. 7)   
1 ( 4. 3)   
1 0 ( 2 2. 7)   
4 ( 9. 3)  
 D ys p n o e a  e x erti o n al  
4 ( 2 0. 0)   
2 ( 1 0. 0)   
5 ( 2 0. 8)   
3 ( 1 3. 0)   
9 ( 2 0. 5)   
5 ( 1 1. 6)  
 I nf e cti v e  p ul m o n ar y  e x a c er b ati o n  of 
 c ysti c fi br o sis  
3 ( 1 5. 0)   
5 ( 2 5. 0)   
5 ( 2 0. 8)   
2 ( 8. 7)   
8  ( 1 8. 2)  
7 ( 1 6. 3)  
 E x er cis e t ol er a n c e  d e cr e a s e d  
5 ( 2 5. 0)   
1 ( 5. 0)   
2 ( 8. 3)   
2 ( 8. 7)   
7 ( 1 5. 9)   
3 ( 7. 0)  
 F or c e d  e x pir at or y  v ol u m e  d e cr e as e d   
4 ( 2 0. 0)   
2 ( 1 0. 0)   
3 ( 1 2. 5)   
1 ( 4. 3)   
7 ( 1 5. 9)   
3 ( 7. 0)  
 C h e st  dis c o mf ort  
2 ( 1 0. 0)   
0   
4 ( 1 6. 7)   
0   
6 ( 1 3. 6)   
0  
 Si n u s  h e a d a c h e  
4  ( 2 0. 0)  
1 ( 5. 0)   
2 ( 8. 3)   
3 ( 1 3. 0)   
6 ( 1 3. 6)   
4 ( 9. 3)  
 W ei g ht  d e cr e as e d  
4 ( 2 0. 0)   
1 ( 5. 0)   
2 ( 8. 3)   
1 ( 4. 3)   
6 ( 1 3. 6)   
2 ( 4. 7)  
 D ys p n o e a  
3 ( 1 5. 0)   
1 ( 5. 0)   
2 ( 8. 3)   
0   
5 ( 1 1. 4)   
1 ( 2. 3)  
 I n cr e as e d  vis c o sit y  of  br o n c hi al  s e cr eti o n  
1 ( 5. 0)   
3 ( 1 5. 0)   
3 ( 1 2. 5)   
2 ( 8. 7)   
4  ( 9. 1)  
5 ( 1 1. 6)  
 D e cr e as e d  a p p etit e  
0   
2 ( 1 0. 0)   
3 ( 1 2. 5)   
4 ( 1 7. 4)   
3 ( 6. 8)   
6 ( 1 4. 0)  
 Di arr h o e a  
0  
0   
3 ( 1 2. 5)   
0   
3 ( 6. 8)   
0  
 Br o n c h o s p as m  
0  
0   
2 ( 8. 3)   
0   
2 ( 4. 5)   
0  
 D ys g e u si a  
2 ( 1 0. 0)   
0   
0   
0   
2 ( 4. 5)   
0  
 H a e m o pt ysis  
1 ( 5. 0)   
0   
1 ( 4. 2)   
4 ( 1 7. 4)   
2 ( 4. 5)   
4 ( 9. 3)  
 Or o p h ar y n g e al  p ai n  
2 ( 1 0. 0)   
0   
0   
0   
2 ( 4. 5)   
0  
 S p ut u m  dis c ol o ur e d  
0   
1 ( 5. 0)   
2 ( 8. 3)   
1 ( 4. 3)   
2 ( 4. 5)   
2 ( 4. 7)  
 W h e e zi n g  
1 ( 5. 0)   
2 ( 1 0. 0)   
1 ( 4. 2)   
0   
2 ( 4. 5)   
2 ( 4. 7)  
 
 
 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
3 0 
T a bl e  5 : S u bj e ct  E a rl y  Dis c o nti n u ati o ns . 
S u bj e ct  E a rl y  Dis c o nti n u ati o n  
 
C o h o rt  1   
C o h o rt  2   
C o h o rts  1 & 2  
T ot al  
A e r o V a n c  
3 2  m g  
Pl a c e b o  
 
A e r o V a n c  
6 4  m g  
Pl a c e b o  
 
A e r o V a n c  
3 2 & 6 4 m g  
Pl a c e b o  
 
 
n ( %)   
n ( %)   
n ( %)   
n ( %)   
n ( %)   
n ( %)   
n ( %)  
S af et y  P o p ul ati o n  
2 0 ( 1 0 0)   2 0 ( 1 0 0)   2 4 ( 1 0 0)   2 3 ( 1 0 0)   4 4 ( 1 0 0)   4 3 ( 1 0 0)   8 7 ( 1 0 0)  
Dis c o nti n u e d  St u d y  Dr u g  Pri or t o 
D a y  2 9 ( Visit  6)  
3 ( 1 5. 0)   
6 ( 3 0. 0)   1 3 ( 5 4. 2)   
1 ( 4. 3)   
1 6 ( 3 6. 4)   7 ( 1 6. 3)   2 3 ( 2 6. 4)  
P ri m a r y  R e a s o n f o r  Dis c o nti n u ati o n  of  St u d y  D r u g ( All  S u bj e cts ) 
 A d v ers e  E v e nt  
1 ( 5. 0)   
5 ( 2 5. 0)   1 0 ( 4 1. 7)   
0  
1 1 ( 2 5. 0)   5 ( 1 1. 6)   1 6 ( 1 8. 4) 
 St u d y  Dr u g I nt ol er a n c e  
0   
1 ( 5. 0)   
2 ( 8. 3)   
0   
2 ( 4. 5)   
1 ( 2. 3)   
3 ( 3. 4)  
 S u bj e ct  Wit h dr e w 
C o ns e nt/ Ass e nt  
1 ( 5. 0)   
0   
0   
0   
1 ( 2. 3)   
0   
1 ( 1. 1)  
 I n v e sti g at or  D e cisi o n 
1 ( 5. 0)   
0   
0   
0   
1 ( 2. 3)   
0   
1 ( 1. 1)  
Ot h er  
0   
0   
1 ( 4. 2)   
1 ( 4. 3)   
1 ( 2. 3)   
1 ( 2. 3)   
2 ( 2. 3)  
3. 2. 4. 1   S e ri o us  A d v e rs e  E v e nts  
N o  d e at hs  w er e r e p ort e d  d uri n g t h e  st u d y.  El e v e n  s u bj e cts e x p eri e n c e d  a t ot al  of  1 5  S eri o us  A d v ers e  E v e nt s 
(S A Es ), i n cl u di n g  1 0  S A Es  of i nf e cti v e  p ul m o n ar y  e x a c er b ati o n  of  c ysti c fi br osis  a n d  1  S A E  e a c h  of i nf e cti v e 
e x a c er b ati o n  of  br o n c hi e ct asi s,  p ai n,  h y p er gl y c e mi a,  p n e u m o ni a,  a n d  pl e ur al  eff usi o n.  N o n e  of t h e  S A Es  w er e 
c o nsi d er e d t o  b e r el at e d t o st u d y  dr u g.  All  of t h e  S A Es r e q uir e d  h os pit ali z ati o n  wit h t h e  e x c e pti o n  of  1  S A E  of 
i nf e cti v e  p ul m o n ar y  e x a c er b ati o n  of  c ysti c fi br osis.  All  S A Es r es ol v e d ( 1 1 wit h o ut  s e q u el a e ). S A Es  w er e 
e x p eri e n c e d  b y  4 s u bj e ct s  a n d  1  s u bj e ct i n t h e  A er o V a n c 3 2  m g  a n d  6 4  m g  gr o u ps, r es p e cti v el y,  a n d  b y  2  a n d 
4  s u bj e cts i n t h e  C o h ort  1  a n d  C o h ort  2  pl a c e b o  gr o u ps, r es p e cti v el y.   
3. 2. 5   Effi c a c y  R es ults 
3. 2. 5. 1   S u bj e cts l ess t h a n  2 1  y e a rs  of  a g e 
A  p ost  h o c  a n al ysis  of t h e  F E V 1 d at a s h o w e d t h at t h e l a c k  of  F E V 1 i m pr o v e m e nt  w as  dri v e n  pri m aril y  b y  a d ult 
s u bj e cts. I n  c o ntr ast,  e n c o ur a gi n g i m pr o v e m e nts i n  F E V1 w er e  o bs er v e d i n  y o u n g er  s u bj e ct s,  as  d es cri b e d  b el o w. 
T h es e r es ult s  ar e  c o nsi st e nt  wit h  pr e vi o us st u di es  usi n g i n h al e d t o br a m y ci n ( T O BI  or  T O BI  P o d h al er ®) f or t h e 
tr e at m e nt  of P.  a er u gi n os a  i nf e cti o n i n  C F,  w h er e  a n i m pr o v e m e nt i n  F E V1 is  pr e d o mi n a ntl y s e e n i n  y o u n g er 
s u bj e cts ( W e ers,  2 0 1 5). I n  or d er t o s el e ct  a n  a p pr o pri at e  a g e  c ut off f or t h e  A er o V a n c s u b gr o u p  a n al ys es,  g ui d a n c e 
w as s o u g ht fr o m  a l ar g e r e tr os p e cti v e st u d y  b y  D as e n br o o k ( D as e n br o o k  E C  M.  C.-W.,  2 0 0 8) ,  w hi c h s h o w e d t h at 
p ersist e nt  M R S A i nf e cti o n i n  C F  s u bj e cts  8 –2 1  y e ars  of  a g e  w as  ass o ci at e d  wit h  a f ast er  d e cli n e i n l u n g f u n cti o n. 
As  d es cri b e d i n  m or e  d et ail  b el o w,  cli n i c all y  m e a ni n gf ul,  b ut st atisti c all y  n o n-si g nifi c a nt, i m pr o v e m e nts  w er e 
o bs er v e d  aft er  A er o V a n c tr e at m e nt i n  s u bj e ct s  <  2 1  y e ars  of  a g e i n  F E V 1,  C F R S D-C RI S S, ti m e t o  n e e d  of  ot h er 
a nti bi oti cs,  a n d ti m e t o  e x a c er b ati o n.   
A  m e a n r e d u cti o n  of  0. 7 l o g 1 0 C F U/ m L fr o m  b as eli n e i n  M R S A  C F U s, t h e  pri m ar y  e n d p oi nt,  w as  o bs er v e d  aft er  2 8 
d a ys  of  A er o V a n c  a d mi nistr ati o n i n s u bj e cts  b el o w  2 1  y e ars  of  a g e  (Fi g ur e  5 ),  al b eit  n ot st atisti c all y  si g nifi c a nt  d u e 
t o t h e li mit e d  n u m b er  of s u bj e ct s. 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
3 1 
 
 
Fi g u r e  5 : C h a n g e i n  M R S A  D e nsit y i n  S p ut u m i n  S u bj e cts l ess t h a n  2 1  Y e a rs  of  A g e . 
I n s u bj e ct s l ess t h a n  2 1  y e ars  ol d, t h e  m e a n  c h a n g e fr o m  b as eli n e i n t h e  d ail y s ym pt o m  di ar y,  C F R S D -C RI S S, 
s h o w e d  a  gr e at er r e d u cti o n i n  C RI S S t h at  w as  o bs er v e d  c o nsi st e ntl y  at  all ti m e  p oi nt s,  as  c o m p ar e d  wit h  pl a c e b o, 
b ut t h e  diff er e n c e  w as  n ot st atisti c all y  si g nifi c a nt.  
T h e  a n al ys es  als o i d e ntifi e d  e n c o ur a gi n g i m pr o v e m e nt i n  F E V 1 i n s u bj e ct s  2 1  y e ars  of  a g e  or  y o u n g er  a cr oss  all 
ti m e  p oi nts  d uri n g t h e tr e at m e nt  p eri o d (Fi g ur e  6 ). T h e  m e a n   abs ol ut e  c h a n g e i n  F E V 1 p er c e nt  pr e di ct e d  o bs er v e d 
i n t h e  A er o V a n c  3 2  m g  bi d  ar m is  c o nsi d er e d  cli ni c all y  m e a ni n gf ul,  wit h  a n i m pr o v e m e nt r a n gi n g  b et w e e n  4 %  a n d 
6  % ( or  6  %  a n d  1 0  %  o n  a r el ati v e  c h a n g e  b asis),  al b eit  n ot st atisti c all y  si g nifi c a nt  d u e t o t h e li mit e d  n u m b er  of 
s u bj e cts.  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
3 2 
 
 
Fi g u r e  6 : A bs ol ut e  C h a n g e f r o m  B as eli n e i n  F E V 1 P e r c e nt  P r e di ct e d i n  S u bj e cts l ess t h a n  2 1  Y e a rs  of  A g e.  
A tr e n d  of  pr ol o n g ati o n  of t h e ti m e t o  us e  of  a n ot h er  a nti bi oti c f or r es pir at or y s y m pt o ms  w as  o bs er v e d i n t h e 
A er o V a n c  ar m  of t h e  3 2  m g  d os e  c o h ort,  as  c o m p ar e d  wit h  pl a c e b o  (Fi g ur e  7 ).  W h er e as i n t his si n gl e  c y cl e st u d y 
s e v er al s u bj e ct s i n t h e  A er o V a n c  ar m  w er e  pr es cri b e d  ot h er  a nti bi oti cs  at t h e s c h e d ul e d  o n e -m o nt h  p ost -tr e at m e nt 
visit ( a p pr o xi m at el y  D a y  5 6), s u c h tr e at m e nt  w o ul d  n ot  b e  e x p e ct e d t o  b e  pr es cri b e d  d uri n g  c hr o ni c  A er o V a n c 
tr e at m e nt,  or i n  a  m ulti pl e-c y cl e st u d y,  b e c a us e t h e ti mi n g  w o ul d  c oi n ci d e  wit h t h e  st art  of  a  n e w  A er o V a n c 
tr e at m e nt  p eri o d.  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
3 3 
 
 
Fi g u r e  7 : Ti m e t o  Us e  of  Ot h e r  A nt i bi oti cs f o r  R es pi r at o r y I nf e cti o n i n  S u bj e cts l ess t h a n  2 1  Y e a rs  of  A g e. 
4   S T U D Y  R A TI O N A L E  
I n th e   Ph as e II st u d y  ( S A V 0 0 5-0 2),  A er o V a n c  d e m o nstr at e d  a r e d u cti o n i n  M R S A  d e nsit y i n s p ut u m  al o n g  wit h 
i m pr o v e m e nt i n r es pir at or y s y m pt o ms, l u n g f u n cti o n, pr ol o n g ati o n  of t h e ti m e t o  n e e d  of  ot h er  a nti bi oti cs,  a n d ti m e 
t o  p ul m o n ar y  e x a c er b ati o n. S u bj e cts  <  2 1  y e ars  of  a g e  s h o w e d t h e  b est i m pr o v e m e nt s  a cr oss  e a c h  of t h e  e n d p oi nts 
w h e n  c o m p ar e d t o t h e  ol d er  p o p ul ati o n .  T h e  c o nsist e n c y  of t h e r es p o ns es  a cr oss t h e  diff er e nt  e n d p oi nts,  as  w ell  as 
t h e  m a g nit u d e  of  c h a n g e, s u p p orts  a d v a n ci n g t h e  pr o d u ct i nt o t h e  n e xt  p h as e  of  d e v el o p m e nt.  
T h e st u d y i s  d esi g n e d  as  a  pl a c e b o -c o ntr oll e d  st u d y  d u e t o t h e l a c k  of  a st a n d ar d  of  c ar e i n t h e tr e at m e nt  of  M R S A 
l u n g i nf e cti on i n  s u bj e cts  wit h C F.  B as e d  o n t h e r e q uir e m e nt  of t h e  F D A, t h e  d ur ati o n  of t h e  pl a c e b o -c o ntr oll e d 
p eri o d  of t h e st u d y  will  b e  3  d osi n g  c y cl es,  e a c h  c y cl e  b ei n g  2 8  d a ys  of tr e at m e nt f oll o w e d  b y  2 8  d a ys  of 
o bs er v ati o n.  A  c y cli c  d osi n g r e gi m e n  w as  c h o s e n  as it i s  w ell  est a bli s h e d f or  e. g.  a nti -ps e u d o m o n al i n h al ati o n 
t h er a p y.  T h e l o w d os e  w as  c h os e n  b as e d  o n  t h e P h as e II st u d y  as it  w as  w ell t ol er at e d  a n d  ass o ci at e d  wit h 
i m pr o v e m e nt s i n  mi cr o bi ol o g y  a n d tr e n ds i n i m pr o v e m e nt  of l u n g f u n cti o n  a n d ti m e t o  a nti bioti c tr e at m e nt, 
w h er e as t h e  hi g h  d os e  w as l ess t ol er at e d  a n d  ass o ci at e d  wit h  a  hi g h er  n u m b er  of tr e at m e nt  dis c o nti n u ati o ns.  
T h e  pri m ar y  a n d s e c o n d ar y  effi c a c y  e n d p oi nts  will  b e  m e as ur e d  a n d  ass ess e d  d uri n g t his  pl a c e b o -c o ntr oll e d  p eri o d.  
I n  or d er t o f urt h er  e v al u at e t h e  s af et y  of  A er o V a n c  d uri n g  m ulti pl e  c y cl es  of  a d mi nistr ati o n, t h e st u d y  will i n cl u d e 
a n  o p e n l a b el  e xt e nsi o n  of  3  a d diti o n al  c y cl es.  D uri n g t h e  e xt e nsi o n,  s u bj e ct s  will  be  f oll o w e d f or  a d v ers e  e v e nt s,  as 
w ell  as f or  mi cr o bi ol o g y  a n d  p ul m o n ar y  f u n cti o n t est s (P F Ts ). I n  a d diti o n t o s af et y  e v al u ati o n, t h e l att er  will  b e 
m e as ur e d t o  ass ess  c o nti n u e d  effi c a c y  of t h e tr e at m e nt  b ut  will  n ot  b e  us e d  as  p art  of t h e f or m al  effi c a c y  e v al u ati o n.  
5   S T U D Y  O B J E C T I V E S  
5. 1   P ri m a r y  O bj e cti v e  
T h e  pri m ar y  o bj e cti v e  of  t h e st u d y i s t o  e v al u at e t h e  effi c a c y  of  A er o V a n c i n i m pr o vi n g l u n g f u n cti o n  of  C F 
p ati e nts  ≤  2 1  y e ars  of  a g e  wit h  p ersi st e nt  M R S A l u n g i nf e cti o n.  
N u m b er  at ri s k :
H a z ar d  R ati o  (9 5  %  CI ): 0 .5 8  (0 .1 7 , 1 .9 7 )
P -v al u e : 0 .3 7 8 4
Tr e at m e nt
Off  Tr e at m e nt
Off  Tr e at m e nt
1 0 
1 0 
9 
9 
9 
8 
8 
8 
8 
5 
5 
5 
4 
0 
0
1 0 
9 
8 
8 
6 
5 
4 
4 
4 
4 
4 
4 
3 
1 
0
0
2 5
5 0
7 5
1 0 0
0 
7 
1 4 
2 1 
2 8 
3 5 
4 2 
4 9 
5 6 
6 3 
7 0 
7 7 
8 4 
9 1 
9 8
St u d y  D a y
P er c e nt  of  P ati e nt s  Wit h o ut  E v e nt
A er o Va n c  3 2  m g 
Pl a c e b o
1 0
= 
n 
: 
Pl a c e b o
, 
1 0
= 
n 
: 
A er o V a n c
, 
y e ar s  of   a g e
2 1 
,  < 
MI T T


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
3 4 
5. 2  
 S e c o n d a r y  O bj e cti v es  
T h e s e c o n d ar y  o bj e cti v es  of t h e st u d y  ar e : 
•   T o  e v al u at e t h e t i m e t o first p ul m o n ar y  e x a c er b ati o n  r e q uiri n g us e  of  a n ot h er  a nti bi oti c  m e di c ati o n ( or al, 
i ntr a v e n o us,  a n d/ or i n h al e d) a n d t h e fr e q u e n c y  of  p ul m o n ar y  e x a c er b ati o ns .  
•   T o  e v al u at e t h e  effi c a c y  of  A er o V a n c i n t h e r e d u cti o n  of r es pir at or y s y m pt o ms  a n d i m pr o v e m e nt i n  q u alit y 
of lif e . 
•   T o  e v al u at e t h e s af et y  a n d t ol er a bilit y  of  A er o V a n c  d uri n g  3 tr e at m e nt  c y cl es ( 2 4  w e e ks) . 
6   I N V E S T I G A TI O N A L  P L A N  
6. 1   St u d y  P o p ul ati o n 
S u bj e cts  wit h  a  di a g n osi s  of  c ysti c  fi br osis  wit h c o nfir m e d  p ersist e nt  M R S A  l u n g i nf e cti o n w h o  m e et t h e i n cl usi o n 
a n d  e x cl usi o n  crit eri a  will  b e  eli gi bl e f or  p arti ci p ati o n i n t his st u d y.  T w o -h u n dr e d ( 2 0 0)  s u bj e ct s  ar e  e x p e ct e d t o  b e 
e nr oll e d i n t h e st u d y  at  a p pr o xi m at el y  8 5  c e nt ers i n t h e  U nit e d  St at es ( U S)  a n d  C a n a d a.  S u bj e ct s  will  b e r a n d o mi z e d 
t o r e c ei v e  A er o V a n c ( n = 1 0 0);  or  pl a c e b o ( n = 1 0 0). It is  a nti ci p at e d t h at  u p t o  2 4 0 s u bj e cts  m a y  n e e d t o  b e s cr e e n e d 
i n  or d er t o  e nr oll t h e t ar g et e d  n u m b er  of s u bj e cts. 
6. 2   St u d y  D esi g n  
S A V 0 0 5 -0 4 is  a r a n d o mi z e d,  m ulti c e nt er,  d o u bl e -bli n d,  pl a c e b o -c o ntr oll e d,  p ar a ll el-gr o u p st u d y t o  e x a mi n e t h e 
s af et y  a n d  effi c a c y  of  A er o V a n c i n t h e tr e at m e nt  of  p ersist e nt  M R S A l u n g i nf e cti o n i n  p ati e nts  di a g n os e d  wit h 
c ysti c fi br osis.  
Aft er  a  S cr e e ni n g  p eri o d ( u p t o  4 2  d a ys)  t o  c o nfir m  eli gi bilit y f or st u d y  p arti ci p ati o n, s u bj e cts will  b e r a n d o m l y 
assi g n e d i n  a  bli n d e d f as hi o n  t o r e c ei v e  eit h er  A er o V a n c 3 0  m g t wi c e  d ail y ( BI D ),  or  pl a c e b o BI D  ( 1: 1  a cti v e t o 
pl a c e b o)  b y i n h al ati o n f or  2 4  w e e ks  or  3  d osi n g  c y cl es ( P eri o d  1).  U p o n  c o m pl eti o n  of  P eri o d  1, s u bj e cts  will 
r e c ei v e  o p e n-l a bel  A er o V a n c  3 0  m g  BI D  f or  a n  a d diti o n al  2 4  w e e ks  or  3  d osi n g  c y cl es ( P eri o d  2), t o  e v al u at e l o n g-
t er m s af et y  of  A er o V a n c.  A  d osi n g  c y cl e is  d efi n e d  b y  2 8  d a ys  of tr e at m e nt f oll o w e d  b y  2 8  d a ys  of  o bs er v ati o n. 
S u bj e cts  m e eti n g t h e  eli gi bilit y  crit eri a  a n d  e n t eri n g t h e st u d y will  b e  str atifi e d  u p o n r a n d o mi z ati o n  o n t h e  b asis  of 
( a)  a g e ( 6– 2 1;  >  2 1), ( b)  B as eli n e  F E V 1 ( ≥ 6 0 %;  < 6 0 %), ( c)  pri or  e x a c er b ati o ns tr e at e d  wit h  a nti bi oti cs  d uri n g t h e 
pr e vi o us  1 2  m o nt hs ( 1 -2;  ≥  3 )  a n d ( d) P.  a er u gi n os a  tr e at m e nt ( n ot tr e at e d; tr e at e d).  
S u bj e cts  o n  a  2 8 -d a y  c y cli c al  o n/ off  a nti -Ps e u d o m o n al  a nti bi oti c r e gi m e n  will  e nt er t h e  S cr e e ni n g  p eri o d  at  a ti m e 
s u c h t h at t h e  B as eli n e  visit  c oi n ci d es  wit h t h e  e n d  of t h eir  a nti -Ps e u d o m o n as  a nti bi oti c  c y cl e.  St u d y  dr u g  will 
t h er e b y b e  a d mi nist er e d  d uri n g t h e  off -c y cl e,  a n d s u bj e cts  c a n t h e n r es u m e  a nti -Ps e u d o m o n al t h er a p y  d uri n g t h e  2 8 -
d a y  o bs er v ati o n  p eri o d ( W e e k  5 t hr o u g h  W e e k  8).  S u bj e cts  c o nti n ui n g  alt er n ati n g  a nti -Ps e u d o m o n al t h er a p y  c a n 
c o nti n u e t h eir tr e at m e nt  d uri n g t h e st u d y  dr u g  a d mi nistr ati o n  a n d  o bs er v ati o n  p eri o d s.  
T h e  pri m ar y  effi c a c y  a n d s af et y  p ar a m et ers  will  b e  m e as ur e d  d uri n g t h e  3 -c y cl e,  d o u bl e -bli n d tr e at m e nt  p orti o n  of 
t h e st u d y ( P eri o d  1).  U p o n  c o m pl eti o n  of t h e  d o u bl e-bli n d  p orti o n, s u bj e cts  will  h a v e t h e  o pti o n  t o  c o nti n u e i nt o  a n 
o p e n -l a b el  p orti o n i n  w hi c h  s u bj e cts  will r e c ei v e  A er o V a n c 3 0  m g  BI D  f or  3,  2 8-d a y  d osi n g  c y cl es ( P eri o d  2).  S e e 
Fi g ur e  8  b el o w.  
 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
3 5 
 
Fi g u r e  8 :  St u d y  D esi g n. 
6. 3   Effi c a c y  a n d  S af et y  E v al u ati o ns 
Effi c a c y  ass ess m e nt s  will i n cl u d e  p ul m o n ar y f u n cti o ns t ests ( P F T),  p ul m o n ar y  e x a c er b ati o ns,  p ati e nt  r e p ort e d 
o ut c o m es  a n d  s p ut u m mi cr o bi ol o g y i n cl u di n g  M R S A  d e nsit y,  v a n c o m y ci n s us c e pti bilit y,  a n d  e m er g e n c e  of 
a d diti o n al  p at h o g e ns.  S af et y  ass ess m e nts  will i n cl u d e  all  a d v ers e  e v e nt s ( A Es),  as  w ell  as st a n d ar d  h e m at ol o g y, 
bi o c h e mistr y,  a n d  uri n e  a n al ys es,  vit al si g ns,  p h ysi c al  e x a mi n ati o n,  a n d  el e ctr o c ar di o gr a m ( E C G).  
6. 4   I n cl usi o n  C rit e ri a 
S u bj e cts  m ust  m e et  all  of  t h e f oll o wi n g  crit eri a t o  b e  c o nsi d er e d  eli gi bl e t o  p arti ci p at e i n t h e st u d y:  
1.   S u bj e cts  ≥  6  y e ars  of  a g e  at ti m e  of I nf or m e d  C o ns e nt  F or m (I C F)  or  Ass e nt  F or m si g ni n g.   
2.   C o nfir m e d  di a g n osis  of  C F,  d et er mi n e d  b y  h a vi n g  cli ni c al f e at ur es  c o nsist e nt  wit h t h e  C F  p h e n ot y p e,  pl us  1 
of t h e f oll o wi n g:  
a.   P ositi v e s w e at  c hl ori d e t est ( v al u e  ≥  6 0  m E q/ L),   
b.   G e n ot y p e  wit h  2  m ut ati o ns  c o nsi st e nt  wit h  C F ( i. e.,  a  m ut ati o n i n  e a c h  of t h e  c ysti c fi br osis 
tr a ns m e m br a n e  c o n d u ct a n c e r e g ul at or [ C F T R]  g e n es). 
3.   P ositi v e s p ut u m  c ult ur e  or  a t hr o at s w a b  c ult ur e f or  M R S A  at  S cr e e ni n g.   
4.   I n  a d diti o n t o t h e S cr e e ni n g s a m pl e,  h a v e  at l e ast  2  pri or s p ut u m  or t hr o at s w a b  c ult ur es  p ositi v e f or  M R S A, 
of  w hi c h  at l e ast  1  s a m pl e is  m or e t h a n  6  m o nt hs  pri or t o  S cr e e ni n g.  At l e ast  5 0 %  of  all  M R S A  c ult ur es 
(s p ut u m  or t hr o at s w a b  c ult ur e)  c oll e ct e d fr o m t h e ti m e  of t h e first  p ositi v e  c ult ur e (i n t h e  pr e vi o us 1  y e ar ) 
m ust  h a v e  t est e d p ositi v e f or  M R S A.  (N ot e:  S cr e e ni n g s a m pl e  m a y  c o u nt t o w ar ds  5 0 %  p ositi v e  c o u nt)  
5.   F or c e d  e x pir at or y  v ol u m e i n  1 s e c o n d ( F E V 1)  ≥ 3 0 %  a n d  ≤   90 %  of  pr e di ct e d t h at is  n or m al f or  a g e,  g e n d er, 
r a c e,  a n d  h ei g ht,  usi n g t h e Gl o b al  L u n g  F u n cti o n I niti ati v e ( G LI ) e q u ati o n.  
6.   At l e ast  1  e pis o d e  of  a c ut e  p ul m o n ar y i nf e cti o n tr e at e d  wit h  n o n -m ai nt e n a n c e  a nti b i oti cs  wit hi n  1 2  m o nt hs 
pri or t o  t h e  B as eli n e v isit. (I niti ati o n  of tr e at m e nt  wit h i nt er mitt e nt i n h al e d  a nti-Ps e u d o m o n al t h er a p y  will 
n ot  q u alif y  as tr e at m e nt  wit h  n o n -m ai nt e n a n c e  a nti bi oti cs).  
7.   If f e m al e  of  c hil d b e ari n g  p ot e nti al,  a n  a c c e pt a bl e  m et h o d  of  c o ntr a c e pti o n  m ust  b e  us e d  d uri n g t h e  c o urs e 
of t h e st u d y  a n d  m ust  b e  c o m bi n e d  wit h  a  n e g ati v e  pr e g n a n c y t est  o bt ai n e d  d uri n g  S cr e e ni n g;  s e x u all y 
a cti v e  m al e s u bj e ct s  of r e pr o d u cti v e  p ot e nti al  w h o  ar e  n o n -st eril e (i. e.,  m al e  w h o  h as  n ot  b e e n st erili z e d  b y 
v as e ct o m y f or  at l e ast  6  m o nt hs ,  a n d  w er e  n ot  di a g n os e d  wit h i nf ertilit y t hr o u g h  d e m o nstr ati o n  of 
a z o os p er mi a i n  a s e m e n s a m pl e  a n d/ or  a bs e n c e  of  v as  d ef er e ns t hr o u g h  ultr as o u n d )  m ust  b e  willi n g t o  us e  a 
b arri er  m et h o d  of  c o ntr a c e pti o n ,  or t h eir f e m al e  p art n er  m ust  us e  a n  a c c e pt a bl e  m et h o d  of  c o ntr a c e pti o n, 
d uri n g t h e  c o urs e  of t h e st u d y.  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
3 6 
F or  p ur p os es  of t his st u d y, t h e  S p o ns or  d efi n es  “ a c c e pt a bl e  m et h o ds  of  c o ntr a c e pti o n ”  as:  
a.   Or al  birt h  c o ntr ol  pill s  a d mi ni st er e d f or  at l e ast  1  m o nt hl y  c y cl e  pri or t o  a d mi ni str ati o n  of t h e  st u d y 
dr u g  
b.   A  s y nt h eti c  pr o g esti n i m pl a nt e d r o d ( e g, I m pl a n o n ® ) f or  at l e ast  1  m o nt hl y  c y cl e  pri or t o t h e  st u d y 
dr u g  a d mi ni str ati o n  b ut  n ot  b e y o n d t h e  4 t h s u c c essi v e  y e ar f oll o wi n g i ns erti o n 
c.   I ntr a ut eri n e  d e vi c es (I U Ds), i ns ert e d  b y a  q u alifi e d cli ni ci a n f or at l e ast  1 m o nt hl y c y cl e  pri or t o st u d y 
dr u g  a d mi ni str ati o n  
d.   M e dr o x y pr o g est er o n e  a c et at e ( e g,  D e p o -Pr o v er a ® )  a d mi ni st er e d f or  a  mi ni m u m  of  1  m o nt hl y  c y cl e 
pri or t o a d mi nistr ati o n  of t h e st u d y  dr u g a n d c o nti n ui n g t hr o u g h  1  m o nt h f oll o wi n g st u d y c o m pl eti o n.  
e.   H yst er e ct o m y  or s ur gi c al st erili z ati o n  
f.  A bsti n e n c e  
g.   D o u bl e  b arri er  m et h o d ( di a p hr a g m  wit h s p er mi ci d al  g el  or  c o n d o ms  wit h  c o ntr a c e pti v e f o a m)  
N O T E :  F or s u bj e cts  pr es cri b e d  Or k a m bi:  Or k a m bi  m a y s u bst a nti all y  d e cr e as e  h or m o n al  c o ntr a c e pti v e 
e x p os ur e, r e d u ci n g t h e  eff e cti v e n ess  a n d i n cr e asi n g t h e i n ci d e n c e  of  m e nstr u ati o n -ass o ci at e d  a d v ers e 
r e a cti o ns.  H or m o n al  c o ntr a c e pti v es, i n cl u di n g  or al, i nj e ct a bl e, tr a ns d er m al,  a n d i m pl a nt a bl e, s h o ul d  n ot  b e 
r eli e d  u p o n  as  a n  eff e cti v e  met h o d  of  c o ntr a c e pti o n  w h e n  c o -a d mi nist er e d  wit h  Or k a m bi.  
8.   A bl e  a n d  willi n g t o  c o m pl y  wit h t h e  pr ot o c ol, i n cl u di n g  a v ail a bilit y f or  all s c h e d ul e d st u d y  visit s  a n d  b e 
a bl e t o  p erf or m  all t e c h ni q u es  n e c ess ar y t o  us e t h e  A er o V a n c i n h al er  a n d  m e as ur e l u n g f u n ct i o n. 
9.   A gr e e  n ot t o s m o k e  d uri n g  a n y  p art  of t h e  cli ni c al tri al ( S cr e e ni n g  vi sit t hr o u g h  e n d  of st u d y).  
1 0.  S u bj e cts  wit h  a  P.  a er u gi n os a  c o -i nf e cti o n  m ust  eit h er  b e st a bl e  o n  a r e g ul ar s u p pr essi o n r e gi m e n  of i n h al e d 
a nti bi oti cs  or  m ust  b e, i n t h e  o pi ni o n  of t h e I n v esti g at or, st a bl e  d es pit e t h e l a c k  of s u c h tr e at m e nt . 
6. 5   E x cl usi o n  C rit e ri a  
I n  a d diti o n t o t h os e  u n a bl e t o  m e et t h e I n cl usi o n Crit eri a, s u bj e cts  w h o  m e et  a n y  of t h e f oll o wi n g  crit eri a  will  b e 
e x cl u d e d fr o m  p arti ci p ati n g i n t h e  st u d y:   
1.   Us e  of  a nti -M R S A tr e at m e nts  pr es cri b e d  as  m ai nt e n a n c e t h er a p y  (I V  or i n h al e d tr e at m e nt wit hi n  2 8  d a ys; 
or al  tr e at m e nt wit hi n  1 4  d a ys)  pri or t o t h e  B as eli n e  vi sit.     
2.   Us e  of  n o n -m ai nt e n a n c e  a nti bi oti c  f or  p ul m o n ar y i nf e cti o n  or  e xtr a p ul m o n ar y  M R S A i nf e cti o n (I V  or 
i n h al e d  a nti bi oti c  wit hi n  2 8  d a ys;  or al  a nti bi oti c  wit hi n  1 4  d a ys)  pri or t o t h e  Bas eli n e  vi sit.     
3.   Hist or y  of  pr e vi o us  all er gi es  or s e nsiti vit y t o  v a n c o m y ci n,  or  ot h er  c o m p o n e nt(s)  of t h e st u d y  dr u g  or 
pl a c e b o  e x c e pt f or  a  hist or y  of r e d -m a n s y n dr o m e.  
4.   I n a bilit y t o t ol er at e i n h al e d  pr o d u cts. 
5.   First ti m e  s p ut u m  c ult ur e  or t hr o at s w a b  c ult ur e  yi el di n g  B.  c e p a ci a ,  or  n o nt u b er c ul o us  M y c o b a ct eri a i n t h e 
pr e vi o us  6  m o nt hs  t o  S cr e e ni n g.  
6.   Hist or y  of l u n g  or  ot h er  s oli d  or g a n tr a ns pl a nt ati o n  or  c urr e ntl y  o n t h e list t o r e c ei v e l u n g  or  ot h er s oli d 
or g a n tr a ns pl a nt ati o n.  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
3 7 
7.   R esist a n c e t o  v a n c o m y ci n  at  S cr e e ni n g ( v a n c o m y ci n r esi st a nt  St a p h yl o c o c c us  a ur e us  [ V R S A],  or 
v a n c o m y ci n i nt er m e di at e r esist a nt  St a p h yl o c o c c us  a ur e us  [ VI S A],  wit h  mi ni m u m i n hi bit or y  c o n c e ntr ati o n 
[ MI C]  ≥  8  µg/ m L).  
8.   Or al  c orti c ost er oi ds i n  d os es  e x c e e di n g  1 0  m g  pr e d nis o n e  p er  d a y  or  2 0  m g  pr e d nis o n e  e v er y  ot h er  d a y,  or 
e q ui p ot e nt  d os es  of  ot h er  c orti c ost er oi d s. 
9.   C h a n g es i n  a nti mi cr o bi al,  br o n c h o dil at or,  a nti -i nfl a m m at or y  or  c orti c ost er oi d  m e di c ati o ns  wit hi n  1 4  d a ys, 
or  c h a n g es i n  C F T R  m o d ul at ors  wit hi n  2 8  d a y s, pri or t o t h e  B as eli n e  visit .  
1 0.  A b n or m al l a b or at or y fi n di n gs  or  ot h er fi n di n gs  or  m e di c al  hi st or y  at  S cr e e ni n g t h at, i n t h e I n v esti g at or's 
o pi ni o n,  w o ul d  c o m pr o mis e t h e s af et y  of t h e s u bj e ct  or t h e  q u alit y  of t h e st u d y  d at a.  
1 1.  I n a bilit y t o t ol er at e i n h al ati o n  of  a s h ort  a cti n g  b et a 2  a g o ni st. 
1 2.  S p O 2  <9 0 %  at  S cr e e ni n g . 
1 3.  C h a n g es i n  p h ysi ot h er a p y t e c h ni q u e  or  p h ysi ot h er a p y s c h e d ul e d  wit hi n  1  w e e k  of t h e  B as eli n e  vi sit . 
1 4.  A d mi nistr ati o n  of  a n y i n v esti g ati o n al  dr u g  or  d e vi c e  wit hi n  4  w e e ks  pri or t o t h e  S cr e e ni n g  visit  a n d  d uri n g 
t h e  c o urs e  of t h e st u d y 
1 5.    Fe m al e  wit h  p ositi v e  pr e g n a n c y t est r es ult  d uri n g  S cr e e ni n g ,  pr e g n a nt ( or i nt e n ds t o  b e c o m e  pr e g n a nt), 
la ct ati n g  or i nt e n ds t o  br e astf e e d  d uri n g t h e  c o urs e  of t h e st u d y . 
1 6.  R e n al i ns uffi ci e n c y,  d efi n e d  as  cr e ati ni n e  cl e ar a n c e  <  5 0  m L/ mi n  usi n g t h e  C o c k cr oft -G a ult  e q u ati o n f or 
a d ults  or  S c h w art z  e q u ati o n  f or c hil dr e n  at t h e  S cr e e ni n g  vi sit.  
1 7.  A b n or m al li v er f u n cti o n,  d efi n e d  as  ≥  4 x  u p p er li mit  of  n or m al ( U L N),  of s er u m  as p art at e  a mi n otr a nsf er as e 
( A S T)  or s er u m  al a ni n e  a mi n otr a nsf er as e ( A L T),  or  k n o wn  cirr h osi s  at  S cr e e ni n g.  
1 8.  Di a g n os e d  wit h  cli ni c all y si g nifi c a nt  h e ari n g l oss.  
1 9.  Hist or y  of  p ositi v e r es ult  f or  h u m a n i m m u n o d efi ci e n c y  vir us ( HI V),  h e p atitis  B  vir us ( H B V)  or  h e p atitis  C 
vir us ( H C V).  
2 0.  Pl a n n e d  h os pit ali z ati o ns f or  pr o p h yl a xis  a nti bi oti c tr e at m e nt  wit hi n  2 8  d a ys  pri or t o  B as eli n e  visit  or  d uri n g 
t h e  o p e n-l a b el  p eri o d ( P eri o d  1). 
6. 6   C rit e ri a f o r  T e r mi n ati o n  of t h e  St u d y  
If t h e  S p o ns or,  I n v esti g at or,  st u d y  m o nit or,  or r e g ul at or y  offi ci als  di s c o v er  c o n diti o ns  arisi n g  d uri n g t h e  st u d y t h at 
i n di c at e  t h at  t h e  s u bj e ct  s af et y  a n d/ or  s ci e ntifi c  v al u e  of  t h e  st u d y  a n d/ or  q u alit y  of  t h e  st u d y  dr u gs  h a v e  b e e n 
c o m pr o mis e d, t h e  st u d y  s h o ul d  b e  h alt e d , or t h e  st u d y  c e nt er’s  p arti ci p ati o n  s h o ul d  b e t er mi n at e d.  C o n diti o ns t h at 
m a y  w arr a nt t er mi n ati o n  of t h e st u d y i n cl u d e,  b ut  ar e  n ot li mit e d t o, t h e f oll o wi n g:  
•   T h e  dis c o v er y  of  a n  u n e x p e ct e d, s eri o us,  or  u n a c c e pt a bl e ris k t o t h e s u bj e cts  e nr oll e d i n t h e st u d y;  
•   A  d e cisi o n  o n t h e  p art  of t h e  S p o ns or t o  s us p e n d  or  dis c o nti n u e t esti n g,  e v al u ati o n,  or  d e v el o p m e nt  of t h e 
pr o d u ct f or  a n y r e as o n;  
•   F ail ur e  of t h e I n v esti g at or t o  e nr oll s u bj e cts i nt o t h e st u d y  at  a n  a c c e pt a bl e r at e;  
•   F ail ur e  of t h e I n v esti g at or t o  c o m pl y  wit h  p erti n e nt  g o v er ni n g  b o d y r e g ul ati o ns;  
•   S u b missi o n  of  k n o wi n gl y f als e i nf or m ati o n fr o m t h e r es e ar c h f a cilit y t o t h e  S p o ns or, st u d y  m o nit or,  m e di c al 
offi c er,  or r e g ul at or y  offi ci al;  a n d,  
•   I ns uffi ci e nt  a d h er e n c e t o  pr ot o c ol r e q uir e m e nt s.  
St u d y t er mi n ati o n  a n d  foll o w -u p s h o ul d  b e  p erf or m e d i n  c o m pli a n c e  wit h  a p pli c a bl e  g o v er ni n g  b o d y r e g ul ati o ns.  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
3 8 
If  a n  I nstit uti o n al   R e vi e w   B o ar d  (I R B),  I n d e p e n d e nt   Et hi cs   C o m mitt e e  (I E C),  or   R es e ar c h   Et hi cs   B o ar d  ( R E B)  
wit h dr a ws  a p pr o v al f or  a st u d y sit e  d u e t o s u bj e ct  s af et y  c o n c er ns r el at e d t o t h e i n v esti g ati o n al  pr o d u ct,  al l sit es  will 
b e  n otifi e d  a n d  n o f urt h er tr e at m e nts  will  b e  gi v e n  u ntil r es ol uti o n  of t h e iss u e  or  d et er mi n ati o n  b y t h e r e vi e w ers t h at 
n o  u n d u e ris k  e xists.  
If t h e st u d y is t er mi n at e d f or s af et y  c o n c er ns,  all s u bj e cts  will  b e f oll o w e d f or  at l e ast  3 0  d a ys  aft er t h e s u bj e ct’s fi n al 
tr e at m e nt,  u nl ess  a l o n g er f oll o w-u p  p eri o d is  w arr a nt e d t o  a d dr ess t h e s af et y  c o n c er n.  S u bj e cts  wit h si g nifi c a nt s af et y 
e v e nt s  will  b e f oll o w e d  u ntil r es ol uti o n  or  st a bili z ati o n  of t h e  e v e nt  as  st at e d  i n S e cti o n  1 2 .  U p on  st u d y t er mi n ati o n, 
t h e  S p o ns or  will  dis c uss  wit h t h e r el e v a nt  R e g ul at or y  a ut h oriti es t o  d et er mi n e t h e  a p pr o pri at e f oll o w  u p  pr o c e d ur es 
a n d l e n gt h  of  m o nit ori n g r e q uir e d t o  a d dr ess s af et y  c o n c er ns.  
7   C O N C U R R E N T  M E DI C A TI O N S  
A ll s u bj e cts s h o ul d  b e  m ai nt ai n e d  o n t h e s a m e  m e di c ati o ns t hr o u g h o ut t h e  d o u bl e -bli n d  P eri o d  1  of t h e  st u d y,  as 
m e di c all y f e asi bl e,  wit h t h e  e x c e pti o n  of t h os e s p e cifi e d i n  S e cti o n  7. 1 . 
7. 1   P r o hi bit e d  M e di c ati o ns  a n d  T r e at m e nt s  
S u bj e cts  m ust  dis c o nti n u e t h e  us e  of I V  or i n h al e d  a nti -M R S A tr e at m e nt s  at l e ast  2 8  d a ys  pri or t o t h e  B as eli n e  vi sit , 
a n d/ or  us e  of  or al  a nti -M R S A tr e at m e nt s  at l e ast  1 4  d a ys  pri or t o t h e  B as eli n e  vi sit  a n d  s h o ul d  n ot  b e  pr es cri b e d 
a nti -M R S A tr e at m e nt s  d uri n g t h e  d o u bl e -bli n d  p orti o n  of t h e tri al  u nl ess t h e  s u bj e ct is  b ei n g tr e at e d f or  a 
p ul m o n ar y  e x a c er b ati o n.  T his  m a y i n cl u d e  or al  or i nj e ct a bl e  a nti bi oti cs  wit h  p ot e nti al  a cti vit y t o  M R S A ( e. g. 
v a n c o m y ci n, t el a v a n ci n, li n e z oli d, t etr a c y cli n es s u c h  as  d o x y c y cli n e  or  mi n o c y cli n e,  
tri m et h o pri m/s ulf a m et h o x a z ol e,  M R S A-a cti v e  c e p h al os p ori ns  ( e. g. c eft ar oli n e ),  cli n d a m y ci n,  d a pt o m y ci n, 
g e nt a mi ci n , or rif a m pi n) . 
7. 2   A nti - Ps e u d o m o n as  A nti bi oti c  T r e at m e nt 
F or  s u bj e cts o n  a  2 8 -d a y  c y cli c al  o n/ off  a nti -P s e u d o m o n al  a nti bi oti c r e gi m e n, t h e y  will  e nt er t h e  S cr e e ni n g  p eri o d 
at  a ti m e  s u c h t h at t h e  B as eli n e  visit  c oi n ci d es  wit h t h e  e n d  of t h eir  a nti -Ps e u d o m o n as  a nti bi oti c  c y cl e.  St u d y  dr u g 
will t h er e b y  b e  a d mi ni st er e d  d uri n g t h e  off -c y cl e ,  a n d s u bj e cts c a n t h e n r es u m e  a nti -Ps e u d o m o n al t h er a p y  d uri n g 
t h e 4- w e e k  o bs er v ati o n  p eri o d s ( W e e k  5 t hr o u g h  W e e k  8,  W e e k  13  t hr o u g h  W e e k  1 6,  W e e k  21  t hr o u g h  W e e k  2 4). 
S u bj e cts  o n  c o nti n ui n g  alt er n ati n g  a nti -Ps e u d o m o n al t h er a p y  ( C A T) c a n  c o nti n u e t h eir tr e at m e nt  d uri n g t h e st u d y 
dr u g  a d mi ni str ati o n  a n d  F oll o w -u p  p eri o d s,  b ut t h e s u bj e ct’s i niti al  d os e  of st u d y  m e di c ati o n  m ust  c oi n ci d e  wit h t h e 
i niti al  d os e  of a ztr e o n a m ( C a yst o n )/ c oli sti m et h at e ( C olisti n) . 
8   S T U D Y  T R E A T M E N T  
8. 1   A e r o V a n c  F o r m ul ati o n   
V a n c o m y ci n  h y dr o c hl ori d e  p o w d er f or i n h al ati o n is  a  w hit e t o  off -w hit e  dr y  p o w d er f or m ul ati o n  of t h e  a cti v e 
p h ar m a c e uti c al i n gr e di e nt ( A PI)  v a n c o m y ci n  h y dr o c hl ori d e,  d e v el o p e d  b y  S a v ar a  P h ar m a c e uti c als.  As s h o w n i n 
T a bl e  6 , i n  a d diti o n t o t h e  a cti v e i n gr e di e nt,  v a n c o m y ci n  h y dr o c hl ori d e  p o w d er f or i n h al ati o n  c o nt ai ns t h e  e x ci pi e nt 
l-l e u ci n e. W at er f or i nj e cti o n i s  us e d  as  a  pr o c essi n g  ai d i n t h e  m a n uf a ct uri n g  pr o c ess  a n d is  pr es e nt i n t h e fi ni s h e d 
dr u g  pr o d u ct.  E a c h  cl e ar , ( H y dr o x y pr o p yl) m et h yl  c ell ul os e (H P M C ), si z e  3 c a ps ul e  c o nt ai ns  a  dr y  p o w d er  of  1 5  m g 
of  v a n c o m y ci n  a n d  2  m g  of  l-l e u ci n e.  Th e  P h as e III  st u d y l a b el  cl ai m  is l o w er e d fr o m  1 6  m g ( P h as e II  d os e) t o 
1 5  m g  p er  c a ps ul e.   T hi s  c h a n g e r efl e ct s i m pr o v e m e nt s i n  a n al yti c al  m et h o ds  a n d  d o es  n ot r e pr es e nt  a  c h a n g e i n t h e 
f or m ul ati o n  or  a ct u al  q u a ntit y  of  v a n c o m y ci n i n t h e  c a ps ul e. I n ot h er  w or ds,  d es pit e  a  c h a n g e i n l a b el  cl ai m, t h e 
a ct u al  c o nt e nt  of  v a n c o m y ci n i n t h e  c a ps ul e  will  b e  c o m p ar a bl e  b et w e e n t h e  P h as e II  a n d  P h as e III  b at c h es . 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
3 9 
T a bl e  6 : F o r m ul ati o n  of  A e r o V a n c . 
I n g r e di e nt  
P u r p os e/ R ol e  
V a n c o m y ci n  H y dr o c hl ori d e  U S P  
A cti v e  p h ar m a c e uti c al i n gr e di e nt  
L -L e u ci n e  U S P  
Dis p ersi o n  a n d st a bilit y  e n h a n c e m e nt  
P urifi e d  W at er  U S P  
M a n uf a ct uri n g  pr o c essi n g  ai d  
8. 2   Pl a c e b o  F o r m ul ati o n   
M at c hi n g  Pl a c e b o is  a  dr y  p o w d er f or m ul ati o n  c o nt ai ni n g i n a cti v e  e x ci pi e nts,  l-l e u ci n e, a n d tr e h al os e . T a bl e  7  
i n di c at es t h e i n gr e di e nt s  of  Pl a c e b o. 
T a bl e  7 : F o r m ul ati o n  of  Pl a c e b o . 
I n g r e di e nt  
P u r p os e/ R ol e  
Tr e h al os e  Di h y dr at e  N F  
B ul ki n g  a g e nt  
L -L e u ci n e  U S P  
Dis p ersi o n  a n d  st a bilit y  e n h a n c e m e nt  
P urifi e d  W at er  U S P  
M a n uf a ct uri n g  pr o c essi n g  ai d  
8. 3   P a c k a gi n g  a n d  L a b eli n g 
A er o V a n c  will  b e s u p pli e d  as si z e  3,  cl e ar  c a p s ul e fill e d  wit h  dr y  p o w d er  v a n c o m y ci n  or  m at c hi n g  pl a c e b o . St u d y 
dr u g is s u p pli e d  i n  a  4-w e e k  cli ni c al  kit.  E a c h  cli ni c al  kit  c o nt ai ns  4  w e e kl y  b o x es  c o nt ai ni n g  8  d ail y  d osi n g  c ar ds. 
E a c h  d ail y  d osi n g  c ar d  will  c o nt ai n  4  c a ps ul es.  T w o  ( 2) c a ps ul es  will  b e  us e d f or t h e  m or ni n g  d os e  a n d  2  c a ps ul es 
f or t h e  e v e ni n g  d os e.  
  
 
 
L a b eli n g:  E a c h  4 -w e e k  cli ni c al  kit,  a n d  c o nt e nts  wit hi n t h e  kit (i . e.,  w e e kl y  b o x es  a n d  d osi n g  c ar ds),  will  b e l a b el e d 
wit h  pr o d u ct  n a m e,  t h e  pr ot o c ol  n u m b er, t h e  n a m e  of t h e S p o ns or  a n d  a d dr ess ,  a n d  dir e cti o ns f or t h e us e  a n d 
st or a g e ( 4-w e e k  cli ni c al  a n d  w e e kl y  kit)  a n d  t h e r e q uir e d a p pli c a bl e r e g ul at or y  a g e n c y  w ar ni n g st at e m e nt s 
( "C a uti o n:  N e w  Dr u g  - Li mit e d  b y  F e d er al  L a w t o I n v esti g ati o n al  Us e. ") . 
8. 4   S u p pl y  of  St u d y  D r u g  at t h e  Sit e  
T h e  S p o ns or ( or  d esi g n e e)  will s hi p  St u d y  Dr u g t o t h e i n v esti g ati o n al sit es  pri or t o  e nr oll m e nt  of t h e  first s u bj e ct. 
T h e i niti al st u d y  dr u g s hi p m e nt  will  b e s hi p p e d  aft er sit e  a cti v ati o n ( i. e.,  all r e q uir e d r e g ul at or y  d o c u m e nt ati o n, 
i n cl u di n g  et hi c’s  a p pr o v al, a n d  a n  e x e c ut e d tri al  c o ntr a ct)   has  b e e n r e c ei v e d  b y t h e  S p o ns or.  S u bs e q u e nt  st u d y  dr u g 
s hi p m e nts  will  b e  m a d e  as  n e c ess ar y  b as e d  u p o n  s u bj e ct r e cr uit m e nt. 
A er o V a n c  will  b e s hi p p e d t o t h e  cli ni c al sit e i n  a n i ns ul at e d  c o nt ai n er  c o ntr oll e d t o  2 -8 ° C.  E a c h s hi p m e nt  will  b e 
e q ui p p e d  wit h  a  T e m p T al e  4  U S B r e c or d er. I nstr u cti o ns  o n  h o w t o st o p t e m p er at ur e r e c or di n g,  d o w nl o a d  d at a  a n d 
e m ail  d at a  will  b e  pr o vi d e d  wit h  e a c h s hi p m e nt.  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
4 0 
8. 5   D os a g e/ D os a g e  R e gi m e n 
T h e i n h al ati o n  p o w d er is  p a c k a g e d i nt o  c a ps ul es,  e a c h  c a ps ul e  c o nt ai ni n g  1 5  m g  of  v a n c o m y ci n.  T h e  d os e i n t his 
st u d y i s  3 0  m g ( 2  c a ps ul es)  BI D  ( at l e ast  6 h o urs  a p art) .  Alt er n ati v el y,  a s u bj e ct m a y  b e r a n d o mi z e d t o r e c ei v e  a 
m at c hi n g  pl a c e b o,  wit h  e q ui v al e nt  n u m b ers  of  c a ps ul es.  
8. 6   Dis p e nsi n g  
D uri n g t h e  B as eli n e  vi sit, t h e  s u bj e ct will  b e  dis p e ns e d  a  4 -w e e k  kit  c o nt ai ni n g  4  w e e kl y  b o x es.  E a c h  b o x  will 
c o nt ai n  8  d ail y  d osi n g  c ar ds  ( 7  +  1  e xtr a). E a c h  d ail y  d osi n g  c ar d  c o nt ai n s 4  c a ps ul es,  2  c a ps ul es f or t h e  m or ni n g 
d os e  a n d  2  c a ps ul es f or t h e  e v e ni n g  d os e.  D uri n g s u bs e q u e nt  visits,  a  r es u p pl y  of st u d y  dr u g  will  b e  dis p e ns e d t h e 
d a y  of t h e  visit  a n d  as i n di c at e d i n t h e s c h e d ul e  of  e v e nts.  
8. 7   M et h o d  of  Assi g ni n g  S u bj e cts t o  T r e at m e nt  G r o u ps 
U p o n t h e  c o m pl eti o n  of t h e  S cr e e ni n g  p eri o d  ( u p t o  4 2  d a ys) t o  c o nfir m i n cl usi o n/ e x cl usi o n  crit eri a, eli gi bl e 
s u bj e cts  will  b e r a n d o mi z e d t o r e c ei v e  eit h er  A er o V a n c  3 0  m g  BI D ,  or  pl a c e b o BI D  ( 1: 1  a cti v e t o  pl a c e b o)  b y 
i n h al ati o n f or t hr e e 4- w e e k l y  c y cl es. A  c e ntr al r a n d o mi z ati o n  s c h e m e  will  b e  pr o d u c e d  wit h  f o ur str atifi c ati o n 
f a ct ors  o n t h e  b asis of  ( a)  a g e ( 6– 2 1;  >  2 1), ( b)  B as eli n e  F E V 1 ( ≥ 6 0 %;  < 6 0 %), ( c)  pri or  e x a c er b ati o ns tr e at e d  wit h 
a nti bi oti cs  d uri n g t h e  pr e vi o us  1 2  m o nt hs ( 1 -2;  ≥  3 )  a n d ( d) P.  a er u gi n os a  tr e at m e nt ( n ot tr e at e d; tr e at e d). 
R a n d o mi z ati o n  will  b e  c arri e d  o ut  vi a I nt er a cti v e  W e b  R es p o ns e (I W R).  
8. 8   Bli n di n g  a n d  U n bli n di n g  of  St u d y  M e di c ati o n  
T hi s  st u d y i n cl u d es  a  d o u bl e-bli n d  p eri o d  a n d  a n  o p e n -l a b el p eri o d.  U p o n  c o m pl eti o n  of t h e  d o u bl e -bli n d  p eri o d, 
s u bj e cts  will  pr o c e e d  o n t o t h e  o p e n -l a b el p eri o d.  T h e s u bj e cts,  cli ni c st aff,  a n d  S p o ns or  will  n ot  k n o w t h e  assi g n e d 
tr e at m e nt d uri n g t h e  d o u bl e -bli n d  p eri o d . I n t h e  c as e  of  a  m e di c al  e m er g e n c y,  w h e n  k n o wl e d g e  of t h e tr e at m e nt 
assi g n m e nt is  ess e nti al t o t h e  w elf ar e  of t h e  s u bj e ct, t h e I n v esti g at or  or  d esi g n e e  m a y r e q u est  u n bli n di n g  of t h at 
s u bj e ct. W h e n e v er f e asi bl e, t h e  S p o ns or s h o ul d  b e  c o ns ult e d i n  a d v a n c e  of  br e a ki n g t h e  bli n d f or  a n y  s u bj e ct. I n  a n y 
c as e, t h e  S p o ns or  m ust  b e  n otifi e d  of t h e  u n bli n di n g,  a n d t h e I n v esti g at or  or  d esi g n e e  will  d o c u m e nt t h e r e as o n(s) 
n e c ess ar y t o  br e a k t h e  bli n d f or  a n y  s u bj e ct. S u bj e ct s  will  b e  d is c o nti n u e d fr o m t h e st u d y if t h e  bli n d is  br o k e n.  
8. 9   I n h al e r  D e vi c e 
T h e  A er o V a n c i n h al er ( M o n o d os e  R S 0 1  M o d el  7 st a n d ar d i n h al er) is  a  u nit  d os e,  dr y  p o w d er i n h al er  d e vi c e t h at 
utili z es si z e  3  c a ps ul es  a n d is  m a n uf a ct ur e d  b y  Pl asti a p e  S. p. A.  A  C a n a di a n  a n d  U S  Dr u g  M ast er  Fil e ( D M F ) h as 
b e e n fil e d.  Fi v e  ( 4  +  1  e xtr a  { w e e kl y }) i n h al ers  will  b e  pr o vi de d  wit hi n  e a c h  4 -w e e k  cli ni c al  kit  a n d l a b el e d  wit h 
st u d y  n u m b er,  n a m e  of  S p o ns or  a n d  a d dr ess  a n d  a  w ar ni n g  st at e m e nt, " C a uti o n:  N e w  D e vi c e  - Li mit e d  b y  F e d er al 
L a w t o I n v esti g ati o n al  Us e. "  T h e  A er o V a n c i n h al er  s h o ul d  b e st or e d  u n d er t h e s a m e  c o n diti o ns  as t h e  dr u g s u p pli es 
(i. e. r efri g er at e d  pri or t o  dis p e nsi n g  a n d  a m bi e nt r o o m t e m p er at ur e  c o n diti o ns  aft er  dis p e nsi n g).  
F or  d et ail e d i nstr u cti o ns  of  us e, s e e  A p p e n di x  6 . 
8. 1 0   A d mi nist r ati o n  I nst r u cti o ns   
A er o V a n c,  3 0  m g  or  m at c hi n g  pl a c e b o ( 2  c a ps ul es)  BI D  will  b e  a d mi ni st er e d  usi n g t h e r el o a d a bl e,  c a ps ul e i n h al er. 
S u bj e cts  will  b e i nstr u ct e d t o t a k e  a s h ort -a cti n g  br o n c h o dil at or  a g e nt  pr e -tr e at m e nt (2  p uffs  of  t h e s h ort  a cti n g 
br o n c h o dil at or  al b ut er ol ,  or  e q ui v al e nt) n o l ess t h a n  1 0  mi n ut es  a n d  u p t o  4 5  mi n ut es  pri or t o st u d y  dr u g 
a d mi nistr ati o n.  A s h ort -a cti n g  br o n c h o dil at or, s u c h  as  al b ut er ol  m a y  al s o  b e  us e d  as r es c u e  m e di c ati o n i n t h e  e v e nt 
of  br o n c h o c o nstri cti o n  c a us e d  b y t h e st u d y  dr u g.   


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
4 1 
8. 1 1   St o r a g e 
St u d y  dr u g s h o ul d  b e st or e d  b y t h e st u d y sit e  at  c o ntr oll e d  r efri g er at e d t e m p er at ur e, 2 º C t o 8 º C pri or t o  dis p e nsi n g . 
If t h e t e m p er at ur e  of st u d y  dr u g st or a g e i n t h e  cli ni c/ p h ar m a c y  e x c e e ds  or f alls  b el o w t his r a n g e, t his  s h o ul d  b e 
r e p ort e d t o t h e  S p o ns or  or  d esi g n e e pri or t o  dis p e nsi n g st u d y  dr u g . T h e  S u bj e cts  will  b e i nstr u ct e d t o st or e t h e 
m e di c ati o n i n  ori gi n al  p a c k a gi n g ( al u mi n u m  f oil blist er  p a c ks  a n d  pr ot e ct e d fr o m li g ht)  at r o o m t e m p er at ur e 
a c c or di n g t o t h e i nstr u cti o ns  o utli n e d  in  t h e I nstr u cti o ns f or  Us e of  A er o V a n c I n h al er li st e d i n  A p p e n di x  6 . 
8. 1 2   St u d y  D r u g  A c c o u nt a bilit y  
A n  a c c ur at e  a n d  c urr e nt  a c c o u nti n g  of t h e  dis p e nsi n g  a n d r et ur n  of st u d y  dr u g f or  e a c h  s u bj e ct will  b e  m ai nt ai n e d 
o n  a n  o n g oi n g  b asis  b y  a  m e m b er  of t h e st u d y sit e st aff.  T h e  n u m b er  of st u d y  dr u g  dis p e ns e d  a n d r et ur n e d  b y t h e 
s u bj e ct will  b e r e c or d e d  o n t h e I n v esti g ati o n al  Dr u g  A c c o u nt a bilit y  R e c or d.  T h e st u d y  m o nit or  will  v erif y t h es e 
d o c u m e nts t hr o u g h o ut t h e  c o urs e  of t h e st u d y.  
8. 1 3   T r e at m e nt  C o m pli a n c e  
T w o  c a ps ul es  will  b e i n h al e d t wi c e  d ail y  as  p er t h e  S c h e d ul e  of  E v e nts.  S u bj e cts  ar e  r e q uir e d t o  bri n g all  us e d  a n d 
u n us e d  blist ers , c a ps ul es ,  a n d i n h al ers b a c k t o t h e r es e ar c h  c e nt er f or  a c c o u nt a bilit y . If a  s u bj e ct  mi sses  a s c h e d ul e d 
d os e  ( m or ni n g  or  e v e ni n g)  a n d  h as at l e ast  6  h o urs  u ntil t h e  n e xt  s c h e d ul e d d os e, t h e  miss e d  d os e s h o ul d  b e t a k e n  as 
s o o n  as  p ossi bl e.  Ot h er wi s e, t h e s u bj e ct s h o ul d  w ait f or t h e  n e xt  s c h e d ul e d  d os e  a n d  n ot i n cr e as e t h e  n u m b er  of 
c a ps ul es t o  m a k e  u p f or t h e  miss e d  d os e . 
8. 1 4   D os e  A dj ust m e nt  
N o  d os e  a dj ust m e nt  of  A er o V a n c  i s all o w e d.  
8. 1 5   A c c o u nt a bilit y  
T h e  I n v esti g at or is  r e q uir e d t o  m ai nt ai n  a d e q u at e  r e c or ds  of t h e  dis p ositi o n  of t h e i n v esti g ati o n al  a g e nt, i n cl u di n g 
d at es,  q u a ntit y, a n d  us e  b y s u bj e cts t hr o u g h o ut t h e st u d y ( C o d e  of  F e d er al  R e g ul ati o ns,  Titl e  2 1,  P art  3 1 2. 5 7 ). R e c or ds 
will  b e  k e pt  o n  pr o d u ct  a c c o u nt a bilit y  a n d i n v e nt or y f or ms.  All  pr o d u ct,  w h et h er  us e d  or  u n us e d,  will  b e  d o c u m e nt e d 
o n  dr u g  a c c o u nt a bilit y f or ms.  A c c o u nt a bilit y  of t h e i n v esti g ati o n al  a g e nt  will  b e  v erifi e d  b y t h e st u d y  m o nit or  d uri n g 
o n -sit e  m o nit ori n g  vi sit s.  
If t h e i n v esti g ati o n i s t er mi n at e d, s us p e n d e d,  dis c o nti n u e d,  or  c o m pl et e d  u p o n i nstr u cti o n fr o m  S a v ar a, t h e 
In v esti g a t or s h all r et ur n  all  us e d  a n d u n us e d s u p pli es  ( blist ers,  c a ps ul es,  a n d i n h al ers) t o  S a v ar a’s  cli ni c al r et ur n 
v e n d or .  T h e s hi p m e nt  m ust  c o nt ai n fi n al dr u g  a c c o u nt a bilit y f or ms,  w hi c h  c o m pl et e t h e  a c c o u nt a bilit y  of t h e  e ntir e 
st u d y  a n d r e c o n cil e  a n y  dis cr e p a n ci es.  
9   S T U D Y  P R O C E D U R E S  A N D  G UI D E LI N E S  
A  S c h e d ul e  of  E v e nts r e pr es e nti n g t h e r e q uir e d t esti n g  pr o c e d ur es t o  b e  p erf or m e d f or t h e  d ur ati o n  of t h e st u d y i s 
di a gr a m m e d i n  A p p e n di x  1 . 
Pri or t o  c o n d u cti n g  a n y st u d y -r el at e d  a cti viti es,  writt e n i nf or m e d  c o ns e nt  a n d t h e c o u ntr y s p e cifi c  p ers o n al 
i nf or m ati o n  a n d  d at a  pri v a c y a ut h ori z ati o n  m ust  b e si g n e d  a n d  d at e d  b y t h e  s u bj e ct or  s u bj e ct’s l e g al r e pr es e nt ati v e. 
If a p pr o pri at e,  ass e nt  m ust  a ls o  b e  o bt ai n e d  pri or t o  c o n d u cti n g  a n y st u d y-r el at e d  a cti viti es. 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
4 2 
9. 1   Cli ni c al  Ass ess m e nt s  
9. 1. 1   C o n c o mit a nt  M e di c ati o ns 
All  m e di c ati o n s t a k e n i n t h e  6  m o nt hs pri or t o  B as eli n e ,  as  w ell  as  all c o n c urr e nt t h er a pi es  d uri n g t h e st u d y,  will  b e 
d o c u m e nt e d  t hr o u g h o ut t h e c o urs e  of t h e st u d y.  D os e, r o ut e,  u nit fr e q u e n c y  of  a d mi nistr ati o n,  a n d i n di c ati o n f or 
a d mi nistr ati o n  a n d  d at es  of  m e di c ati o n  will  b e  c a pt ur e d.  
9. 1. 2   D e m o g r a p hi cs   
D e m o gr a p hi c i nf or m ati o n ( d at e  of  birt h,  s e x, r a c e a n d  et h ni cit y )  will  b e r e c or d e d  at t h e  S cr e e ni n g  visit. 
9. 1. 3   M e di c al  Hist o r y   
R el e v a nt  m e di c al  hist or y, i n cl u di n g  hist or y  of  c urr e nt  dis e as e,  ot h er  p erti n e nt r es pir at or y  hi st or y,  a n d i nf or m ati o n 
r e g ar di n g  u n d erl yi n g  dis e as es  will  b e r e c or d e d  at t h e S cr e e ni n g  visit  a n d  c o nfir m e d  d uri n g t h e  B as el i n e  visit.  
9. 1. 4   P h y si c al  E x a mi n ati o n  
A  c o m pl et e  p h ysi c al  e x a mi n ati o n  will  b e  p erf or m e d  b y  eit h er t h e  In v esti g at or  or  a  S u b -In v esti g at or  as i n di c at e d  o n 
t h e  S c h e d ul e  of  E v e nt s. C o m pl et e  p h ysi c al  e x a mi n ati o ns  will i n cl u d e  a  mi ni m u m  of  a r e vi e w  of t h e s u bj e ct’s 
g e n er al  a p p e ar a n c e,  h e a d,  e y es,  e ars,  n os e,  a n d t hr o at ( H E E N T),  n e c k,  h e art, l u n gs,  a b d o m e n,  e xtr e miti es, s ki n,  a n d 
g e n er al  n e ur ol o gi c al  s yst e m.   
S y m pt o m -ori e nt e d  or  bri ef  p h ysi c al  e x a mi n ati o ns  will  b e  p erf or m e d  at ti m e  p oi nts  n ot e d i n t h e  S c h e d ul e  of  E v e nts 
a n d  as  cli ni c all y i n di c at e d.  N e w  a b n or m al  p h ysi c al  e x a m fi n di n gs  n ot  pr es e nt  d uri n g t h e  b as eli n e  vi sit s s h o ul d  b e 
r e c or d e d  as A Es  a n d  f oll o w e d d uri n g s u bs e q u e nt  visit s. 
9. 1. 5   Vit al  Si g ns 
B o d y t e m p er at ur e,  bl o o d  pr ess ur e,  p ul s e ,  S p O2 a n d r es pir ati o ns  will  b e  p erf or m e d  aft er r esti n g f or  5  mi n ut es  as 
i n di c at e d i n t h e  S c h e d ul e  of  E v e nts. 
9. 1. 6   1 2- l e a d  El e ct r o c a r di o g r a m ( E C G) 
A  1 2 -l e a d  E C G  will  b e  p erf or m e d  d uri n g t h e st u d y as i n di c at e d  o n t h e  S c h e d ul e  of  E v e nts.  All  E C G s will  b e  
tr a ns mitt e d t o t h e  C R O fr o m t h e l a pt o p ( C P S/ B E A M S). T h e tr a ci n g s will  b e  pr o c ess e d  a n d  a  c o nfir m e d  E C G ( o v er -
r e a d  b y  a c e ntr ali z e d  C ar di ol o gist)  will  b e  r et ur ne d  t o t h e sit e, g e n er all y  wit hi n  2  b usi n ess  d a ys . A s u m m ar y  of t h e 
re a di n gs  will  b e  pr o vi d e d t o t h e sit e f or t h eir  r e c or ds. It  will  b e t h e r es p o nsi bilit y  of t h e In v esti g at or  or  a  S u b -
In v esti g at or  t o r e vi e w t h e tr a ci n gs f or s af et y. Cli ni c all y si g nifi c a nt fi n di n gs,  n ot  pr es e nt  d uri n g t h e  B as eli n e  visit , 
s h o ul d  b e r e c or d e d  as  a n  A E .  
9. 1. 7   C F R S D -C RI S S  
T h e  C ysti c  Fi br osi s  R es pir at or y  S y m pt o m  Di ar y  –  C hr o ni c  R es pir at or y I nf e cti o n  S y m pt o m  S c or e ( C F R S D -C RI S S), 
is  a n  8-it e m  p ati e nt-r e p ort e d  o ut c o m e ( P R O) s y m pt o m  m e as ur e t h at is  p art  of t h e  C ysti c  Fi br osis  R es pir at or y 
S y m pt o m  Di ar y ( C F R S D).  T h e  C F R S D -C RI S S  is  d esi g n e d t o  e v al u at e t h e  eff e ct  of tr e at m e nt  o n t h e  s e v erit y  of 
s y m pt o ms  of r es pir at or y i nf e cti o n i n  s u bj e cts  wit h  C ysti c  Fi br osis ( C F).  Ass ess m e nt s i n t h e  C F R S D -C RI S S 
c o m pris e t h e  8 s y m pt o m it e ms  of  t h e  C F R S D:  diffi c ult y br e at hi n g,  c o u g h,  c o u g h  u p  m u c us,  c h est ti g ht n ess,  w h e e z e, 
f e eli n g f e v eris h, tir e d,  a n d  c hill s/s w e at s.  
T h e  ass ess m e nt s  s h o ul d  b e  c o m pl et e d  w e e kl y  b y  t h e  s u bj e ct  at  h o m e  at  b e dti m e.    T h e    C F R S D -C RI S S   will  b e 
a d mi nist er e d  usi n g  a n  e -Di ar y  ( h a n d  h el d  d e vi c e) t h at will  b e  pr o vi d e d t o  e a c h s u bj e ct . 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
4 3 
9. 1. 8   C F Q - R 
T h e  C ysti c  Fi br osis  Q u esti o n n air e -R e vis e d  ( C F Q -R) is  a  dis e as e -s p e cifi c  h e alt h-r el at e d  q u alit y  of lif e  m e as ur e  f or 
c hil dr e n,  a d ol es c e nt s ,  a n d  a d ults    wit h    C F.   T h e    C F Q -R    m e as ur es  f u n cti o ni n g  i n  a  v ari et y  of  d o m ai ns,  i n cl u di n g 
P h ysi c al  F u n cti o ni n g,   Vit alit y,   H e alt h  P er c e pti o ns,   R es pir at or y  S y m pt o ms,   Tr e at m e nt   B ur d e n,   R ol e  F u n cti o ni n g, 
E m oti o n al  F u n cti o ni n g , a n d  S o ci al  F u n cti o ni n g.  T h e   C R Q -R    will  b e  a d mi ni st er e d  usi n g  a n  e -Di ar y  t h at  will  b e 
pr o vi d e d t o  e a c h s u bj e ct  e v er y t w o  w e e ks . 
9. 1. 9   E Q- 5 D- 5 L  &  E Q- 5 D y  
T h e  E ur o Q ol -5 D ( E Q -5 D) is  a  m or e  g e n er al  q u esti o n n air e  w hi c h is  wi d el y  us e d t o  m e as ur e  h e alt h  o ut c o m e i n t er ms 
of  m o bilit y, s elf -c ar e,  us u al  a cti viti es,  p ai n/ dis c o mf ort,  a n xi et y/ d e pr essi o n.  T h e  5- l e v el i nstr u m e nt ( E Q-5 D -5 L) 
w hi c h  us es  a  5 -p oi nt s c al e ( n o  pr o bl e ms, sli g ht  pr o bl e ms,  m o d er at e  pr o bl e ms, s e v er e  pr o bl e ms,  a n d  e xtr e m e 
pr o bl e ms)  will  b e  us e d i n t h e l o c al l a n g u a g e . F or s u bj e cts  1 5  y e ars  or  y o u n g er t h e  E Q -5 D  Y o ut h ( E Q -5 D y)  will  b e 
us e d.  T his i nstr u m e nt  will  b e  us e d t o  m e as ur e  o v er all s elf -r at e d  h e alt h st at us. T h e  q u esti o n n air e  will  b e  c o n d u ct e d 
i n t h e  cli ni c  d uri n g t h e  vi sit. 
9. 1. 1 0   P ul m o n a r y  F u n cti o n  T ests  ( P F T) 
All s u bj e cts  will  u n d er g o st a n d ar di z e d  p ul m o n ar y f u n cti o n t esti n g  as i n di c at e d i n t h e  S c h e d ul e  of  E v e nts t o 
d et er mi n e t h eir f or c e d  vit al  c a p a cit y ( F V C ), p e a k  e x pir at or y fl o w r at e ( P E F R ), f or c e d  e x pir at or y fl o w ( F E F) 
b et w e e n  2 5 %  a n d  7 5 %  of  F V C ( F E F 2 5 -7 5) a n d  F E V 1.  P ul m o n ar y f u n cti o n t esti n g  will  b e  p erf or m e d  a c c or di n g t o 
A m eri c a n  T h or a ci c  S o ci et y ( A T S ) g ui d eli n es ( 2 0 0 5).  S u bj e ct s  will  b e t est e d  usi n g t h e  s a m e  s pir o m etr y  e q ui p m e nt 
pr o vi d e d  b y t h e  S p o ns or .  U p t o  8 eff orts s h o ul d  b e  p erf or m e d t o  o bt ai n  3  a c c e pt a bl e  a n d r e pr o d u ci bl e t est r es ults. 
T h e  b est r es ults fr o m t h e  3  a c c e pt a bl e  a n d r e pr o d u ci bl e  eff orts f or  P F Ts  will  b e r e c or d e d  o n t h e  s u bj e ct ’s  C R Fs  a n d 
a  c o p y  of t h e s pir o m etr y r e p orts  will  b e r et ai n e d  wit h t h e  s u bj e ct’s s o ur c e  d o c u m e nts.  
P r e -d os e  P F Ts  will  b e  p erf or m e d  at  all  visits  pri or t o t h e  s u bj e ct a d mi ni st eri n g t h e  br o n c h o dil at or  pr e -tr e at m e nt  a n d 
st u d y  dr u g ( A er o V a n c/ pl a c e b o).  T h e  B as eli n e  P F T  m ust  b e  p erf or m e d  a n d  m e et i n cl usi o n  crit eri a,  pri or t o  b ei n g 
r a n d o mi z e d t o st u d y  m e di c ati o n,  aft er  w hi ch  a d mi nistr ati o n  of  br o n c h o dil at or  a n d st u d y  dr u g  will  b e  d o n e  as 
d es cri b e d  b el o w.  
 
T h e s e q u e n c e  of  e v e nt s  o n t h e  d a ys  of st u d y  dr u g  a d mi nistr ati o n  will  b e  p erf or m e d  as f oll o ws:   
•   S u bj e cts  will  p erf or m t h eir  m or ni n g  air w a y  cl e ar a n c e  at  h o m e i n  a  n or m al f as h i o n (e g ,  a d mi nist eri n g  a 
s h ort-a cti n g  br o n c h o dil at or, f oll o w e d  b y  h y p ert o ni c s ali n e,  v est,  P ul m o z y m e ® ,  a n d  p ot e nti all y  a l o n g-a cti n g 
br o n c h o dil at or/ c orti c ost er oi d i n h al ati o n).  A s  a r e mi n d er,  all s u bj e ct s s h o ul d  b e  m ai nt ai n e d  o n t h e  s a m e 
m e di c ati o ns t hr o u g h o ut t h e  e ntir e st u d y  p eri o d,  as  m e di c all y f e asi bl e,  wit h t h e  e x c e pti o n  of t h os e s p e cifi e d 
i n S e cti o n  7. 1 . 
•   S u bj e cts  will t h e n  c o m e t o t h e  cli ni c  d uri n g t h e  m or ni n g.  T h e  s u bj e cts ar e  n ot  all o w e d t o  us e  al b ut er ol ( or 
ot h er s h ort -a cti n g  br o n c h o dil at or) f or  2  h o urs  pri or t o  P F Ts.  T h e  s u bj e cts will  h a v e  P F Ts  p erf or m e d first, 
t h e n  a s elf-a d mi nist er e d  pr e -tr e at m e nt  wit h  a s h ort-a cti n g  br o n c h o dil at or  n o l ess t h a n  1 0  mi n ut es  a n d  u p t o 
4 5  mi n ut es  pri or t o t h e  s elf -a d mi ni str ati o n  of st u d y  dr u g ( A er o V a n c  or  Pl a c e b o)  u n d er s u p er vi si o n.   
•   T h e  s u bj e cts s h o ul d f oll o w t his  e x a ct s a m e  pr o c e d ur e  at  all tr e at m e nt  vi sit s,  a n d t h er e b y, t h e y s h o ul d  n ot 
t a k e t h eir  m or ni n g st u d y  dr u g  u ntil t h e y  h av e  c o m e t o t h e  cli ni c,  c o m pl et e d  P F Ts, t h e n  pr e -tr e at e d  wit h  a 
s h ort-a cti n g  br o n c h o dil at or, f oll o w e d  b y st u d y  dr u g  a d mi nistr ati o n.  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
4 4 
9. 1. 1 1   S p ut u m  Mi c r o bi ol o g y  
A s p ut u m s a m pl e  will  b e  c oll e ct e d  a n d  c ult ur e d f or  M R S A  as  p er t h e ti m e  p oi nts  o utli n e d i n t h e  S c h e d ul e  o f  E v e nts. 
Ass ess m e nt  of s p ut u m s a m pl es  will  i n cl u d e i d e ntifi c ati o n  a n d  q u a ntifi c ati o n  of  M R S A a n d  s us c e pti bilit y t o 
v a n c o m y ci n ( MI C)  at  all  ti m e p oi nts, a n d  s us c e pti bilit y t o  a st a n d ar d  p a n el  of  a nti bi oti cs  at  B as eli n e,  W e e k  2 0  a n d 
W e e k  4 4 . .  Ass ess m e nts will  b e  c o n d u ct e d  d uri n g t h e st u d y  b y  a n  e x p eri e n c e d  c e ntr ali z e d  mi cr o bi ol o g y l a b or at or y 
a c c or di n g t o t h e  C e ntr al  L a b or at or y  M a n u al . 
S u bj e cts  a bl e t o  s p o nt a n e o usl y  e x p e ct or at e s p ut u m s a m pl es  at  S cr e e ni n g s h o ul d  d o s o t hr o u g h o ut t h e st u d y.  If a 
s u bj e ct b e c o m es  u n a bl e t o s p o nt a n e o usl y  e x p e ct or at e s p ut u m s a m pl es  d uri n g  a s u bs e q u e nt  visit , t h e  s u bj e ct s h o ul d  
c o nti n u e t o  att e m pt  t o  pr o vi d e s a m pl es i n f ut ur e  vi sit s. S u bj e ct s  w h o  ar e  u n a bl e t o  e x p e ct or at e  a s p ut u m s a m pl e  will 
h a v e t hr o at s w a b s t a k e n. 
S u bj e cts  n ot  a bl e t o s p o nt a n e o usl y  e x p e ct or at e s p ut u m s a m pl es  at  S cr e e ni n g  will  h a v e t hr o at s w a bs t a k e n i nst e a d. 
T h e i n a bilit y t o  c oll e ct  s p ut u m ( aft er t h e  S cr e e ni n g  visit)  will  n ot  b e  c o nsi d er e d  a  pr ot o c ol  d e vi ati o n.  
S u bj e cts  wit h  a  n e g ati v e  c ult ur e (s p ut u m  or  t hr o at s w a b)  at  S cr e e ni n g  will  h a v e t h e  o p p ort u nit y t o  pr o vi d e  a s e c o n d  
s a m pl e  d uri n g t h e  S cr e e ni n g  p eri o d t o  c o nfir m  a  p ositi v e  c ult ur e.   
9. 1. 1 2   E m e r g e n c e  of  A d diti o n al  P at h o g e ns  
E m er g e n c e  of  a d diti o n al  p at h o g e ns  d uri n g  a n d  aft er t h e st u d y  dr u g  a d mi nistr ati o n  will  b e  m o nit or e d i n s p ut u m  or 
t hr o at s w a b  mi cr o bi ol o g y  c ult ur es  alr e a d y  b ei n g  c oll e ct e d.  T h e  pr es e n c e  of t h e f oll o wi n g  p at h o g e ns  will  b e 
d et er mi n e d  at  B as eli n e,  W e e k  2 0,  a n d  W e e k  4 4 : Ps e u d o m o n as  a er u gi n os a , A c hr o m o b a ct er  x yl os o xi d a ns , 
As p er gill us f u mi g at us , B ur k h ol d eri a  c e p a ci a  c o m pl e x,  a n d  St e n otr o p h o m o n as  m alt o p hili a . 
9. 1. 1 3   Ti m e t o  A nti bi oti c  Us e  a n d  E x a c e r b ati o n  Ass ess m e nt  
If a  s u bj e ct i s tr e at e d  wit h  a nti bi oti cs f or  a  p ul m o n ar y i nf e cti o n , t h e In v esti g at or  will r e c or d r e as o ns f or tr e at m e nt 
i niti ati o n i n t h e  C R F a n d  ass ess  w h et h er t h er e is  a  p ul m o n ar y  e x a c er b ati o n . A t t h e  dis cr eti o n  of t h e In v esti g at or , t h e 
s u bj e ct  will  h a v e t h e  o pti o n t o  c o nti n u e st u d y  dr u g  d uri n g  tr e at m e nt  of t h e  p ul m o n ar y  e x a c er b ati o n u nl ess t h e 
p ul m o n ar y i nf e cti o n is tr e at e d  wit h  I V  v a n c o m y ci n, i n  w hi c h  c as e st u d y  dr u g s h o ul d  b e  dis c o nti n u e d d uri n g I V 
tr e at m e nt  a n d  m a y  b e r es u m e d t h er e aft er  wit h o ut  a dj usti n g t h e d osi n g  c y cl es . S u bj e cts  will  b e  all o w e d t o r e m ai n  o n 
st u d y  aft er t h e  p ul m o n ar y i nf e cti o n is r es ol v e d.  
9. 2   Cli ni c al  L a b o r at o r y  M e as u r e m e nts  
All l a b or at or y t est s  will  b e  p erf or m e d  b y  a  c e ntr al l a b or at or y.  
9. 2. 1   H e m at ol o g y  a n d  Bl o o d  C h e mist r y  P r ofil es  
Bl o o d  will  b e  o bt ai n e d  a n d s e nt t o  t h e  c e ntr al l a b or at or y f or  e v al u ati o n.  A n y t ests  d et er mi n e d  as  a b n or m al  a n d 
cli ni c all y si g nifi c a nt  b ut  n ot  pr es e nt  a t b as eli n e s h o ul d  b e r e c or d e d  as  a n  A E . 
T h e  h e m at ol o g y  a n d  cli ni c al  c h e mistr y l a b or at or y  a n al ys es  will  b e  p erf or m e d  at  a  c e ntr al l a b or at or y  a n d  as  p er t h e 
A p p e n di x   1, S c h e d ul e  of  E v e nts.  R ef er e n c e r a n g es  will  b e s u p pli e d  a n d  us e d  b y t h e I n v esti g at or t o  ass ess t h e 
l a b or at or y  d at a f or  cli ni c al si g nifi c a n c e  a n d  p at h ol o gi c al  c h a n g es.  
T h e i n ci d e n c e  of  cli ni c all y si g nifi c a nt  l a b or at or y  v al u es,  as  w ell  as  cli ni c all y si g nifi c a nt s hifts i n l a b or at or y  v al u es, 
s h o ul d  b e r e p ort e d  as  a n  A E i n t h e s u bj e ct’s  C R F (s e e  als o  S e cti o n  1 2  f or r e p orti n g  of  A Es r el at e d t o l a b or at or y 
a b n or m aliti es).  T h e I n v esti g at or  will  ass ess  a n y  cli ni c all y si g nifi c a nt  v al u es r el e v a nt t o t h e  s u bj e ct  p o p ul ati o n t o 
d et er mi n e if t er mi n ati o n  of t h e st u d y  dr u g is r e q uir e d . 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
4 5 
N ot e: I n t h e  e v e nt  of  a b n or m al l a b or at or y t est s, f oll o w -u p l a b or at or y t ests  m a y  b e  c o n d u ct e d.  A n y  cli ni c all y 
si g nifi c a nt  a b n or m aliti es  n ot e d i n l a b or at or y t est s s h o ul d  b e  dis c uss e d  wit h t h e  S p o ns or  or  d esi g n e e.  Cr e ati ni n e 
cl e ar a n c e f or  ki d n e y f u n cti o n  ass ess m e nt  at  S cr e e ni n g  will  b e  d et er mi n e d  b y  C o c kr oft -G a ult  c al c ul ati o n i n  a d ults  or 
S c h w art z  e q u ati o n i n  c hil dr e n.  
9. 2. 2   P r e g n a n c y  T est  
A s er u m  pr e g n a n c y t est  will  b e  o bt ai n e d fr o m f e m al e  s u bj e ct s w h o  ar e  of  c hil d b e ari n g  a g e  pri or t o t h eir 
p arti ci p ati o n i n t h e  st u d y , as i n di c at e d i n A p p e n di x  1 , S c h e d ul e  of  E v e nts . 
9. 2. 3   U ri n al y sis  
Uri n e  will  b e  o bt ai n e d  as i n di c at e d i n  A p p e n di x  1 , S c h e d ul e  of  E v e nts,  pr o c ess e d  a n d  m ail e d t o t h e  c e ntr al 
l a b or at or y f or  e v al u ati o n. 
9. 3   P h a r m a c o ki n eti c  M e as u r e m e nts  
S u bj e ct  pl as m a  a n d s p ut u m s a m pl e  will  b e  o bt ai n e d f or t h e  m e as ur e m e nt  of  v a n c o m y ci n  c o n c e ntr ati o n i n  p ati e nts 
w h o  p arti ci p at e i n t h e  P K  s u b-st u d y.  T h e  pr e-d os e  p h ar m a c o ki n eti c s a m pl es  will  b e  c oll e ct e d  wit hi n  6 0  mi n ut es  
pri or t o t h e st art  of  d osi n g  at t h e  ti m es i n di c at e d i n t h e  s c h e d ul e of  e v e nts . 
P h ar m a c o ki n eti c  bl o o d s a m pl es  will  b e  c oll e ct e d i n  e v a c u at e d t u b es  a n d  pr o c ess e d  wit hi n  1  h o ur  of s a m pl e 
c oll e cti o n  a n d  k e pt  fr o z e n at  -7 0  ° C  u ntil s hi p m e nt .  P h ar m a c o ki n eti c s p ut u m s a m pl es  will  b e  c oll e ct e d i n s p e ci m e n 
c oll e cti o n  c u ps  a n d  k e pt  fr o z e n at  -2 0  ° C  u ntil s hi p m e nt.  S u bj e cts  will  b e  as k e d t o  att e m pt t o  pr o d u c e  a s a m pl e  at 
t h e ti m es  n ot e d i n A p p e n di x I , S c h e d ul e  of  E v e nts . If  a s u bj e ct m a k es  a n  att e m pt  b ut is  u n a bl e t o  pr o d u c e  a s a m p l e 
wit hi n t h e s p e cifi e d  wi n d o w, t h e f ail e d  att e m pt  will  n ot  b e  c o nsi d er e d  a  pr ot o c ol  d e vi ati o n. If  n o  bl o o d is  c oll e ct e d 
d u e t o  b a d  a c c essi bilit y  of  v ei ns,  n o  ot h er  v e ni p u n ct ur e  will  b e  m a d e  at t h at  vi sit.  T h e l a c k  of  bl o o d  c oll e cti o n, if it 
w as  att e m pt e d,  will  n ot  b e  c o u nt e d  as  a  pr ot o c ol  d e vi ati o n.  
9. 4   U ns c h e d ul e d  Visit(s)  
Visits  o c c urri n g  o utsi d e  of t h e s c h e d ul e d  vi sit s list e d i n  A p p e n di x I ,  S c h e d ul e  of  E v e nts s h o ul d  c o m pl et e t h e 
pr o c e d ur es  n ot e d  u n d er  W e e k  4 4 / Earl y  T er mi n ati o n  visit , t o  ass ess  a  p ot e nti al e x a c er b ati o n  or  ot h er  cli ni c al  e v e nt 
aft er st u d y tr e at m e nt  a d mi nistr ati o n.  
Ass ess m e nts t o  b e  c o m pl et e d f or  a n  u ns c h e d ul e d  visit, f or  a n y  ot h er r e as o n,  will  b e  at t h e  In v esti g at or ’s  dis cr eti o n. 
1 0   P R E C A U TI O N  
1 0. 1   P r e g n a n c y  
Alt h o u g h  pr e g n a n c y  i s n ot  c o nsi d er e d  a n  A E,  t h e I n v esti g at or ( or his  or  h er  d esi g n e e)  is  r es p o nsi bl e  f or  r e c or di n g 
i n  t h e  s u bj e ct’s  s o ur c e  d o c u m e nt   a n y   pr e g n a n c y   d uri n g   or   wit hi n   3 0   d a ys   aft er   c o m pl eti n g   st u d y  tr e at m e nt. 
A n y s u bj e ct ( or s u bj e ct’s  p art n er)  w h o  b e c o m es  pr e g n a nt  d uri n g t h e st u d y s h o ul d  b e f oll o w e d t hr o u g h  d eli v er y  or 
t er mi n ati o n  of t h e  pr e g n a n c y. I n  a d diti o n, s u bj e ct s  w h o  b e c o m e  pr e g n a nt  d uri n g t h e st u d y  m ust  dis c o nti n u e st u d y 
dr u g  a d mi ni str ati o n  im m e di at el y.   
I n  pr e g n a n ci es t h at  pr o gr ess t o t er m,  a n y  c o n g e nit al  a b n or m aliti es/ birt h  d ef e cts i n t h e  offs pri n g  of  a s u bj e ct  w h o 
r e c ei v e d st u d y  m e di c ati o n s h o ul d  b e r e p ort e d  as  a n  S A E.  T h e  o ut c o m e  of t h e  pr e g n a n c y  a n d t h e  pr es e n c e  or 
a bs e n c e  of  a  c o n g e nit al  a b n or m alit y  will  b e  d o c u m e nt e d  b y  c o m pl eti o n  of  a  Pr e g n a n c y  Q u esti o n n air e  a n d  a 
Pr e g n a n c y  O ut c o m e  F or m i n  a c c or d a n c e  wit h  G C P  a n d I C H  g ui d eli n es  a n d  St a n d ar d  O p er ati n g  Pr o c e d ur es ( S O Ps ).  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
4 6 
F e m al e s u bj e ct s s h o ul d  als o  n otif y t h e I n v esti g at or if t h e y  b e c o m e  pr e g n a nt  wit hi n  3 0  d a ys  aft er l ast  d os e  of st u d y 
m e di c ati o n.  M al e s u bj e ct s s h o ul d  n otif y t h e I n v esti g at or if  a f e m al e  p art n er  b e c o m es  pr e g n a nt  wit hi n  3 0  d a ys  aft er 
l ast  d os e  of st u d y  m e di c ati o n.  T h e  S p o ns or  m ust  b e  n otifi e d  of  all  pr e g n a n ci es r e p ort e d t o th e I n v esti g at ors . 
1 1   S A F E T Y  E V A L U A TI O N S  
I n t hi s st u d y, s af et y will  b e  e v al u at e d  t hr o u g h A E  m o nit ori n g,  cli ni c al  e v al u ati o ns ( i. e.,  vit al si g ns,  p h ysi c al 
e x a mi n ati o ns,  E C Gs),  a n d  l a b or at or y t est s (i. e.,  h e m at ol o g y,  s er u m  c h e mi stri es,  a n d  uri n al ysi s)  fr o m t h e si g ni n g 
of  i nf or m e d c o ns e nt  u ntil  t h e l ast st u d y vi sit.  
D efi niti o ns  a n d  r e p orti n g pr o c e d ur es  pr o vi d e d  i n t his pr ot o c ol  c o m pl y  wit h  c urr e nt  I C H  E 6   a n d   ot h er  
a p pli c a bl e   i nt er n ati o n al  a n d   l o c al  r e g ul at or y  r e q uir e m e nts.  T h e     Me di c al     Mo nit or   assi g n e d   b y   t h e  S p o ns or   will  
pr o m ptl y   r e vi e w  all   i nf or m ati o n  r el e v a nt  t o  t h e  s af et y of  A er o V a n c . T h e  I n v esti g at or will  c ar ef ull y  m o nit or  
e a c h  s u bj e ct t hr o u g h o ut t h e  st u d y f or A Es  a n d  will  b e f oll o w e d  u ntil  a d e q u at el y r es ol v e d.  M e di c al  q u eri es s h o ul d 
b e  a d dr ess e d t o t h e  M e di c al  M o nit or.  
C e cili a  G a nsl a n dt,  M. D   
M e di c al  M o nit or  
S a v ar a,  A p S   
Sl ots m ar k e n  1 7,  2.t v.  
D K -2 9 7 0  H ors h ol m , D e n m ar k  
C ell:  + 4 6  7 0 5  7 9 7 0 7 5  
E m ail:  C e cili a. G a nsl a n dt @s a v ar a p h ar m a. c o m   
1 2   A D V E R S E  E V E N T  R E P O R TI N G  A N D  D O C U M E N T A T I O N  
1 2. 1   A d v e rs e  E v e nts 
At  e a c h  vi sit,  all  A Es  t h at ar e  o bs er v e d,  eli cit e d  b y  t h e I n v esti g at or, or  r e p ort e d b y  t h e  s u bj e ct will  b e  r e c or d e d 
i n t h e a p pr o pri at e  s e cti o n of  t h e C R F  a n d  e v al u at e d  b y t h e I n v esti g at or.  Mi ni m u m  i nf or m ati o n r e q uir e d f or e a c h  
A E  i n cl u d es  d es cri pti o n  of  t h e e v e nt,  d ur ati o n   (st art a n d  e n d  d at es),  s e v erit y, ass ess m e nt  of  s eri o us n ess,  a n d  
c a us al  r el ati o ns hi p t o st u d y  dr u g.   
A n  a d v ers e  e v e nt ( A E) is  a n y  u nf a v or a bl e  or  u ni nt e n d e d si g n, s y m pt o m,  or  dis e as e t e m p or all y  ass o ci at e d  wit h t h e 
us e  of st u d y tr e at m e nt,  w h et h er  or  n ot  c o nsi d er e d r el at e d t o t h e st u d y tr e at m e nt.  Cli ni c al  c h a n g es  pri or t o t h e first 
d os e  of st u d y  dr u g  will  n o t  b e  c o nsi d er e d  a d v ers e  e v e nt s b ut  will  b e i n cl u d e d i n t h e  s u bj e ct’s  m e di c al  hist or y.  All 
A Es  m ust  b e r e c or d e d i n t h e s o ur c e  d o c u m e nt s  a n d  o n t h e  A d v ers e  E v e nt  C R F, r e g ar dl ess  w h et h er  t h e  e v e nt is 
c o nsi d er e d r el at e d t o st u d y  m e di c ati o n.   
T hi s  d efi niti o n i n cl u d es  a n  e x a c er b ati o n  of  pr e -e xisti n g  m e di c al  c o n diti o ns  or  e v e nts,  hist ori c al  c o n diti o n  n ot 
pr es e nt  pri or t o st u d y tr e at m e nt,  w hi c h r e a p p e ar f oll o wi n g  st u d y tr e at m e nt, i nt er c urr e nt ill n ess es,  h y p ers e nsiti vit y 
r e a cti o ns,  dr u g i nt er a cti o n,  or t h e si g nifi c a nt  w ors e ni n g  of t h e  dis e as e  u n d er i n v esti g ati o n t h at i s  n ot r e c or d e d 
els e w h er e i n t h e  C R F.  A nti ci p at e d  d a y -t o-d a y fl u ct u ati o ns  of  pr e -e xisti n g  c o n diti o ns t h at  d o  n ot r e pr es e nt  a 
cli ni c all y si g nifi c a nt  e x a c er b ati o n  or  w ors e ni n g  n e e d  n ot  b e  c o nsi d er e d  A Es.  
F or  all  A Es, t h e  In v esti g at or  m ust  p urs u e  a n d  o bt ai n i nf or m ati o n  a d e q u at e  b ot h t o  d et er mi n e t h e  n at ur e  a n d  o ut c o m e 
of t h e  a d v ers e  e v e nt  a n d t o  ass ess  w h et h er it  m e ets t h e  crit eri a f or  cl assifi c ati o n  as  a s eri o us  a d v ers e  e v e nt ( S A E) 
r e q uiri n g i m m e di at e  n otifi c ati o n  of t h e M e di c al   Mo nit or.  F oll o w -u p  of  cli ni c all y  si g nifi c a nt  A Es  of  at l e ast  a  gr a d e 
3  (s e e S e cti o n  1 2. 2  f or  d efi niti o n),  e v e n  aft er t h e  d at e  of t h er a p y  dis c o nti n u ati o n, i s r e q uir e d  u ntil r es ol uti o n  or 
st a bili z ati o n is j u d g e d  a c c e pt a bl e  b y t h e  In v esti g at or.  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
4 7 
T h e  In v esti g at or  or  S u b -I n v esti g at or m ust i nt er pr et  all  l a b or at or y fi n di n gs  a n d si g n  a n d  d at e t h e l a b or at or y r e p ort t o 
c o nfir m t h eir r e vi e w.  A n y  gr a d e  3  or  hi g h er l a b or at or y  a b n or m aliti es t h at  ar e  eit h er  s eri o us  or  u n e x p e ct e d s h o ul d  b e 
pr o m ptl y r e p ort e d t o t h e  S p o ns or’s   Me di c al   Mo nit or.  A n y  cli ni c all y si g nifi c a nt l a b or at or y  a b n or m alit y  will  b e 
r e c or d e d  as  a n  a d v ers e  e v e nt o n t h e  C R F, i n cl u di n g t h e  di a g n osi s, if  a n y,  ass o ci at e d  wit h t h e l a b  a b n or m alit y.  T h e 
A E s h o ul d  b e r e c or d e d  as t h e  u n d erl yi n g  a b n or m alit y  or  di a g n osis ( e g , r e n al i ns uffi ci e n c y), if  o n e is  d et er mi n e d,  as 
o p p os e d t o t h e  o bs er v e d  d e vi ati o n i n t h e l a b or at or y  r es ult (e g ,  el e v at e d  cr e ati ni n e). 
I n  a d diti o n t o r e c or di n g  cli ni c all y si g nifi c a nt l a b or at or y  a b n or m aliti es,  c h a n g es t o  cli ni c al si g ns  a n d s y m pt o ms  will 
als o  b e  ass ess e d  at  b as eli n e  a n d  at  all  pl a n n e d  a n d  u n pl a n n e d st u d y  visits  at  w hi c h  ot h er  cli ni c al  ass ess m e nts  ar e t o 
b e  c arri e d  o ut.   
A d diti o n al t est s  a n d  ot h er  e v al u ati o ns r e q uir e d t o  est a blis h t h e si g nifi c a n c e  or  eti ol o g y  of  a  cli ni c all y si g nifi c a nt 
a b n or m al r es ult  or t o  m o nit or t h e  c o urs e  of  a n  A E  ar e t o  b e  o bt ai n e d  w h e n  cli ni c all y i n di c at e d. I n  p arti c ul ar, if  a 
cli ni c all y si g nifi c a nt  a b n or m al r es ult is  o bs er v e d t h at i s  n ot r es ol v e d  b y t h e fi n al st u d y  vi sit, r e p e at e d t est s s h o ul d  b e 
p erf or m e d  a n d f oll o w  u p  c o nti n u e d  u ntil r es ol uti o n  or st a bili z ati o n  of t h e  A E.  
F or  all  A Es r es ulti n g i n  dis c o nti n u at i o n  of t h e st u d y  dr u g, t h e  e v e nt  m ust  b e  ass ess e d  b y t h e  s af et y  c o m mitt e e t o 
d et er mi n e if t h e  e v e nt  m e ets t h e  d efi niti o n  of  a  d os e li miti n g t o xi cit y ( D L T).  T h e  c o m mitt e e  will  ass ess t h e  e v e nt 
t y p e, t e m p or al r el ati o ns hi p  of t h e  e v e nt t o  d osi n g,  a n d s e v erit y of t h e  e v e nt . 
1 2. 2   S e v e rit y  
S e v erit y  will  b e  gr a d e d  utili zi n g T a bl e  8  b el o w.  
T a bl e  8 : A E  S e v e rit y  G r a di n g . 
S e v e rit y ( T o xi cit y  G r a d e)   
D es c ri pti o n  
Mil d ( 1)  
Tr a nsi e nt  or  mil d  dis c o mf ort;  n o li mit ati o n i n  a cti vit y;  n o  m e di c al 
i nt er v e nti o n  or t h er a p y r e q uir e d.  T h e s u bj e ct m a y  b e  a w ar e  of t h e si g n 
or s y m pt o m  b ut t ol er at es it r e as o n a bl y  w ell.  
M o d er at e ( 2)  
Mil d t o  m o d er at e li mit ati o n i n  a cti vit y,  n o  or  mi ni m al  m e di c al 
i nt er v e nti o n/t h er a p y r e q uir e d. 
S e v er e ( 3)  
M ar k e d li mit ati o n i n  a cti vit y,  m e di c al i nt er v e nti o n/t h er a p y r e q uir e d, 
h os pit ali z ati o ns  p ossi bl e.  
Lif e -t hr e at e ni n g ( 4) 
T h e  s u bj e ct is  at ri s k  of  d e at h  d u e t o t h e  a d v ers e  e x p eri e n c e  as it 
o c c urr e d.  T hi s  d o es  n ot r ef er t o  a n  e x p eri e n c e t h at  h y p ot h eti c all y 
mi g ht  h a v e  c a us e d  d e at h if it  w er e  m or e s e v er e.  
1 2. 3   R el ati o ns hi p t o  St u d y  T r e at m e nt  
T h e r el ati o ns hi p  or  ass o ci ati o n  of t h e  A E t o  a st u d y tr e at m e nt,  w hi c h i n cl u d es  pr o c ur e m e nt  pr o c e d ur es, s h o ul d  b e 
s p e cifi e d  b y t h e  In v esti g at or  usi n g t h e f oll o wi n g  d efi niti o ns:  
T a bl e  9 : R el at e d n ess . 
R el at e d n ess   
D es c ri pti o n  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
4 8 
U nr el at e d    
Cli ni c al  e v e nt  wit h  a n i n c o m p ati bl e ti m e r el ati o ns hi p t o st u d y  dr u g  a d mi ni str ati o n,  a n d t h at 
c o ul d  b e  e x pl ai n e d  b y  u n d erl yi n g  dis e as e  or  ot h er  dr u gs  or  c h e mi c al s  or is i n c o ntr o v erti bl y 
n ot r el at e d t o t h e st u d y  dr u g.   
U nli k el y    
Cli ni c al  e v e nt  w h os e ti m e r el ati o ns hi p t o st u d y  dr u g  a d mi nistr ati o n  m a k es  a  c a us al 
c o n n e cti o n i m pr o b a bl e,  b ut t h at  c o ul d  pl a usi bl y  b e  e x pl ai n e d  b y  u n d erl yi n g  dis e as e  or  ot h er 
dr u gs  or  c h e mi c als.   
P ossi bl e    
Cli ni c al  e v e nt  wit h  a r e as o n a bl e ti m e r el ati o ns hi p t o st u d y  dr u g  a d mi nistr ati o n,  b ut t h at 
c o ul d  als o  b e  e x pl ai n e d  b y  c o n c urr e nt  dis e as e  or  ot h er  dr u gs  or  c h e mi c al s.   
Pr o b a bl e    
Cli ni c al  e v e nt  wit h  a r e as o n a bl e ti m e r el ati o ns hi p t o st u d y  dr u g  a d mi nistr ati o n  a n d is 
u nli k el y t o  b e  attri b ut e d t o  c o n c urr e nt  dis e as e  or  ot h er  dr u gs  or  c h e mi c al s.   
R el at e d    
Cli ni c al  e v e nt  wit h  pl a usi bl e ti m e r el ati o ns hi p t o st u d y  dr u g  a d mi nistr ati o n,  a n d t h at  c a n n ot 
b e  e x pl ai n e d  b y  c o n c urr e nt  dis e as e  or  ot h er  dr u gs  or  c h e mi c al s   
1 2. 4   S e ri o us  A d v e rs e  E v e nts ( S A E) 
A n  S A E is  d efi n e d  as  a n y  A E  o c c urri n g  at  a n y  d os e t h at r es ult s i n  a n y  of t h e f oll o wi n g  o ut c o m es:  
1.   Is f at al: a p pli es  if t h e s u bj e ct’s d e at h  is a  dir e ct  o ut c o m e  of   a n A E . 
2.   Is lif e t h r e at e ni n g:  a p pli es if t h e  s u bj e ct, i n t h e  vi e w  of  t h e I n v esti g at or, is  at  s u bst a nti al ris k  of  d yi n g fr o m 
t h e  A E  as it  o c c urs. It  d o es  n ot  a p pl y if t h e  A E  c o ul d  h y p ot h eti c all y  h a v e  c a us e d  d e at h  h a d it  b e e n  m or e s e v er e. 
3.   R e q ui r es  o r  p r ol o n gs  i n -p ati e nt  h os pit ali z ati o n:  a p pli es  if  t h e   A E  r e q uir es  at  l e ast  a  2 4 -h o ur  i n -p ati e nt 
h os pit ali z ati o n  or, if i n t h e  o pi ni o n  of t h e I n v esti g at or,  pr ol o n gs  a n  e xisti n g  h os pit ali z ati o n.  A  h os pit ali z ati o n f or 
a n  el e cti v e  pr o c e d ur e  or  a r o uti n el y s c h e d ul e d tr e at m e nt is  n ot  a n  S A E  b y t his  crit eri o n  b e c a us e  a  “ pr o c e d ur e ”  or 
a  “tr e at m e nt ” is  n ot  a n  u nt o w ar d  m e di c al  o c c urr e n c e.  A n  e m er g e n c y r o o m  visit  of l ess t h a n  2 4  h o urs  b y its elf  d o es 
n ot  c o nstit ut e  a  S A E.   
4.   R es ults i n  p e r m a n e nt  o r si g nifi c a nt  dis a bilit y/i n c a p a cit y:  a p pli es if t h e  “ dis a bilit y ”  c a us e d  b y t h e r e p ort e d 
A E r es ults i n  a s u bst a nti al  disr u pti o n  of t h e s u bj e ct’s  a bilit y t o  c arr y  o ut  n or m al lif e f u n cti o ns.   
5.   Is  a  c o n g e nit al  a n o m al y/ bi rt h  d ef e ct:  a p pli es if  a  s u bj e ct  e x p os e d t o  a  m e di ci n al  (i n v esti g ati o n al)  pr o d u ct 
gi v es  birt h t o  a  c hil d  wit h  c o n g e nit al  a n o m al y  or  birt h  d ef e ct.   
M e di c al  a n d s ci e ntifi c j u d g m e nt s h o ul d  b e  e x er ci s e d i n  d et er mi ni n g s eri o us n ess i n  ot h er  sit u ati o ns, s u c h  as 
i m p ort a nt  m e di c al  e v e nts t h at  m a y  n ot  b e i m m e di at el y lif e- t hr e at e ni n g, r es ult i n  d e at h,  or  h os pit ali z ati o n,  b ut  m a y 
j e o p ar di z e t h e s u bj e ct  or m a y r e q uir e i nt er v e nti o n t o  pr e v e nt  o n e  of t h e  ot h er  o ut c o m es list e d i n t h e  d efi niti o n 
a b o v e.  T h es e  e v e nts  s h o ul d  b e  c o nsi d er e d s eri o us  a n d s u bj e ct t o r e p orti n g  pr o c e d ur es s p e cifi e d  b el o w.  
Ot h er i m p ort a nt  m e di c al  e v e nts  m a y  als o  b e  c o nsi d er e d  a n  S A E  w h e n,  b as e d  o n  a p pr o pri at e  m e di c al j u d g m e nt, t h e y 
j e o p ar di z e t h e s u bj e ct or r e q uir e i nt er v e nti o n t o  pr e v e nt  o n e  of t h e  o ut c o m es list e d.   
1 2. 4. 1   S e ri o us  A d v e rs e  E v e nt  R e p o rti n g  
Wit hi n   2 4  h o u rs   of  b e c o mi n g  a w ar e   of  a n y  S A E   (r e g ar dl ess  of its  r el ati o ns hi p  t o  i n v esti g ati o n al  pr o d u ct) t h at  
o c c urs   d uri n g  t h e  cli ni c al   st u d y,  t h e st u d y p ers o n n el  at  t h e sit e m ust  c o m pl et e  t h e S A E  R e p ort   F or m  ( e v e n if all  
i nf or m ati o n r e g ar di n g t h e S A E  is u n k n o w n  or  i n c o m pl et e), a n d  f a x  or e m ail  it t o t h e  S af et y  Offi c er list e d  b el o w. 
S h o ul d  y o u  n ot  b e  a bl e t o  c o nt a ct t h e  S af et y  Offi c er,  y o u  m ust r e a c h  o ut t o t h e  S p o ns or  M e di c al  M o nit or.  T hi s 
e ns ur es ti m el y r e p orti n g  of  a p pli c a bl e   r e p orts t o all  R e g ul at or y  A ut h oriti es.  T h e  f or m m ust  b e  si g n e d  b y  t h e 
Pri n ci p al   I n v esti g at or or  d esi g n e e,  a n d  if n ot  a v ail a bl e,  t h e u nsi g n e d  r e p ort s h o ul d  b e  f a x e d or  e m ail e d  f or 
i niti al  pr o c essi n g  a n d r es u b mitt e d  aft er t h e I n v esti g at or’s si g n at ur e  h as  b e e n  o bt ai n e d. Aft er s u b missi o n, t h e st u d y 
p ers o n n el s h o ul d  a w ait  a  c o nfir m ati o n  of r e c ei pt fr o m t h e  S af et y  O ffi c er a n d/ or t h e  S p o ns or; if  n ot r e c ei v e d t h e 
r e p ort  m ust  b e r es u b mitt e d. 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
4 9 
 
S af et y  Offi c e r  
S p o ns o r -M e di c al  M o nit o r  
S p o ns o r -Cli ni c al  O p e r ati o ns  
F a x:  1 -8 0 0 -3 5 2 -8 1 3 3  
I N C Dr u g S af et y @i n cr es e ar c h. c o m 
 
C e cili a  G a nsl a n dt,  M. D   
Sl ots m ar k e n  1 7,  2.t v.  
D K -2 9 7 0  H ors h ol m , D e n m ar k  
C ell:  + 4 6  7 0 5  7 9 7 0 7 5  
C e cili a. G a nsl a n dt @s a v ar a p h ar m a. c o m   
 
J essi c a J a c ks o n  
Dir e ct or  of  Cli ni c al  O p er ati o ns  
6 8 3 6  B e e  C a v es  R d,  B uil di n g III, 
S uit e  2 0 0  
A usti n,  T e x as  7 8 7 4 6,  U S A  
C ell:  8 3 2 -2 3 1 -6 2 8 3  
j essi c a.j a c ks o n @s a v ar a p h ar m a. c o m 
 
 
T h e  i niti al writt e n  r e p ort s h o ul d  b e f oll o w e d  b y f ull  writt e n s u m m ar y  d et aili n g r el e v a nt  as p e cts  of t h e  S A E i n 
q u esti o n  usi n g t h e  pr o vi d e d  S A E r e p ort f or m.  W h er e  a p pli c a bl e, i nf or m ati o n fr o m r el e v a nt  h os pit al  c as e r e c or ds 
a n d  a ut o ps y r e p orts s h o ul d  b e  o bt ai n e d.  T h e  S A E s h o ul d  al s o  b e r e c or d e d  o n t h e  A E  p a g e  of t h e s u bj e ct’s  C R F.  T h e  
S af et y  Offi c er  a n d  M e di c al   M o nit or   will   r e vi e w  t h e  S A E   d o c u m e nt ati o n   r e c ei v e d  f or  a c c ur a c y   a n d  
c o m pl et e n ess  a n d  f oll o w-u p  wit h  t h e I n v esti g at or t o o bt ai n  missi n g  i nf or m ati o n, if  r e q uir e d. 
If  a n  A E d o es  n ot  m e et t h e r e g ul at or y  d efi niti o n  of  “s eri o us ”  b ut is  c o nsi d er e d  b y t h e I n v esti g at or t o  b e r el at e d t o 
t h e st u d y  m e di c ati o n  a n d  of s u c h  cli ni c al  c o n c er n  as t o i nfl u e n c e t h e  o v er all  ass ess m e nt  of s af et y, it  m ust  b e 
r e p ort e d  as  d efi n e d f or  a n  S A E. 
All  A Es  a n d  S A Es  will  b e f oll o w e d  u ntil t h e  e v e nt  h as r es ol v e d, t h e  e v e nt  h as r e a c h e d  a  n e w  b as eli n e,  a n d f or  a 
mi ni m u m  of  3 0  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g,  or  u ntil t h e  e n d  of t h e st u d y.  F oll o w -u p  S A E i nf or m ati o n 
s h o ul d  b e s u b mitt e d  as  n e w i nf or m ati o n  b e c o m es  a v ail a bl e  b y  usi n g t h e f oll o w -u p  S A E r e p ort f or m  a n d 
f a xi n g/ e m aili n g t his f or m t o t h e S af et y  Offi c er  a n d  M e di c al  M o nit or  or  d esi g n e e. If t h e f oll o w -u p i nf or m ati o n 
c h a n g es t h e I n v esti g at or’s  ass ess m e nt  of s eri o us n ess  or  c a us alit y  or r el ati o ns hi p t o t h e st u d y  dr u g, t hi s  c h a n g e 
s h o ul d  b e  n ot e d  o n t h e f oll o w-u p  S A E f or m.  T h e i niti al  a n d  a n y f oll o w -u p  S A E r e p orts s h o ul d  b e  pl a c e d i n t h e 
s u bj e ct’s fil e.  U p o n r e c ei vi n g  a n y  u p d at es, t h e I n v esti g at or  m ust r e vi e w  a n d r et ai n t h e  u p d at es  a n d i m m e di at el y 
s u b mit  a  c o p y  of t his i nf or m ati o n t o t h e I R B/I E C/R E B.  T h e I n v esti g at or s h o ul d  als o  c o m pl y  wit h I R B/ I E C/R E B 
pr o c e d ur es f or r e p orti n g  a n y  ot h er  s af et y i nf or m ati o n.   
I n  a d diti o n, if t h e In v esti g at or l e ar ns  of  a n  S A E  o c c urri n g  aft er t h e l ast f oll o w -u p  visit,  b ut  wi t hi n  3 0  d a ys  aft er t h e 
l ast  a d mi nistr ati o n  of t h e st u d y tr e at m e nt,  h e/ s h e s h o ul d r e p ort t h e  e v e nt  wit hi n  2 4  h o urs t o t h e  c o nt a ct  p ers o ns f or 
dr u g s af et y  as  d es cri b e d  a b o v e . 
1 2. 5   S us p e ct e d  U n e x p e ct e d  S e ri o us  A d v e rs e  R e a cti o ns ( S U S A Rs)  
T h e  F D A  a n d/ or  ot h er  a p pli c a bl e  R e g ul at or y  A ut h oriti es  a n d  all  p arti ci p ati n g I n v esti g at ors  will  b e  n otifi e d  b y  a 
writt e n I n v esti g ati o n al  N e w  Dr u g  A p pli c ati o n (I N D) s af et y r e p ort  a n d/ or  ot h er  a p pli c a bl e r e g ul at or y r e p ort ( e g , 
e x p e dit e d  c as e r e p ort)  of  a n y s us p e ct e d  a d v ers e r e a cti o n t h at is  b ot h s eri o us  a n d  u n e x p e ct e d  (i. e.  a  S U S A R),  n o l at er 
t h a n  1 5  c al e n d ar  d a ys fr o m t h e  “ d at e l e ar n e d ”  of t h e  e v e nt. I n  a d diti o n,  all  a p pli c a bl e r e g ul at or y  b o di es  will  b e 
n otifi e d  wit hi n  7  c al e n d ar  d a ys  of  a n y  u n e x p e ct e d f at al  or lif e -t hr e at e ni n g  s us p e ct e d  a d v ers e r e a cti o n. 
A n  u nt o w ar d  a n d  u ni nt e n d e d r es p o ns e t o  a  n o n -st u d y  dr u g is, b y  d efi niti o n , n ot  a  S U S A R. 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
5 0 
1 3   DI S C O N T I N U A TI O N  A N D  WI T H D R A W A L  O F  S U B J E C T S 
1 3. 1   E a rl y  Dis c o nti n u ati o n  a n d  Wit h d r a w al  of  St u d y  a n d  St u d y  D r u g  
A s u bj e ct  m a y  b e  dis c o nti n u e d fr o m st u d y  or st u d y  tr e at m e nt  at  a n y ti m e if t h e s u bj e ct, t h e In v esti g at or,  or t h e 
S p o ns or f e els t h at it i s  n ot i n t h e  s u bj e ct’s  b est i nt er est t o  c o nti n u e.  T h e f oll o wi n g is  a list  of  p ossi bl e r e as o ns f or 
st u d y tr e at m e nt  dis c o nti n u ati o n:   
•   S u bj e ct  wit h dr a w al  of  c o ns e nt  ( or  ass e nt) 
•   S u bj e ct is  n ot  c o m pli a nt  wit h st u d y  pr o c e d ur es  
•   E x a c er b ati o n ( us e  of  a nti mi cr o bi al  m e di c ati o n t o tr e at r es pir at or y s y m pt o ms)  - aft er  c o m pl eti o n  of 
a nti mi cr o bi al tr e at m e n t st u d y  dr u g  m a y  b e r est art e d  at t h e  dis cr eti o n  of t h e I n v esti g at or. 
•   A d v ers e  e v e nt t h at i n t h e  o pi ni o n  of t h e  In v esti g at or  w o ul d  b e i n t h e  b est i nt er est  of t h e s u bj e ct t o 
dis c o nti n u e st u d y tr e at m e nt  
•   Pr ot o c ol  vi ol ati o n r e q uiri n g  dis c o nti n u ati o n  of st u d y tr e at m e nt  
•   L ost t o f oll o w -u p  
•   S p o ns or r e q u est f or  e arl y t er mi n ati o n  of st u d y  
•   P ositi v e  pr e g n a n c y t est (f e m al es)  
S u bj e cts  w h o  ar e  dis c o nti n u e d fr o m st u d y tr e at m e nt  b ef or e  c o m pl eti n g t h e  e ntir e  d ur ati o n  of t h e  Tr e at m e nt  P eri o d 
s h o ul d  c o nti n u e  cli ni c  vi sit s  a c c or di n g t o t h e st u d y s c h e d ul e i n  A p p e n di x I , S c h e d ul e  of  E v e n t f or  P eri o d  1; this 
i n cl u d es t h e r e p orti n g  of  a n y  A Es, i n cl u di n g  S A Es. S u bj e ct s  w h o  dis c o nti n u e  st u d y  m e di c ati o n i n  P eri o d  1  will  n ot 
b e  all o w e d t o  pr o c e e d t o  P eri o d  2.  
S u bj e cts  w h o  dis c o nti n u e st u d y tr e at m e nt,  a n d  w h o  ar e  n ot  willi n g t o  c o nti n u e  cli ni c  visits ( e g ,  wit h dr a w al  of 
c o ns e nt) s h o ul d  b e  e n c o ur a g e d t o  c o m pl et e t h e  W e e k  4 8/  E n d  of  St u d y ( E O S)  ass ess m e nts  as i d e ntifi e d i n t h e 
S c h e d ul e  of  E v e nts.  
T h e  d at e t h e s u bj e ct  dis c o nti n u es st u d y tr e at m e nt, t h e  pri m ar y r e as o n f or st u d y tr e at m e nt  dis c o nti n u ati o n, st u d y 
t er mi n ati o n,  a n d/ or t er mi n ati o n  of  p arti ci p ati o n (e g ,  wit h dr a w al  of  c o ns e nt),  will  b e  c a pt ur e d  wit hi n t h e  C R F. 
W h e n s u bj e cts  wit h dr a w  c o ns e nt fr o m st u d y  p arti ci p ati o n, it  m ust  b e r e c or d e d  o n t h e  C R F  w h et h er t h e  wit h dr a w al 
of  c o ns e nt  a p pli es t o s p e cifi c  as p e cts  of t h e st u d y s u c h  as  dis c o nti n u ati o n  of st u d y tr e at m e nt,  p arti ci p ati o n i n st u d y 
visits,  c o nt a ct  b y st u d y  p ers o n n el,  or  a c c ess t o i nf or m ati o n  a b o ut  p ot e nti al  S A Es. If s p e cifi c  c o ns e nt  h as  n ot  b e e n 
wit h dr a w n, st u d y  p ers o n n el  s h o ul d  c o nt a ct t h e s u bj e ct ( or  a  pr e vi o usl y  a p pr o v e d  d esi g n e e s u c h  as  a  c ar e gi v er, 
p art n er,  or f a mil y  m e m b er)  at t h e s c h e d ul e d  F oll o w -u p  vi sit t o i n q uir e  a b o ut  h e alt h st at us.   
1 3. 2   R e pl a c e m e nt  of  S u bj e cts  
S u bj e cts  w h o  wit h dr a w fr o m t h e st u d y tr e at m e nt  will  n ot  b e r e pl a c e d .   
1 4   P R O T O C O L  VI O L A TI O N S  
A  pr ot o c ol  vi ol ati o n  o c c urs  w h e n t h e  s u bj e c t or  In v esti g at or  f ail s t o  a d h er e t o si g nifi c a nt  pr ot o c ol r e q uir e m e nts 
aff e cti n g t h e i n cl usi o n,  e x cl usi o n,  s u bj e ct s af et y, or  pri m ar y  e n d p oi nt  crit eri a.  Pr ot o c ol  vi ol ati o ns f or t his st u d y 
i n cl u d e,  b ut  ar e  n ot li mit e d t o, t h e f oll o wi n g: 
•   F ail ur e t o  m e et i n cl usi o n/ e x cl usi o n  crit eri a  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
5 1 
•   Us e  of  a  pr o hi bit e d  c o n c o mit a nt  m e di c ati o n  
•   F ail ur e t o  c o n d u ct  pr ot o c ol r e q uir e d  pr o c e d ur es  
•   N o n -c o m pli a nt  wit h st u d y  dr u g r e gi m e n  
•   F ail ur e t o  c o m pl y  wit h  G o o d  Cli ni c al  Pr a cti c e ( G C P)  g ui d eli n es.   
T h e  S p o ns or  will  d et er mi n e if  a  pr ot o c ol  vi ol ati o n  will r es ult i n  wit h dr a w al  of  a  s u bj e ct. 
W h e n  a  pr ot o c ol  vi ol ati o n  o c c urs, it  will  b e  di s c uss e d  wit h t h e  In v esti g at or  a n d  a  Pr ot o c ol  Vi ol ati o n  F or m  d et aili n g 
t h e  vi ol ati o n  will  b e  g e n er at e d.  T his f or m  will  b e si g n e d  b y  a  S p o ns or r e pr es e nt ati v e  a n d t h e I n v esti g at or.  A  c o p y  of 
t h e f or m  will  b e fil e d i n t h e sit e’s r e g ul at or y  bi n d er  a n d  S p o ns or’s fil es.  T h e  Et hi cs  C o m mitt e e s h o ul d  b e i nf or m e d 
of t h e  vi ol ati o n.  
1 5   D A T A  S A F E T Y  M O NI T O RI N G   
S af et y  o v ersi g ht f or t his tri al  will  b e  c o n d u ct e d  b y t h e  C ysti c  Fi br osi s  F o u n d ati o n  T h er a p e uti cs ( C F F T)  D at a  a n d 
S af et y  M o nit ori n g  B o ar d ( D S M B).  A s u b c o m mitt e e  of t h e  D S M B,  a  D at a  M o nit ori n g  C o m mitt e e ( D M C),  will 
s er v e as t h e r e vi e w  b o ar d f or t his tri al.  T h e  D M C  will  c o nsist  of  at l e ast  2  p h ysi ci a ns  e x p eri e n c e d i n tr e ati n g  C F, 
a n d  a  bi ost ati sti ci a n  wit h  e x p ertis e i n  cli ni c al tri al  s af et y m o nit ori n g.  T h e  D M C  m e m b ers  will  all  b e i n d e p e n d e nt t o 
S a v ar a  a n d t o t h e  cli ni c al i n v esti g at ors.  
 
S p e cifi c all y, t h e  D M C is r es p o nsi bl e f or:  
 
•   R e vi e wi n g  cli ni c al tri al  d esi g n (i n cl u di n g r el e v a nt  d at a fr o m  pri or  cli ni c al tri als  a n d  In v esti g at or  B r o c h ur es 
r e g ar di n g t h e  dr u g  b ei n g st u di e d); 
•   R e vi e wi n g  S A Es  a n d t o xi cit y  d at a;  
•   E x a mi ni n g  u n bli n d e d  a c c u m ul at e d  o ut c o m e  a n d  s af et y  d at a i n  or d er t o  m a k e r e c o m m e n d ati o ns  c o n c er ni n g 
c o nti n u ati o n, t er mi n ati o n  or  m o difi c ati o n  of t h e tri al,  b as e d  o n t h e  eff e cts  of t h e i nt er v e nti o ns  u n d er  st u d y . 
T er mi n ati o n  or  m o difi c ati o n  will  o nl y  b e f or  n e c ess ar y s af et y r e as o ns;  
•   R e vi e wi n g  cli ni c al tri al  d esi g n  m o difi c ati o ns  pr o p os e d  b y t h e  T h er a p e u ti cs  D e v el o p m e nt  N et w or k (T D N ) or 
S p o ns or  a n d  a n y f ut ur e  a m e n d m e nts  pri or t o i m pl e m e nt ati o n;   
•   R e vi e wi n g  t h e  g e n er al  pr o gr ess  of  t h e  cli ni c al  tri al    wit h  r e g ar d  t o  a c cr u al/ wit h dr a w als  or  dr o p -o ut  r at es, 
pr ot o c ol  vi ol ati o ns  a n d/ or  d e vi ati o ns,  a n d tri al  c o n d u ct  
1 6   S T A TI S T I C A L  M E T H O D S  A N D  C O N SI D E R A TI O N S  
Pri or t o t h e  a n al ysis  of t h e fi n al  st u d y  d at a,  a  d et ail e d  St atisti c al  A n al ysis  Pl a n ( S A P)  will  b e  writt e n  d es cri bi n g  all  
a n al ys es t h at  will  b e  p erf or m e d.  T h e  S A P  will  c o nt ai n  a n y  m o difi c ati o ns  or  cl arifi c ati o ns  t o t h e  a n al ysis  pl a n 
d es cri b e d  b el o w  t h at  m a y  b e  n e c ess ar y.  
1 6. 1   D at a  S ets  A n al y z e d 
All st atisti c al t esti n g  will  b e t w o -si d e d  a n d  will  b e  p erf or m e d  at t h e  0. 0 5 si g nifi c a n c e l e v el.   D es cri pti v e st atisti cs 
will  b e  pr o vi d e d  b y tr e at m e nt  gr o u p  at  b as eli n e  a n d  at  e a c h  criti c al ti m e  p oi nt.   C at e g ori c al  v ari a bl es  will  b e 
s u m m ari z e d  b y  c o u nt s  a n d  b y  p er c e nt a g e  of s u bj e ct s i n  c orr es p o n di n g  c at e g ori es.  C o nti n u o us  v ari a bl es  will  b e 
s u m m ari z e d  wit h  m e a ns, st a n d ar d  d e vi ati o ns,  m e di a ns,  mi ni m u ms,  a n d  m a xi m u ms.   
T h e f oll o wi n g  p o p ul ati o ns  will  b e  us e d f or  effi c a c y  a n al ys es:   
- I nt e nt-t o-Tr e at ( I T T)  p o p ul ati o n  will i n cl u d e  all r a n d o mi z e d s u bj e cts ≤  2 1  y e ars  of  a g e . 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
5 2 
- T h e  P er -Pr ot o c ol ( P P)  p o p ul ati o n  will i n cl u d e  I T T s u bj e ct s  w h o  a d h er e t o  all  k e y  pr ot o c ol  pr o c e d ur es, t o  b e 
s p e cifi e d i n  a s e p ar at e  St atist i c al  A n al ysis  Pl a n ( S A P).  
Pri m ar y  effi c a c y  a n al ys es, f or  w hi c h f ull  c o ntr ol  of  T y p e I  err or  will  b e i m pl e m e nt e d,  will  b e i n t h e  gr o u p  of 
p ati e nts  w h o  ar e  ≤  2 1  y e ars  of  a g e.  
S u p p orti n g  a n al ys es i n  p ati e nt s  w h o  ar e  >  2 1  y e ars  of  a g e  will  b e  pr es e nt e d,  wit h  e m p h asi s  o n  esti m ati o n  of t h e 
tr e at m e nt  eff e ct, r at h er t h a n st ati sti c al si g nifi c a n c e t esti n g. 
1 6. 2   D e m o g r a p hi c  a n d  B a s eli n e  C h a r a ct e risti cs  
T h e  esti m at e d r es p o ns e r at e  a n d its  c o nfi d e n c e i nt er v al  will  b e  esti m at e d  a n d  ass ess e d  b y t h e f o ll o wi n g a  pri ori  
s u b gr o u ps:  
•   
A g e  gr o u p  ( 6 –2 1  y e ars  ol d  a n d  >  2 1 ) 
•   
B as eli n e  F E V 1 ( ≥ 6 0 %;  < 6 0 %) 
•  
P ri or  e x a c er b ati o ns tr e at e d  wit h  a nti bi oti cs  d uri n g t h e  pr e vi o us  1 2  m o nt hs ( 1-2;  ≥  3 )  
•  
P.  a er u gi n os a  tr e at m e nt ( n ot tr e at e d; tr e at e d) 
1 6. 3   A n al y sis  of  P ri m a r y  E n d p oi nt  
T h e  pri m ar y  effi c a c y  e n d p oi nt is t h e  m e a n  a bs ol ut e  c h a n g e fr o m  B as eli n e i n  F E V 1 p er c e nt  pr e di ct e d  i n  p ati e nts  w h o 
ar e  ≤  2 1  y e ars  of  a g e .  T h e e n d p oi nt  will  b e  a n al y z e d s e q u e nti all y  at  W e e k  4 ( e n d  of  C y cl e  1) ,  W e e k  1 2 ( e n d  of 
C y cl e  2),  a n d  at  W e e k  2 0 ( e n d  of  C y cl e  3). If  a st atisti c all y si g nifi c a nt  diff er e n c e i s  o bs er v e d i n f a v or  of  A er o V a n c 
c o m p ar e d t o  pl a c e b o  aft er  C y cl e  1, t h e n t h e  m e a n  c h a n g e i n t h e  F E V 1 p er c e nt  pr e di ct e d fr o m  B as eli n e t o  e n d  of 
C y cl e  2  will  b e  a n al y z e d.  Si mil arl y, if t h e  eff e ct  aft er  C y cl e  2 is st ati sti c all y si g nifi c a nt, t h e n t h e  a n al ysi s  of 
B as eli n e t o  e n d  of  C y cl e  3  will  b e r e p ort e d.  T h e  d at a  will  b e  a n al y z e d  usi n g  a n  a n al ysis  of  c o v ari a n c e  m o d el  wit h 
b as eli n e  F E V 1 p er c e nt  pr e di ct e d  as  a  c o v ari at e  a n d t h e str atifi c ati o n f a ct ors  as fi x e d  eff e cts.  
A li n e ar r e gr essi o n  m o d el  will  b e fitt e d  usi n g  s u bj e cts  wit h  o bs er v e d  v al u es f or t h e  e n d p oi nt ( W e e k  4,  1 2  a n d  2 0, 
r es p e cti v el y), t h e  c o v ari at es  B as eli n e  F E V1 p er c e nt  pr e di ct e d,  a n d  e arli er  o n -tr e at m e nt  m e as ur e m e nt s  of  F E V1 
p er c e nt  pr e di ct e d t h at  ar e  a v ail a bl e (if  a n y),  a n d t h e str atifi c ati o n f a ct ors.   F ull  d et ails  will  b e i n cl u d e d i n t h e  S A P.  
F or  c o nfir m ati o n  of t h e  pri m ar y  e n d p oi nt , a s e nsiti vit y  a n al ysis  will  b e  c o n d u ct e d  w h er e  missi n g  d at a  will  b e 
i m p ut ed  i n  diff er e nt  w a ys.   T h es e  will i n cl u d e: 
•   W o rst  r e as o n a bl e  c as e  a n al ysis : s u bj e ct s i n t h e  A er o V a n c  gr o u p  wit h  a  missi n g  F E V1 p er c e nt  pr e di ct e d  will  b e 
assi g n e d  t h e    m e di a n  f or  t h e  pl a c e b o  gr o u p  a n d  s u bj e cts  i n  t h e  pl a c e b o  gr o u p    wit h  a  missi n g  F E V
1 p er c e nt 
pr e di ct e d  will  b e  assi g n e d t h e  m e di a n f or t h e  A er o V a n c  gr o u p.  
•   B est  r e as o n a bl e  c as e  a n al ysis : s u bj e cts  i n t h e  A er o V a n c  gr o u p  wit h  a  missi n g  F E V1 p er c e nt  pr e di ct e d  will  b e 
assi g n e d  t h e    m e di a n  f or  t h e   A er o V a n c  gr o u p  a n d  s u bj e cts  i n  t h e  pl a c e b o  gr o u p   wit h  a    missi n g  F E V1 p er c e nt 
pr e di ct e d  will  b e  assi g n e d t h e  m e di a n f or t h e  pl a c e b o  gr o u p.  
•   Ti p pi n g  p oi nt  a n al ysis :  I n t h e  e v e nt t h at  st atisti c al  si g nifi c a n c e i n f a v o ur  of  A er o V a n c is  d et er mi n e d fr o m t h e 
pri m ar y  a n al ysis,  s u bj e cts  i n  eit h er  gr o u p  wit h  a  missi n g  F E V1 p er c e nt  pr e di ct e d  will  b e  assi g n e d  s u c c essi v el y 
m or e  e xtr e m e  v al u es t o  fi n d t h e  p oi nt  at  w hi c h  st atisti c al  si g nifi c a n c e is l ost  (i. e. t h e  2 -si d e d  P -v al u e  b e c o m es 
gr e at er t h a n  0. 0 5).  
1 6. 4   A n al y sis  of  S e c o n d a r y  E n d p oi nts  
Of t h e s e c o n d ar y  e n d p oi nts,  t h e  distri b uti o ns  of ti m e t o first p ul m o n ar y  e x a c er b ati o n  wil l  b e  c o m p ar e d  b et w e e n t h e 
tr e at m e nt  ar ms  usi n g  a  C o x  pr o p orti o n al  h a z ar ds r e gr essi o n  m o d el i n cl u di n g t h e  eff e cts  of tr e at m e nt  gr o u p,  a n d t h e 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
5 3 
str atifi c ati o n f a ct ors.  T h e  n u m b er  of  d a ys fr o m r a n d o mi z ati o n  u ntil t h e  d at e  of first  e x a c er b ati o n  will  b e  c al c ul at e d 
a n d s u m m ari z e d  usi n g  a  K a pl a n -M ei er lif e t a bl e  pr es e nt ati o n.  S u bj e cts  w h o  d o  n ot  e x p eri e n c e  a n  e x a c er b ati o n  pri or 
t o  dis c o nti n u ati o n fr o m t h e st u d y  will  b e  c e ns or e d  at t h e  d at e  of  dis c o nti n u ati o n fr o m t h e st u d y. 
T h e  c h a n g es i n  C F Q -R  a n d  C F R S D -C RI S S s c or e,  r el ati v e  c h a n g e fr o m  b as eli n e i n  F E V1 p er c e nt  pr e di ct e d,  will  all 
b e  a n al y z e d si mil arl y  at  W e e k  4 ,  1 2 a n d  2 0  usi n g  a n al ysis  of  c o v ari a n c e i n cl u di n g  b as eli n e  c o v ari at e  a n d 
str atifi c ati o n f a ct ors.   
T h e  n u m b er  of s u c c essf ul r es p o ns e  c y cl es  e a c h s u bj e ct  a c hi e v es  o v er t h e  3  c y cl es  of t h er a p y  will  b e  us e d t o  cr e at e 
a  2  ×  4  c o nti n g e n c y t a bl e  c o nsisti n g  of t h e  2 tr e at m e nts ( A er o V a n c  a n d  Pl a c e b o)  a n d t h e  c o u nts  of  all  p ati e nts 
a cr oss t h e  4 l e v el s  of r es p o ns e ( 0,  1,  2,  or  3 s u c c essf ul tr e at m e nt  c y cl es).  A r es p o ns e i n  a  c y cl e i s  d efi n e d  b y  at l e ast 
a  5  % r el ati v e i m pr o v e m e nt i n  F E V 1 p er c e nt  pr e di ct e d  at t h e  e n d  of  e a c h  c y cl e ( W e e k  4,  W e e k  1 2,  a n d  W e e k  2 0). If 
t h e r el ati v e  F E V1 i m pr o v e m e nt is l ess t h a n  5  %, t h e s u bj e ct is  c o nsi d er e d  a f ail ur e i n t h at  c y cl e,  b ut t h e f ail ur e  d o es 
n ot  pr e cl u d e  s u c c ess i n f ut ur e  c y cl es.  If  a s u bj e ct r e c ei v es  c o n c o mit a nt  n o n-m ai nt e n a n c e  a nti bi oti c t h er a p y  f or 
p ul m o n ar y i nf e cti o n  ( e. g. f or  p ul m o n ar y  e x a c er b ati o n), t h e s u bj e ct is  c o nsi d er e d  a f ail ur e i n t h at  c y cl e b ut t h e 
f ail ur e  d o es  n ot  pr e cl u d e s u c c ess i n f ut ur e  c y cl es. A n  a p pr o pri at e  pr o p orti o n al  o d ds  m o d el f or  or d er e d  c at e g ori es 
will  b e  us e d t o  a n al y z e  t h es e  d at a. 
Fr e q u e n c y  of  p ul m o n ar y  e x a c er b ati o ns  will  b e  c o m p ar e d  b et w e e n t h e  gr o u ps  usi n g  a  n e g ati v e  bi n o mi al  m o d el f or 
c o u nt  d at a,  a dj usti n g f or  e a c h  s u bj e ct’s l e n gt h  of f oll o w-u p.   T h e r a n d o mi z ati o n str atifi c ati o n f a ct ors  will  b e 
i n cl u d e d i n t h e  m o d el  as fi x e d  eff e cts. 
Ar e a  u n d er t h e  F E V 1– ti m e  pr ofil e  will  b e  a n al y z e d  usi n g  a n al ysi s  of  c o v ari a n c e i n cl u di n g t h e s u bj e ct’s  b as eli n e 
F E V 1 a n d t h e str atifi c ati o n f a ct ors.  
1 6. 5   M ulti pli cit y /  C o nt r ol  of  T y p e I  e r r o r  r at e  
T h e s e q u e n c e  of st atisti c al t esti n g  will  b e  as f oll o ws:  
•   A g e  gr o u p  6 – 2 1:  
o   Pri m ar y  e n d p oi nt ( m e a n  a bs ol ut e  c h a n g e fr o m  B as eli n e i n  F E V 1 p er c e nt  pr e di ct e d)  at  4  w e e ks, t h e n  1 2 
w e e ks, t h e n  2 0  w e e ks.  
o   S e c o n d ar y  e n d p oi nts:  
   ti m e t o first p ul m o n ar y  e x a c er b ati o n  
   c h a n g e i n  C F Q - R at  4  w e e ks, t h e n  1 2  w e e ks, t h e n  2 0  w e e ks  
   c h a n g e i n  C F R S D -C RI S S  s c or e  at  4  w e e ks, t h e n  1 2  w e e ks, t h e n  2 0  w e e ks  
   r el ati v e  c h a n g e fr o m  b as eli n e i n  F E V1 p er c e nt  pr e di ct e d  at  4  w e e ks, t h e n  1 2  w e e ks, t h e n  2 0 
w e e ks.  
   n u m b er  of s u c c essf ul r es p o ns e  c y cl es.  
   fr e q u e n c y  of p ul m o n ar y  e x a c er b ati o ns.  
   A U C  of  F E V 1-ti m e  pr ofil e. 
T h e st atisti c al  d e ci si o n r ul e f or  m o vi n g t o  e a c h  a n al ysis  will  b e  b as e d  o n t h e s e q u e n c e list e d  a b o v e  a n d  m e eti n g  a 
t hr es h ol d  of  P  < 0. 0 5  at  e a c h st a g e.   S e nsiti vit y  a n al ys es  will  n ot i m p a ct  o n t h e  d e ci si o n t o  m o v e f or w ar d  or st o p 
t esti n g. S u b gr o u p  a n al ys es f or t h e str atifi c ati o n f a ct ors ( ot h er t h a n  a g e  gr o u p)  ar e f or  d es cri pti v e  a n d s u p p orti v e 
p ur p os es  a n d  will  n ot i m p a ct t h e  d e cisi o n t o  m o v e f or w ar d  or st o p t esti n g.  
Alt h o u g h t h e  a b o v e s e q u e n c e i s i m pl e m e nt e d t o  c o ntr ol t y p e I  err or, r es ult s  of  all t h e  a n al ys es  will  b e i n cl u d e d i n 
t h e fi n al r e p ort. 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
5 4 
I n  a d diti o n t o t h e  a b o v e,  all  a n al ys es  will  b e r e p e at e d i n t h e  gr o u p  of p ati e nt s   > 2 1  y e ars  of  a g e.   Esti m at es  of 
tr e at m e nt eff e cts  a n d  9 5 %  c o nfi d e n c e i nt er v al s  will  b e  pr o d u c e d.   N o mi n al  p -v al u es  will  al s o  b e  pr o d u c e d  b ut  o nl y 
f or  d es cri pti v e  p ur po s es.  N o  T y p e I  err or  c o ntr ol  will  b e i m pl e m e nt e d f or t h e  p ati e nt s  > 2 1  y e ars  of  a g e.  
1 6. 6   S af et y  A n al y sis 
A si n gl e s et  of s af et y  a n al ys es  will  b e  pr o d u c e d i n cl u di n g  all  p ati e nt s  (t h os e ≤  2 1  y e ars  ol d  a n d t h os e  > 2 1  y e ars  ol d, 
c o m bi n e d).   Sel e ct e d  a n al ys es  will  b e r e p e at e d f or t h e t w o  gr o u ps s e p ar at el y (s u bj e ct  ≤  2 1  y e ars  ol d  a n d  s u bj e cts 
> 2 1  y e ars  ol d, r es p e cti v el y ).   
E xt e nt  of  e x p os ur e  a n d  d osi n g  c o m pli a n c e  will  b e s u m m ari z e d  b y tr e at m e nt  gr o u p.  A d v ers e  e v e nt s  will  b e  m a p p e d 
t o  pr ef err e d t er ms  a n d s yst e m  or g a n  cl ass es  usi n g t h e  M e di c al  Di cti o n ar y f or  R e g ul at or y A cti viti es ( M e d D R A).  
T h e i n ci d e n c e  of  A Es ( e v er  h a vi n g)  a n d t h e fr e q u e n c y  of  A Es (t ot al  n u m b er)  a n d  9 5 %  c o nfi d e n c e i nt er v als  will  b e 
t a b ul at e d  b y tr e at m e nt  gr o u p, s yst e m  or g a n  cl ass,  a n d  pr ef err e d t er m.  S eri o us  a d v ers e  e v e nt s ( S A Es)  will  b e 
s u m m ari z e d i n  a  si mil ar f as hi o n.  A d v ers e  e v e nt s u m m ari es  b y s e v erit y  a n d r el ati o ns hi p t o st u d y  dr u g  will  al s o  b e 
pr o vi d e d.  T h e  A E s u m m ari es  will  b e  pr es e nt e d f or  all s u bj e cts  a n d  b y t h e t w o  a g e  gr o u ps.  
L a b or at or y  p ar a m et ers  will  b e s u m m ari z e d  usi n g  d es cri pti v e st atisti cs  at  B as eli n e  a n d  at  e a c h  p ost -b as eli n e  visit. 
C h a n g es fr o m  B as eli n e  will  als o  b e s u m m ari z e d. I n  a d diti o n, s hift t a bl es (i. e., l o w -n or m al -hi g h  at  B as eli n e  v ers us 
l o w-n or m al -hi g h  at  e a c h  p ost -b as eli n e  vi sit i n  a  3 -b y -3  c o nti n g e n c y t a bl e)  will  b e  pr o vi d e d t o  ass ess  c h a n g es fr o m 
B as eli n e i n l a b or at or y  v al u es.   
Vit al si g ns  will  b e s u m m ari z e d  usi n g  d es cri pti v e st ati sti cs  at  B as eli n e  a n d  at  e a c h  p ost -B as eli n e  visit.  C h a n g es fr o m 
B as eli n e  will  al s o  b e s u m m ari z e d.  
El e ctr o c ar di o gr a m  p ar a m et ers  will  b e s u m m ari z e d  usi n g  d es cri pti v e st atisti cs  at  B as eli n e  a n d  at  e a c h  p ost -b as eli n e 
visit  w h er e  a n  E C G  ass ess m e nt  w as  m a d e.  C h a n g es fr o m  B as eli n e  will  als o  b e s u m m ari z e d. I n  a d diti o n, s hift t a bl es 
(i. e.,  n or m al,  n ot  cli ni c all y si g nifi c a nt [ N C S],  cli ni c all y si g nifi c a nt [ C S])  at  B as eli n e  v ers us  n or m al,  N C S,  C S  at 
e a c h  p ost -b as eli n e  vi sit i n  a   3-b y -3  c o nti n g e n c y t a bl e)  will  b e  pr o vi d e d t o  ass ess  c h a n g es fr o m  B as eli n e . 
1 6. 7   I nt e ri m  A n al y sis 
N o i nt eri m  a n al ysi s  will  b e  c o n d u ct e d.  
1 6. 8   S a m pl e  Si z e  a n d  R a n d o mi z ati o n  
A t ot al  of  2 0 0 s u bj e cts  will  b e  e nr oll e d i nt o t h e st u d y ( 1 5 0 s u bj e ct s  ≤  2 1  y e ars  ol d,  5 0 s u bj e cts  >  2 1  y e ars  ol d).  T h e 
pri m ar y  a n al ysis  p o p ul ati o n  will  b e t h e s u bj e cts   ≤ 2 1  y e ars  of  a g e. I n t h e si n gl e  c y cl e  P h as e II  st u d y,  wit h  missi n g 
d at a i m p ut e d  usi n g  c o ns er v ati v e r ul es  a d o pt e d  b y t h e  F D A,  a  diff er e n c e i n t h e  m e a n  a bs ol ut e  c h a n g e i n  F E V 1 
p er c e nt  pr e di ct e d  of  4.  3  %  a n d  a r o ot  m e a n s q u ar e  d e vi ati o n  of  6. 3  %  w er e  o bs er v e d  b et w e e n t h e tr e at m e nt  ar ms i n 
s u bj e cts  <  2 1  y e ars  of  a g e.  B as e d  o n t h es e  n u m b ers,  a s a m pl e si z e  of  4 5 s u bj e ct s  p er  ar m  w o ul d  pr o vi d e  8 9  % 
p o w er t o  d et e ct  a st atisti c all y  si g nifi c a nt  diff er e n c e  at  al p h a l e v el  of  0. 0 5.  T o  a c c o u nt f or  p ot e nti al  dr o p  o uts  a n d/ or 
s m all er eff e ct si z e i n  a t hr e e -c y cl e st u d y,  a s a m pl e si z e  of  7 5  p er  ar m  will  b e  e nr oll e d  i n t h e  pri m ar y  a nal ysi s 
p o p ul ati o n ,  w hi c h if  all  c o m pl et e d  w o ul d  pr o vi d e  9 0 %  p o w er t o  d et e ct  a  diff er e n c e  of  3. 4 %  at  2 0  w e e ks  ass u mi n g 
t h e s a m e st a n d ar d  d e vi ati o n  of  6. 3%.  I n  a d diti o n,  a p pr o xi m at el y  2 5  s u bj e cts p er  ar m i n t h e  o v er  2 1 -y e ar  a g e  gr o u p 
will  b e i n cl u d e d.  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
5 5 
1 7   D A T A  C O L L E C T I O N,  R E T E N TI O N  A N D  M O NI T O RI N G 
1 7. 1   D at a  C oll e cti o n I nst r u m e nt s  
T h e I n v esti g at or  will  pr e p ar e  a n d  m ai nt ai n  a d e q u at e  a n d  a c c ur at e s o ur c e  d o c u m e nts  d esi g n e d t o r e c or d  all 
o bs er v ati o ns  a n d  ot h er  p erti n e nt  d at a f or  e a c h  s u bj e ct tr e at e d  wit h t h e st u d y  dr u g.  
St u d y  p ers o n n el  at  e a c h sit e  will  e nt er  d at a fr o m s o ur c e  d o c u m e nts  c orr es p o n di n g t o  a  s u bj e ct’s  visit i nt o t h e 
pr ot o c ol -s p e cifi c  C as e  R e p ort  F or m ( C R F  w h e n t h e i nf or m ati o n  c orr es p o n di n g t o t h at  visit is  a v ail a bl e ). S u bj e cts  
will  n ot  b e i d e ntifi e d  b y  n a m e i n t h e st u d y  d at a b as e  or  o n  a n y st u d y  d o c u m e nt s t o  b e  c oll e ct e d  b y t h e  S p o ns or ( or 
d esi g n e e),  b ut  will  b e i d e ntifi e d  b y  a sit e  n u m b er,  s u bj e ct n u m b er  a n d i niti als.  
If  a  c orr e cti o n is r e q uir e d f or a n  e C R F, t h e ti m e  a n d  d at e st a m ps tr a c k t h e  p ers o n  e nt eri n g  or  u p d ati n g  e C R F  d at a 
a n d  cr e at es  a n  el e ctr o ni c  a u dit tr ail.  T h e I n v esti g at or is r es p o nsi bl e f or  all i nf or m ati o n  c oll e ct e d  o n s u bj e ct s  e nr oll e d 
i n t his st u d y. All  d at a  c oll e ct e d  d uri n g  t hi s st u d y m ust  b e r e vi e w e d  a n d  v erifi e d f or  c o m pl et e n ess  a n d  a c c ur a c y  b y 
t h e I n v esti g at or,  vi a  el e ctr o ni c si g n at ur e. A  c o p y  of t h e  C R F  will r e m ai n  at t h e I n v esti g at or’s sit e  at t h e  c o m pl eti o n 
of t h e st u d y . 
1 7. 2   D at a  M a n a g e m e nt  P r o c e d u r es 
T h e  d at a  will  b e  e nt er e d i nt o  a  v ali d at e d  d at a b as e.  T h e  D at a  M a n a g e m e nt  gr o u p  will  b e r es p o nsi bl e f or  d at a 
pr o c essi n g, i n  a c c or d a n c e  wit h  pr o c e d ur al  d o c u m e nt ati o n.  D at a b as e l o c k  will  o c c ur  o n c e  q u alit y  ass ur a n c e 
pr o c e d ur es  h a v e  b e e n  c o m pl et e d.   
All  pr o c e d ur es f or t h e  h a n dli n g  a n d  a n al ysis  of  d at a  will  b e  c o n d u ct e d  usi n g  g o o d  c o m p uti n g  pr a cti c es  m e eti n g 
F D A  g ui d eli n es, f oll o wi n g t h e  D at a  M a n a g e m e nt  Pl a n,  a n d st a yi n g  wit hi n t h e  d el e g at e d  St a n d ar d  O p er ati n g 
Pr o c e d ur es ( S O Ps), f or  h a n dli n g  a n d  a n al ysis  of  d at a f or  cli ni c al tri al s. 
1 7. 3   D at a  Q u alit y  C o nt r ol  a n d  R e p o rti n g 
Aft er  d at a  h a v e  b e e n  e nt er e d i nt o t h e  st u d y  d at a b as e,  a s yst e m  of  c o m p ut eri z e d  d at a  v ali d ati o n  c h e c ks  will  b e 
i m pl e m e nt e d  a n d  a p pli e d t o t h e  d at a b as e  o n  a r e g ul ar  b asis. Q u eri es  ar e  e nt er e d, tr a c k e d,  a n d r es ol v e d t hr o u g h t h e 
E D C s yst e m  dir e ctl y .  Th e st u d y  d at a b as e  will  b e  u p d at e d i n  a c c or d a n c e  wit h t h e r es ol v e d  q u eri es.  All  c h a n g es t o 
t h e st u d y  d at a b as e  will  b e  d o c u m e nt e d. 
1 7. 4   A r c hi v al  of  D at a 
T h e  d at a b as e is s af e g u ar d e d  a g ai nst  u n a ut h ori z e d  a c c ess  b y  est a blis h e d s e c urit y  pr o c e d ur es;  a p pr o pri at e  b a c k u p 
c o pi es  of t h e  d at a b as e  a n d r el at e d s oft w ar e fil es  will  b e  m ai nt ai n e d.  D at a b as es  ar e  b a c k e d  u p  b y t h e  d at a b as e 
a d mi nistr at or i n  c o nj u n cti o n  wit h  a n y  u p d at es  or  c h a n g es t o t h e  d at a b as e.   
At  criti c al j u n ct ur es  of t h e  pr ot o c ol,  d at a f or  a n al ysi s is l o c k e d  a n d  cl e a n e d  p er  est a blis h e d  pr o c e d ur es.  
1 7. 5   A v ail a bilit y  a n d  R et e nti o n  of I n v esti g ati o n al  R e c o r ds 
T h e I n v esti g at or  m ust  m a k e st u d y  d at a  a c c essi bl e t o t h e  m o nit or,  ot h er  a ut h ori z e d r e pr es e nt ati v es  of t h e  S p o ns or ( or 
d esi g n e e), I R B/I E C ,  a n d  R e g ul at or y  A g e n c y (e g ,  F D A) i ns p e ct ors  u p o n r e q u est. A fil e f or  e a c h  s u bj e ct m ust  b e 
m ai nt ai n e d t h at i n cl u d es t h e si g n e d I nf or m e d  C o ns e nt,  HI P A A  A ut h ori z ati o n  a n d  Ass e nt  F or m  a n d  c o pi es  of  all 
s o ur c e  d o c u m e nt ati o n r el at e d t o t h at  s u bj e ct. T h e I n v esti g at or  m ust  e ns ur e t h e r eli a bilit y  a n d  a v ail a bilit y  of s o ur c e 
d o c u m e nts fr o m  w hi c h t h e i nf or m ati o n  o n t h e  C R F  w as  d eri v e d.  
All st u d y  d o c u m e nts ( s u bj e ct fil es, si g n e d i nf or m e d  c o ns e nt f or ms,  c o pi es  of  C R Fs,  St u d y  Fil e  N ot e b o o k,  et c.)  m ust 
b e  k e pt s e c ur e d f or  a  p eri o d  of  2  y e ars f oll o wi n g  m ar k eti n g  of t h e i n v esti g ati o n al  pr o d u ct  or f or  2  y e ars  aft er  c e nt ers 
h a v e  b e e n  n otifi e d t h at t h e I N D  h as  b e e n  dis c o nti n u e d.  T h er e  m a y  b e  ot h er  cir c u mst a n c es f or  w hi c h t h e  S p o ns or is 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
5 6 
r e q uir e d t o  m ai nt ai n st u d y r e c or ds  a n d, t her ef or e, t h e  S p o ns or s h o ul d  b e  c o nt a ct e d  pri or t o r e m o vi n g  st u d y r e c or ds 
f or  a n y r e as o n. 
1 7. 6   M o nit o ri n g  
M o nit ori n g  visits  will  b e  c o n d u ct e d  b y r e pr es e nt ati v es  of t h e  S p o ns or  a c c or di n g t o t h e  U. S.  C F R  Titl e  2 1  P arts  5 0, 
5 6,  a n d  3 1 2  a n d I C H  G ui d eli n es f or  G C P ( E 6).  B y si g ni n g t hi s  pr ot o c ol, t h e I n v esti g at or  gr a nts  p er mi ssi o n t o t h e 
S p o ns or ( or  d esi g n e e),  a n d  a p pr o pri at e r e g ul at or y  a ut h oriti es t o  c o n d u ct  o n -sit e  m o nit ori n g  a n d/ or  a u diti n g  of  all 
a p pr o pri at e st u d y  d o c u m e nt ati o n.  
1 7. 7   S u bj e ct   C o nfi d e nti alit y 
I n  or d er t o m ai nt ai n  s u bj e ct c o nfi d e nti alit y,  o nl y  a  sit e  n u m b er,  s u bj e ct n u m b er  a n d  s u bj e ct i niti al s  will i d e ntif y  all 
st u d y s u bj e cts o n  C R Fs  a n d  ot h er  d o c u m e nt ati o n s u b mitt e d t o t h e  S p o ns or.  A d diti o n al  s u bj e ct c o nfi d e nti alit y iss u es 
ar e  c o v er e d i n t h e  Cli ni c al  St u d y  A gr e e m e nt.  
1 8   A D MI NI S T R A T I V E,  E T HI C A L,  R E G U L A T O R Y  C O N SI D E R A TI O N S  
T h e st u d y  will  b e  c o n d u ct e d  a c c or di n g t o t h e  D e cl ar ati o n  of  H elsi n ki,  Pr ot e cti o n  of  H u m a n  V ol u nt e ers ( 2 1  C F R 
5 0), I nstit uti o n al  R e vi e w  B o ar ds ( 2 1  C F R  5 6),  a n d  O bli g ati o ns  of  Cli ni c al I n v esti g a t ors ( 2 1  C F R  3 1 2). 
T o  m ai nt ai n  c o nfi d e nti alit y,  all l a b or at or y s p e ci m e ns,  e v al u ati o n f or ms, r e p orts  a n d  ot h er r e c or ds  will  b e i d e ntifi e d 
b y  a  c o d e d  n u m b er  a n d i niti al s  o nl y.  All st u d y r e c or ds  will  b e  k e pt i n  a l o c k e d r o o m  wit h li mit e d  a c c ess.  Cli ni c al 
i nf or m ati o n  will  n ot  b e r el e as e d  wit h o ut  writt e n  p er missi o n  of t h e s u bj e ct,  e x c e pt  as  n e c ess ar y f or  m o nit ori n g  b y t h e 
F D A.  T h e I n v esti g at or  m ust  als o  c o m pl y  wit h  all  a p pli c a bl e  pri v a c y r e g ul ati o ns ( e g ,  H e alt h I ns ur a n c e  P ort a bilit y 
a n d  A c c o u nt a bilit y  A ct  of  1 9 9 6,  E U  D at a  Pr ot e cti o n  Dir e cti v e  9 5/ 4 6/ E C).  
1 8. 1   P r ot o c ol  A m e n d m e nt s  
A n y  a m e n d m e nt t o t h e  pr ot o c ol  will  b e  a p pr o v e d  b y t h e  S p o ns or.  Pr ot o c ol  a m e n d m e nt s  c a n n ot  b e i m pl e m e nt e d 
wit h o ut  pri or  writt e n I R B/I E C  a p pr o v al  e x c e pt  as  n e c ess ar y t o  eli mi n at e i m m e di at e s af et y  h a z ar ds t o  s u bj e cts. A 
pr ot o c ol  a m e n d m e nt i nt e n d e d t o  eli mi n at e  a n  a p p ar e nt i m m e di at e  h a z ar d t o  s u bj e cts m a y  b e i m pl e m e nt e d 
i m m e di at el y,  pr o vi d e d t h e I R Bs  ar e  n otifi e d. 
1 8. 2   I nstit uti o n al  R e vi e w  B o a r ds  a n d  I n d e p e n d e nt  Et hi cs  C o m mitt e es 
T h e  pr ot o c ol  a n d  c o ns e nt  f or m  will  b e r e vi e w e d  a n d  a p pr o v e d  b y t h e I R B/I E C  of  e a c h  p arti ci p ati n g  c e nt er  pri or t o 
st u d y i niti ati o n. S eri o us  a d v ers e  e v e nts  will  b e r e p ort e d t o t h e I R B/I E C i n  a c c or d a n c e  wit h t h e st a n d ar d  o p er ati n g 
pr o c e d ur es  a n d  p oli ci es  of t h e I R B/I E C,  a n d t h e I n v esti g at or  will  k e e p t h e I R B/I E C i nf or m e d  as t o t h e  pr o gr ess  of 
t h e st u d y. T h e I n v esti g at or  will  o bt ai n  ass ur a n c e  of I R B/I E C  c o m pli a n c e  wit h r e g ul ati o ns.  
A n y  d o c u m e nt s t h at t h e I R B/I E C  m a y  n e e d t o f ulfill its r es p o nsi biliti es (s u c h  as  pr ot o c ol,  pr ot o c ol  a m e n d m e nts, 
I n v esti g at or’s  Br o c h ur e,  c o ns e nt f or ms, i nf or m ati o n  c o n c er ni n g s u bj e ct r e cr uit m e nt,  p a y m e nt  or  c o m p e ns ati o n 
pr o c e d ur es,  or  ot h er  p erti n e nt i nf or m ati o n)  will  b e s u b mitt e d t o t h e I R B/I E C.  T h e I R B/I E Cs  writt e n  a p pr o v al  of t h e 
st u d y  pr ot o c ol  a n d t h e i nf or m e d  c o ns e nt f or m  will  b e i n t h e  p oss essi o n  of t h e I n v esti g at or  b ef or e t h e st u d y i s 
i niti at e d. T h e I R B/I E Cs  a p pr o v al st at e m e nt  will  b e tr a ns mitt e d  b y t h e I n v esti g at or t o t h e  S p o ns or  or  d esi g n e e  pri or 
t o t h e s hi p m e nt  of st u d y s u p pli es t o t h e sit e. T his  a p pr o v al  m ust r ef er t o t h e st u d y  b y  e x a ct  pr ot o c ol titl e  a n d  n u m b er 
a n d s h o ul d i d e ntif y t h e  d o c u m e nt s r e vi e w e d  a n d t h e  d at e  of r e vi e w.  
Pr ot o c ol  a n d/ or i nf or m e d  c o ns e nt  m o difi c ati o ns  or  c h a n g es  m a y  n ot  b e i niti at e d  wit h o ut  pri or  writt e n I R B/I E C 
a p pr o v al  e x c e pt  w h e n  n e c ess ar y t o  eli mi n at e i m m e di at e  h a z ar ds t o t h e  s u bj e cts or  w h e n t h e  c h a n g e(s) i n v ol v es  o nl y 
l o gisti c al  or  a d mi nistr ati v e  as p e cts  of t h e st u d y. S u c h  m o difi c ati o ns  will  b e s u b mitt e d t o t h e I R B/I E C  a n d  writt e n 
v erifi c ati o n t h at t h e  m o difi c ati o n  w as s u b mitt e d  a n d s u bs e q u e ntl y  a p pr o v e d s h o ul d  b e  o bt ai n e d.   


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
5 7 
T h e I R B/I E C  m ust  b e i nf or m e d  of r e visi o ns t o  ot h er  d o c u m e nts  ori gi n all y s u b mitt e d f or r e vi e w; s eri o us  a n d/ or 
u n e x p e ct e d  a d v ers e  e x p eri e n c es  o c c urri n g  d uri n g t h e st u d y i n  a c c or d a n c e  wit h t h e st a n d ar d  o p er ati n g  pr o c e d ur es 
a n d  p oli ci es  of t h e I R B;  n e w i nf or m ati o n t h at  m a y  aff e ct  a d v ers el y t h e s af et y  of t h e  s u bj e ct s  of t h e  c o n d u ct  of t h e 
st u d y;  a n  a n n u al  u p d at e  a n d/ or r e q u est f or r e -a p pr o v al;  a n d  w h e n t h e st u d y  h as  b e e n  c o m pl et e d.  
1 8. 3   I nf o r m e d  C o ns e nt  F o r m   
I nf or m e d  c o ns e nt  will  b e  o bt ai n e d i n  a c c or d a n c e  wit h t h e  D e cl ar ati o n  of  H elsi n ki, I C H  G C P,  U S  C o d e  of  F e d er al 
R e g ul ati o ns f or  Pr ot e cti o n  of  H u m a n  S u bj e ct s ( 2 1  C F R  5 0. 2 5[ a,  b],  C F R  5 0. 2 7,  a n d  C F R  P art  5 6,  S u b p art  A), t h e 
H e alt h I ns ur a n c e  P ort a bilit y  a n d  A c c o u nt a bilit y  A ct ( HI P A A, if  a p pli c a bl e),  a n d l o c al r e g ul ati o ns.  
T h e I n v esti g at or  will  pr e p ar e t h e i nf or m e d  c o ns e nt f or m,  ass e nt  a n d  HI P A A  a ut h ori z ati o n  a n d  pr o vi d e t h e 
d o c u m e nts t o t h e  S p o ns or  or  d esi g n e e f or  a p pr o v al  pri or t o s u b missi o n t o t h e I R B/I E C.  T h e  c o ns e nt f or m  g e n er at e d 
b y t h e I n v esti g at or  m ust  b e  a c c e pt a bl e t o t h e  S p o ns or  a n d  b e  a p pr o v e d  b y t h e I R B/I E C.  T h e  writt e n  c o ns e nt 
d o c u m e nt  will  e m b o d y t h e  el e m e nts  of i nf or m e d  c o ns e nt  as  d es cri b e d i n t h e I nt er n ati o n al  C o nf er e n c e  o n 
H ar m o ni z ati o n  a n d  will  als o  c o m pl y  wit h l o c al r e g ul ati o ns.  T h e I n v esti g at or  will s e n d  a n I R B/I E C -a p pr o v e d  c o p y 
of t h e I nf or m e d  C o ns e nt  F or m t o t h e  S p o ns or ( or  d esi g n e e) f or t h e st u d y fil e.  
A  pr o p erl y  e x e c ut e d,  writt e n, i nf or m e d  c o ns e nt  will  b e  o bt ai n e d fr o m  e a c h  s u bj e ct pri or t o  e nt eri n g t h e  s u bj e ct i nt o 
t h e tri al. I nf or m ati o n s h o ul d  b e  gi v e n i n  b ot h  or al  a n d  writt e n f or m  a n d s u bj e cts ( or t h eir l e g al r e pr es e nt ati v es)  m ust 
b e  gi v e n  a m pl e  o p p ort u nit y t o i n q uir e  a b o ut  d et ails  of t h e st u d y.  If  a p pr o pri at e  a n d r e q uir e d  b y t h e l o c al I R B/I E C, 
ass e nt fr o m t h e  s u bj e ct will  al s o  b e  o bt ai n e d.  If  a s u bj e ct is  u n a bl e t o si g n t h e i nf or m e d  c o ns e nt f or m (I C F)  a n d t h e 
HI P A A  a ut h ori z ati o n,  a l e g al r e pr es e nt ati v e  m a y si g n f or t h e  s u bj e ct.  A  c o p y  of t h e si g n e d  c o ns e nt f or m ( a n d 
ass e nt)  will  b e  gi v e n t o t h e  s u bj e ct or l e g al r e pr es e nt ati v e  of t h e  s u bj e ct a n d t h e  ori gi n al  will  b e  m ai nt ai n e d  wit h t h e 
s u bj e ct’s r e c or ds. 
1 8. 4   P u bli c ati o ns   
T h e  pr e p ar ati o n  a n d s u b mitt al f or  p u bli c ati o n  of  m a n us cri pts  c o nt ai ni n g t h e st u d y r es ults  s h all  b e i n  a c c or d a n c e 
wit h  a  pr o c ess  d et er mi n e d  b y  m ut u al  writt e n  a gr e e m e nt  a m o n g t h e st u d y  S p o ns or  a n d  p arti ci p ati n g i nstit uti o ns.  T h e 
p u bli c ati o n  or  pr es e nt ati o n  of  a n y st u d y r es ult s s h all  c o m pl y  wit h  all  a p pli c a bl e  pri v a c y l a ws, i n cl u di n g,  b ut  n ot 
li mit e d t o, t h e  H e alt h I ns ur a n c e  P ort a bilit y  a n d  A c c o u nt a bilit y  A ct  of  1 9 9 6.  
It is t h e  S p o ns or’s i nt e nt t o  e v e nt u all y  p u blis h t h e r es ults  of t his st u d y.  T h e  S p o ns or  will  s e p ar at el y  a gr e e  wit h t h e 
C o or di n ati n g I n v esti g at or  a n d t h e  P ri n ci p al I n v esti g at ors  o n  a  p u bli c ati o n  str at e g y,  w hi c h  will i n cl u d e t h e  n a m es  of 
t h e  a ut h ors  of t h e  p u bli c ati o n(s).  T h e  S p o ns or  m ust r e vi e w  a n d  a p pr o v e  a n y  m a n us cri pts  or  a bstr a cts  pr e p ar e d f or 
s u b missi o n t o s ci e ntifi c j o ur n als  or f or  pr of essi o n al  m e eti n g s.  D at a fr o m i n di vi d u al st u d y  c e nt ers s h all  n ot  b e 
p u blis h e d s e p ar at el y.  
1 8. 5   I n v esti g at o r  R es p o nsi biliti es  
B y si g ni n g t h e  A gr e e m e nt  of I n v esti g at or f or m, t h e I n v esti g at or  a gr e es t o:  
1.   C o n d u ct t h e st u d y i n  a c c or d a n c e  wit h t h e  pr ot o c ol  a n d  o nl y  m a k e  c h a n g es  aft er  n otif yi n g t h e  S p o ns or ( or 
d esi g n e e),  e x c e pt  w h e n t o  pr ot e ct t h e s af et y, ri g hts  or  w elf ar e  of s u bj e ct s.  
2.   P ers o n all y  c o n d u ct  or s u p er vi s e t h e st u d y ( or i n v esti g ati o n).  
3.   E ns ur e t h at t h e r e q uir e m e nt s r el ati n g t o  o bt ai ni n g i nf or m e d  c o ns e nt  a n d I R B r e vi e w  a n d  a p pr o v al  m e et f e d er al 
g ui d eli n es,  as  st at e d i n  §  2 1  C F R,  p arts  5 0  a n d  5 6.  
4.   R e p ort t o t h e  S p o ns or  or  d esi g n e e  a n y  A Es t h at  o c c ur i n t h e  c o urs e  of t h e st u d y, i n  a c c or d a n c e  wit h  § 2 1  C F R 
3 1 2. 6 4.  


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
5 8 
5.   E ns ur e t h at  all  ass o ci at es,  c oll e a g u es  a n d  e m pl o y e es  assisti n g i n t h e  c o n d u ct  of t h e st u d y  ar e i nf or m e d  a b o ut 
t h eir  o bli g ati o ns i n  m e eti n g t h e  a b o v e  c o m mit m e nts. 
6.   M ai nt ai n  a d e q u at e  a n d  a c c ur at e r e c or ds i n  a c c or d a n c e  wit h  § 2 1  C F R  3 1 2. 5 7  a n d t o  m a k e t h os e r e c or ds 
a v ail a bl e f or i ns p e cti o n  wit h t h e  S p o ns or ( or  d esi g n e e).  
7.   E ns ur e t h at  a n I R B t h at  c o m pli es  wit h t h e r e q uir e m e nt s  of  § 2 1  C F R  p art  5 6  will  b e r es p o nsi bl e f or i niti al  a n d 
c o nti n ui n g r e vi e w  a n d  a p pr o v al  of t h e  cli ni c al st u d y.  
8.   Pr o m ptl y r e p ort t o t h e I R B  a n d t h e  S p o ns or ( or  d esi g n e e)  all  c h a n g es i n t h e r es e ar c h  a cti vit y  a n d  al l 
u n a nti ci p at e d  pr o bl e ms i n v ol vi n g ris ks t o s u bj e ct s  or  ot h ers (t o i n cl u d e  a m e n d m e nts  a n d I N D s af et y r e p orts).  
9.   S e e k I R B  a p pr o v al  b ef or e  a n y  c h a n g es  ar e  m a d e i n t h e r es e ar c h st u d y,  e x c e pt  w h e n  n e c ess ar y t o  eli mi n at e 
h a z ar ds t o t h e  p ati e nts/s u bj e ct s.  
1 0.  C o m pl y  wit h  all  ot h er r e q uir e m e nts r e g ar di n g t h e  o bli g ati o ns  of  cli ni c al i n v esti g at ors  a n d  all  ot h er  p erti n e nt 
r e q uir e m e nts li st e d i n  §  2 1  C F R  p art  3 1 2. 
 


S a v ar a  P h ar m a c e uti c al s  
 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8- A P R - 2 0 1 8 
C o nfi d e nti al  
5 9 
1 9.   
R E F E R E N C E S  
1.   C F F  P ati e nt  R e gistr y.  2 0 1 4.  
2.   M et hi cilli n r esist a nt  St a p h yl o c o c c us  a ur e us ( M R S A) i nf e cti o n i n  c ysti c fi br osis.  Mi all  L S,  M c Gi nl e y  N T, 
Br o w nl e e  K G,  C o n w a y  S P. s.l.  :  Ar c h  Dis  C hil d,  2 0 0 1,  V ol.  8 4,  p p.  1 6 0-1 6 2.  
3.   P a nt o n -V al e nti n e  L e u k o ci di n -P ositi v e  M et hi cilli a n -R esist a nt  St a p h yl o c o c c us  a ur e us  L u n g I nf e cti o n i n 
P ati e nts  wit h  C ysti c  Fi br osis.  Eli z ur  A,  Ors c h el n  R C,  F er k ol  T W,  et  al. s.l.  :  C h est,  2 0 0 7,  V ol.  1 3 1,  p p. 
1 7 1 8 -1 7 2 5.  
4.   Pr e v al e n c e  a n d i m p a ct  o n  F E V 1  g 1  d e cli n e  of  c hr o ni c  m et hi cilli n -r esist a nt  St a p h yl o c o c c us  a ur e us ( M R S A) 
c ol o ni ati o n i n  p ati e nts  wit h  C ysti c  Fi br osi s:  A si n gl e -c e nt er  c as e  c o ntr ol st u d y  of  1 6 5  p ati e nts.  V a n d er h el st 
E,  D e  M eirl eir  L,  V er b a n c k  S.  et  al. s.l.  : J  C ysti c  Fi br osis,  2 0 1 2,  V ol.  1 1,  p p.  2-7.  
5.   P ersi st e nt  M et hi cilli n -r esist a nt  St a p h yl o c o c c us  a ur e us  a n d  R at e  of  F E V 1  D e cli n e i n  C ysti c  Fi br osis. 
D as e n br o o k  E C,  M erl o  C A,  Di e n er -W est  M,  et.  al. s.l.  :  A m J  R es pir  Crit  C ar e  M e d,  2 0 0 8,  V ol.  1 7 8,  p p. 
8 1 4 -8 2 1.  
6.   Ass o ci ati o n  B et w e e n  R es pir at or y  Tr a ct  M et hi cilli n -R esist a nt  St a p h yl o c o c c us  a ur e us  a n d  S ur vi v al i n  C ysti c 
Fi br osis.  D a s e n br o o k  E C,  C h e c kl e y  W,  M erl o  C A,  et  al. s.l.  : J A M A,  2 0 1 0,  V ol.  3 0 3,  p p.  2 3 8 6-2 3 9 2.  
7.   Utiliz ati o n  of  a nti bi oti cs f or  m et hi cilli n -r esist a nt  St a p h yl o c o c c us  a ur e us i nf e cti o n i n  c ysti c fi br osis.  Z o b ell 
J T,  E p ps  K L,  Y o u n g  D C,  M o nt a g u e  M,  Ols o n J,  A m p of o  K,  C hi n  MJ,  M ars h all  B C,  D as e n br o o k  E.  6, s.l.  : 
P e di atri c  P ul m o n ol o g y,  2 0 1 5,  V ol.  5 0,  p p.  5 5 2 – 5 5 9.  
8.   Eff e ct  of i n h al e d  v a n c o m y ci n  o n  eli mi n ati o n  of  m et hi cil -li n-r esi st a nt  St a p h yl o c o c c us  a ur e us (i n  J a p a n es e). 
S hir ai  M, I d e  K,  S at o  M,  T a n a k a  Y,  S at o  A,  C hi d a  K. s.l.  :  Ni h o n  K y o b u  S hi k k a n  G a k k ai  Z ass hi,  1 9 9 5, 
V ol.  3 3,  p p.  1 2 3 3 -1 2 3 9.  
9.   P ul m o n ar y  vs s yst e mi c  d eli v er y  of  a nti bi oti cs:  c o m -p aris o n  of  v a n c o m y ci n  dis p ositi o n i n t h e is ol at e d r at 
l u n g. V all e,  MJ.,  L o p e z,  F G,  H url e,  A.,  a n d  N a v arr o,  A.  1 0, s.l.  :  A nti mi cr o b.  A g e nt s  C h e m ot h er. ,  2 0 0 7, 
V ol.  5 1,  p p.  3 7 7 1 -3 7 7 4.  
1 0.  P e n et r ati o n  of  v a n c o m y ci n i nt o  h u m a n l u n g tiss u e.  Cr u ci a ni  M,  G atti  G,  L a z z ari ni  L,  et  al. s.l.  : J 
A nti mi cr o b  C h e m ot h er,  1 9 9 6,  V ol.  3 8,  p p.  8 6 5 -8 6 9.  
1 1.  A n al ysis  of  v a n c o m y ci n  e ntr y i nt o  p ul m o n ar y li ni n g fl ui d  b y  br o n c h o al v e ol ar l a v a g e i n  criti c all y ill 
p ati e nts.  L a m er  C  et  al.  2, s.l.  :  A nti mi cr o b  A g e nts  C h e m ot h er,  1 9 9 3,  V ol.  3 7,  p p.  2 8 1-6.  
1 2.  I n h al e d  a nti mi cr o bi al t h er a p y –  B arri ers t o  eff e cti v e tr e at m e nt.  J.,  W e ers. s.l. :  A d v a n c e d  Dr u g  D eli v er y 
R e vi e ws,  2 0 1 5,  p p.  2 4 -4 3.  
 
 


S a v ar a  P h ar m a c e uti c al s  
 
                 
Pr ot o c ol  S A V 0 0 5 -0 4  
1 8 A P R - 2 0 1 8  
                                                                       C o nfi d e nti al                                         
 
                                             6 0 
A P P E N DI X  1.   S C H E D U L E  O F E V E N T S  
  


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           6 1 
A P P E N DI X   2. Bl o o d  V ol u m e  C al c ul ati o n  
 Ass ess m e nt  
S a m pl e  v ol u m e 
( m L) 
N u m b e r  of  s a m pl es  
Esti m at e d t ot al  v ol u m e 
( m L) 
C B C ( h e m at ol o g y)  
3  
9  
2 7  
Bl o o d  C h e mistr y  
2. 5  
4  
1 0  
S er u m  Pr e g n a n c y  
  4  
  5 *  
2 0  
P h ar m a c o ki n eti cs 
S a m pl e  
6 
1 
6 
Esti m at e d  T ot al  ( m L) 
  
                                                                                      6 3  
* I n cl u d es  Bl o o d C h e mistr y  c oll e cti o n.  


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           6 2 
A P P E N DI X   3.  C Y S TI C   FI B R O SI S    R E S PI R A T O R Y   S Y M P T O M    DI A R Y  ( C F R S D ©) 
S E L F - R E P O R T  – W E E K L Y  V E R SI O N  2 . 0 
( O nl y t h e first 8  q u esti o ns  will  b e  c o m pl et e d  b y  s u bj e cts i n t his st u d y t o  pr o vi d e t h e  C F R S D-
C RI S S .) 
 
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           6 3 
 
 
 
C y sti c  Fi br o si s  R e s pir at or y  
S y m pt o m  Di ar y  –  ( C F R S D© ) 
 
 
S elf- R e p ort  –  V er si o n  2. 0 
 
7- D a y  R e c all  
 
 
U ni v er sit y  Of  W a s hi n gt o n  
S e attl e  Q u alit y  of  Lif e  Gr o u p  a n d  D e p art m e nt  of  M e di ci n e  
 
 
 
 
 
 
 
 
 
 
 
 
 
©  U ni v er sit y  of  W a s hi n gt o n  
 
D o  n ot r e pr o d u c e  or  cir c ul at e  wit h o ut  p er mi s si o n  of  t h e  a ut h or s. 
 
T hi s  w or k  h a s  b e e n  s u p p ort e d  wit h  a  gr a nt fr o m t h e  C y sti c  Fi br o si s  
F o u n d ati o n  
 
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           6 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           6 5 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           6 6 
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           6 7 
 
 
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           6 8 
 
 
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           6 9 
 
A P P E N DI X   4. C ysti c  Fi br osis  q u esti o n n air e  -  re vis e d  ( C F Q -R)  S elf - R e p ort  –  T w o  W e e k 
R e c all ;  v ersi o n  2 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           7 0 
T E E N/ A D U L T  V E R SI O N  F O R  A G E S  1 4  T H R O U G H  A D U L T H O O D  
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           7 1 
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           7 2 
 
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           7 3 
P A R E N T  V E R SI O N  F O R  C HI L D R E N  A G E S  6 -1 3 ( P A R E N T S  R E P O R TI N G  O N  T H E 
C HI L D’ S  H R Q O L)  
 
 
 
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           7 4 
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           7 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           7 6 
A P P E N DI X   5.  E Q- 5 D-5 L  &  E Q- 5 D y  
a d d  c o p y  of  q u esti o n n air es  
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           7 7 
 
 
 
 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           7 8 
A P P E N DI X   6. I nstr u cti o ns f or  Us e  of  A er o V a n c I n h al er 
I N S T R U C TI O N S  F O R  U S E  O F  A E R O V A N C  I N H A L E R  
Pl e as e r e a d t h e f oll o wi n g i nstr u cti o ns  c ar ef ull y t o l e ar n  h o w t o  us e  a n d  c ar e f or  y o ur 
A er o V a n c  i n h al er. 
•   O nl y  us e t h e  A er o V a n c i n h al er  pr o vi d e d.  D o  n ot  us e  A er o V a n c  or  Pl a c e b o 
c a ps ul es  w it h  a n y  ot h er i n h al er,  a n d  d o  n ot  us e t h e  A er o V a n c i n h al er t o t a k e 
a n y  ot h er  c a ps ul e  m e di ci n e.  
•   D o  n ot s w all o w t h e  c a ps ul es.   T h e  p o w d er i n t h e  c a ps ul es is f or  y o u t o i n h al e. 
T h e  A er o V a n c  i n h al er  e n a bl es  y o u t o i n h al e t h e  pr o d u ct  c o nt ai n e d i n  a n A er o V a n c  or 
Pl a c e b o  c a ps ul e.  
A er o V a n c  a n d  Pl a c e b o  c a ps ul es  ar e s u p pli e d i n  al u mi n u m f oil  p e el a bl e l a mi n at e d  blist ers . 
E a c h  blist er stri p   c o nt ai ns  4  c a ps ul es i n  a  2  x  2  c o nfi g ur ati o n s e p ar at e d  b y  a  p erf or ati o n 
i nt o  m or ni n g  a n d  e v e ni n g  d os es.  T h er e  ar e  7  blist er stri ps pl us  1 s p ar e  blist er stri p i n  e a c h 
w e e kl y  b o x.  F o ur  w e e kl y  b o x es,  4  A er o V a n c i n h al ers  pl us  1 s p ar e i n h al er, t h es e 
i nstr u cti o ns f or  us e,  a  q ui c k st art s h e et,  a n d  a r et ur ns  b a g  ar e i n cl u d e d i n  e a c h  2 8-d a y 
cli ni c al  kit.   
H o w t o  us e  y o u r i n h al e r  
1.   
P ull  off t h e  c a p.  
2.    
O p e n  t h e i n h al er: 
H ol d t h e  b as e  of t h e i n h al er fir ml y  a n d t wist t h e  m o ut h pi e c e i n t h e  dir e cti o n  of t h e  arr o w. 
T his  o p e ns t h e i n h al er.  
3.   
Pr e p ar e  t h e  c a ps ul e: 
I m m e di at el y  b ef or e  us e,  wit h  dr y  h a n ds,  c ar ef ull y t e ar  a n d r e m o v e t h e  e n d  of t h e  blist er 
stri p.  P e el   o p e n t h e f oil  blist er fr o m  o n e  of t h e  h al v es  o nl y, t a ki n g  c ar e t o  o nl y  e x p os e  o n e 
of t h e t w o  c a ps ul es fr o m t h at  h alf.  R e m o v e  o n e  c a ps ul e.  D o  n ot  o p e n  b y  p us hi n g t h e 
c a ps ul e t hr o u g h t h e f oil si n c e t his  c a n  d a m a g e t h e  c a ps ul e.  
4.   
I ns ert  t h e  c a ps ul e: 
Pl a c e t h e  c a ps ul e i nt o t h e  c a ps ul e  c h a m b er.  
N e v e r  pl a c e  a  c a ps ul e  di r e ctl y i nt o t h e  m o ut h pi e c e.  
5.  
Cl os e t h e i n h al er:  
Cl os e t h e i n h al er  u ntil  y o u  h e ar  a  “ cli c k ”.  
6.  
Pi er c e t h e  c a ps ul e:  
H ol d t h e i n h al er  u pri g ht  wit h t h e  m o ut h pi e c e  p oi nti n g  u p.  
Pi er c e t h e  c a ps ul e  b y fir ml y  pr essi n g t o g et h er  b ot h si d e  b utt o ns  at t h e s a m e ti m e.  D o t his 
o nl y  o n c e.  
Y o u s h o ul d  h e ar  a  “ cli c k ”  as t h e  c a ps ul e is  b ei n g  pi er c e d.  


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           7 9 
7.  
R el e as e t h e si d e  b utt o ns f ull y.  
8.  
Br e at h e  o ut:  
B ef or e  pl a ci n g t h e  m o ut h pi e c e i n  y o ur  m o ut h,  br e at h e  o ut f ull y. 
D o  n ot  bl o w i nt o t h e  m o ut h pi e c e. 
9.  
I n h al e t h e  m e di ci n e:  
T o  br e at h e t h e  m e di ci n e  d e e pl y i nt o  y o ur  air w a ys:  
•   H ol d t h e i n h al er i n  a  h ori z o nt al  ori e nt ati o n.  T h e si d e  b utt o ns s h o ul d  b e f a ci n g 
l eft  a n d ri g ht.  D o  n ot  pr ess t h e si d e  b utt o ns. 
•   Pl a c e t h e   m o ut h pi e c e i n  y o ur  m o ut h  a n d  cl os e  y o ur li ps fir ml y  ar o u n d t h e 
m o ut h pi e c e.  
•   Br e at h e i n  q ui c kl y   a n d  d e e pl y. 
As  y o u  br e at h e i n t hr o u g h t h e i n h al er, t h e  c a ps ul e s pi ns  ar o u n d i n t h e  c h a m b er  a n d  y o u 
s h o ul d  h e ar  a  w hirri n g  n ois e. If  y o u  d o  n ot  h e ar  a  w hirri n g  n o is e, th e  c a ps ul e  m a y  b e st u c k 
i n t h e  c a ps ul e  c h a m b er. If t his  h a p p e ns: 
•   O p e n t h e i n h al er  a n d  c ar ef ull y l o os e n t h e  c a ps ul e  b y t a p pi n g t h e  b as e  of t h e 
i n h al er.  Cl os e t h e i n h al er.  D o  n ot  pr ess t h e si d e  b utt o ns  a g ai n. 
•   I n h al e t h e  m e di ci n e  a g ai n  b y r e p e ati n g  St e ps  8  a n d  9. 
Y o u  m a y  e x p eri e n c e  a sli g ht t ast e  as t h e  m e di ci n e  g o es i nt o  y o ur l u n gs.  T his is  n or m al.  
O c c asi o n all y,  v er y s m all  pi e c es  of t h e  c a ps ul e  c a n  g et  p ast t h e s cr e e n  a n d  e nt er  y o ur 
m o ut h. If t his  h a p p e ns,  y o u  m a y  b e  a bl e t o f e el t h es e  pi e c es  o n  y o ur t o n g u e. It is  n ot 
h ar mf ul if t h es e  pi e c es  ar e s w all o w e d  or i n h al e d.  T h e  c h a n c es  of t h e  c a ps ul e s h att eri n g  will 
b e i n cr e as e d if t h e  c a ps ul e is  a c ci d e nt all y  pi er c e d  m or e t h a n  o n c e ( St e p  6).  
1 0.  
H ol d   y o ur br e at h:  
 Aft er  y o u  h a v e i n h al e d t h e  m e di ci n e:  
•   H ol d  y o ur  br e at h f or  at l e ast  5- 1 0 s e c o n ds  or  as l o n g  as  y o u  c o mf ort a bl y  c a n 
w hil e t a ki n g t h e i n h al er  o ut  of  y o ur  m o ut h. 
•   T h e n  br e at h e  o ut. 
•   O p e n t h e i n h al er t o s e e if  a n y  p o w d er is l eft i n t h e  c a ps ul e.  
If t h er e is  p o w d er l eft i n t h e  c a ps ul e: 
•   Cl os e t h e i n h al er. 
•   R e p e at  St e ps  8,  9  a n d  1 0. 
M ost  p e o pl e  ar e  a bl e t o  e m pt y t h e  c a ps ul e  wit h  o n e  or t w o i n h al ati o ns.  
A d diti o n al i nf or m ati o n: 
S o m e  p e o pl e  m a y  o c c asi o n all y  c o u g h  bri efl y s o o n  aft er i n h ali n g t h e  m e di ci n e. If  y o u  d o, 
d o n’t  w orr y.  As l o n g  as t h e  c a ps ul e is  e m pt y,  y o u  h a v e r e c ei v e d  e n o u g h  of  y o ur  m e di ci n e. 


 
S a v ar a  P h ar m a c e uti c al s  
                
Pr ot o c ol  S A V 0 0 5 -0 4  
 
1 8- A P R - 2 0 1 8                                                        C o nfi d e nti al                                                           8 0 
1 1.    
Aft er  y o u  h a v e fi nis h e d t a ki n g t h e st u d y  dr u g: 
O p e n t h e  m o ut h pi e c e  a g ai n  a n d r e m o v e t h e  e m pt y  c a ps ul e  b y ti p pi n g it  o ut  of t h e  c a ps ul e 
c h a m b er.  P ut t h e  e m pt y  c a ps ul e i n t h e  pl asti c  w ast e  b a g  pr o vi d e d f or r et ur n t o t h e  cli ni c al 
sit e. 
R e p e at  St e ps  3 t o  1 1  wit h t h e s e c o n d  of t h e t w o  c a ps ul es i n t h at  h alf  of t h e  blist er stri p.  
Cl os e t h e i n h al er  a n d r e pl a c e t h e  c a p.  
D o  n ot st o r e t h e  c a ps ul es i n t h e  A e r o V a n c  i n h al e r. 
    
R E M E M B E R:  
•   D o  n ot s w all o w  A er o V a n c  or  Pl a c e b o  c a ps ul es.  
•   O nl y  us e t h e  A er o V a n c i n h al er  pr o vi d e d. 
•   A er o V a n c  a n d  Pl a c e b o  c a ps ul es  m ust  al w a ys  b e st or e d i n t h e s e al e d f oil  blist er, 
a n d  o nl y r e m o v e d i m m e di at el y  b ef or e  us e.  
•   N e v er  pl a c e  a n  A er o V a n c  or  Pl a c e b o  c a ps ul e  dir e ctl y i nt o t h e  m o ut h pi e c e  of t h e 
A er o V a n c  i n h al er. 
•   D o  n ot  pr ess t h e si d e  b utt o ns  m or e t h a n  o n c e. 
•   N e v er  bl o w i nt o t h e  m o ut h pi e c e  of t h e  A er o V a n c i n h al er. 
•   Al w a ys r el e as e t h e  p us h  b utt o ns  b ef or e i n h al ati o n.  
•   D o  n ot  cl e a n t h e  A er o V a n c i n h al er. 
•   N e v er t a k e t h e  A er o V a n c  i n h al er  a p art. 
•   D o  n ot st or e t h e  c a ps ul es i n t h e  A er o V a n c  i n h al er. 
•   Al w a ys  k e e p t h e  A er o V a n c i n h al er  a n d  A er o V a n c  a n d  Pl a c e b o  c a ps ul es i n  a  dr y 
pl a c e.  
 

SAP_001.pdf: 
 
SAV005-04 
A Phase III, randomized, double-blind, placebo-
controlled study of AeroVanc for the treatment of 
persistent methicillin-resistant Staphylococcus 
aureus lung infection in cystic fibrosis patients 
 
NCT03181932 
 
05 November 2020 


Statistical Analysis Plan 
 
 
This document is proprietary and confidential to Syneos Health. 
03.007A.03     
  Syneos Health 
Page 1 of 126 
 
Sponsor Name: 
Savara Inc. 
Protocol Number and Title: 
 
SAV005-04 
 
A Phase III, randomized, double-blind, placebo-
controlled study of AeroVanc for the treatment of 
persistent methicillin-resistant Staphylococcus aureus 
lung infection in cystic fibrosis patients  
Protocol Version and Date: 
V 2.0 18-Apr-2018 
Syneos Health Project Code: 
1006732 
Author(s):  Wayne Schuck 
 Principal Biostatistician 
SAP Version:  3.0 Amendment 2 
SAP Version Date:  05-Nov-2020 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Savara, Inc. 
Acceptance of this document constitutes agreement by the recipient that no 
information contained herein will be published or disclosed without prior written 
authorization from an official of Savara, Inc.  However, this document may be disclosed 
to appropriate Institutional Review Board and Ethics Committees or duly authorized 
representatives of a national regulatory authority under the condition that they are 
requested to keep it confidential. In the event of an actual or suspected breach of this 
obligation, Syneos Health should be notified promptly. 


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
Syneos Health #1006732 
 
This document is proprietary and confidential to Syneos Health. 
03.007A.03     
  Syneos Health 
Page 2 of 126 
Revision History 
 
Version # 
Date 
(dd-mmm-
yyyy) 
Document Owner 
Revision Summary 
0.1 
30-Mar-2018 
W. Schuck 
Initial Release Version 
0.2 
04-May-2018 
W. Schuck 
Protocol Amendment requires SAP to be updated 
0.3 
08-Jun-2018 
W. Schuck 
Updated base on Savara comments 
1.0 
18-Sep-2018 
W. Schuck 
Updated base on Savara comments 
1.1 
18-Feb-2020 
W. Schuck 
-  Clarification/update on Tipping Point analysis 
-  Move Frequency of pulmonary exacerbations to 
be the first secondary endpoint to be tested 
-  Add analysis and summary tables for all primary 
and secondary endpoints by Trikafta use 
1.2 
10-Apr-2020 
W. Schuck 
-  Added sensitivity analyses using strata based on 
eCRF data instead of IWR reported strata used in 
actual randomization 
-  Typographical updates 
1.3 
28-Apr-2020 
W. Schuck 
Updates regarding changes in the analysis due to 
COVID-19 pandemic, including the addition of 
Appendix B 
1.4 
08-May-2020 
W. Schuck 
Updated base on Savara comments to the COVID-
19 pandemic changes 
1.5 
12-May-2020 
W. Schuck 
Updated base on Savara comments 
2.0 
15-May-2020 
W. Schuck 
Final for Sign-off 
2.1 
09Oct2020 
W. Schuck 
-  Update definition of start of first pulmonary 
exacerbation 
-  Update definition of a new pulmonary 
exacerbation 
-  Incorporate use of PFT grades in selection of 
measures to be used in analyses. 


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
Syneos Health #1006732 
 
This document is proprietary and confidential to Syneos Health. 
03.007A.03     
  Syneos Health 
Page 3 of 126 
Version # 
Date 
(dd-mmm-
yyyy) 
Document Owner 
Revision Summary 
2.2 
28Oct2020 
W. Schuck 
- Added baseline imputation method for CFRSD-
CRISS and CRQ-R 
- Clarified adverse event count methods 
- included grading requirements for PFT use in 
analyses 
- Added programmatic definition of P. aeruginosa 
treatment for sensitivity analysis 
3.0 
05-Nov-2020 
W. Schuck 
Final for Sign-off 
 
 


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
Syneos Health #1006732 
 
This document is proprietary and confidential to Syneos Health. 
03.007A.03     
  Syneos Health 
Page 4 of 126 
 
 
I confirm that I have reviewed this document and agree with the content. 
 
APPROVALS 
Syneos Health 
 
 
 
Lead Biostatistician 
Wayne Schuck 
Principal Biostatistician 
 
Date (dd-mmm-yyyy) 
 
 
Senior Reviewing Biostatistician 
Myra Yao 
Associate Director, Biostatistics 
Date (dd-mmm-yyyy) 
Savara Inc. 
 
 
 
Mette Stockner, MD 
Senior Director Pharmacovigilance and AeroVanc 
Project Lead 
 
 
Date (dd-mmm-yyyy) 
 
 
 
Wayne Schuck
Electronically signed by: Wayne Schuck
Reason: I am the author
Date: Nov 5, 2020 11:57 EST
Nov 5, 2020
Electronically signed by: Myra Yao
Reason: I am the reviewer
Date: Nov 5, 2020 12:04 EST
Nov 5, 2020
Electronically signed by: Mette Stockner
Reason: I am the approver
Date: Nov 5, 2020 18:49 GMT+1
Nov 5, 2020


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
Syneos Health #1006732 
 
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TABLE OF CONTENTS 
Contents 
 
PREFACE .................................................................................................................. 9 
 
GLOSSARY OF ABBREVIATIONS ......................................................................... 10 
 
PURPOSE ............................................................................................................... 12 
 
Responsibilities ................................................................................................................. 12 
 
Timings of Analyses .......................................................................................................... 12 
 
STUDY OBJECTIVES ............................................................................................. 13 
 
Primary Objective .............................................................................................................. 13 
 
Secondary Objective(s) ..................................................................................................... 13 
 
Brief Description ................................................................................................................ 13 
 
Subject Selection ............................................................................................................... 14 
 
Inclusion Criteria ......................................................................................................... 14 
 
Exclusion Criteria ........................................................................................................ 16 
 
Determination of Sample Size .......................................................................................... 18 
 
Treatment Assignment & Blinding ................................................................................... 18 
 
Administration of Study Medication ................................................................................ 19 
 
Study Procedures and Flowchart ..................................................................................... 19 
 
ENDPOINTS ............................................................................................................ 21 
 
Secondary Efficacy Endpoints ......................................................................................... 21 
 
Exploratory Endpoints ...................................................................................................... 21 
 
Pharmacokinetic Endpoints ............................................................................................. 22 
 
Safety Endpoints ................................................................................................................ 22 
 
ANALYSIS POPULATIONS .................................................................................... 23 
 
All Enrolled Population ..................................................................................................... 23 
 
Safety Population ............................................................................................................... 23 


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
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Intent-to-Treat Population ................................................................................................. 23 
 
Per Protocol Population .................................................................................................... 23 
 
Pharmacokinetic Population ............................................................................................ 24 
 
Protocol Deviations ........................................................................................................... 24 
 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ........................................... 25 
 
General Methods ................................................................................................................ 25 
 
Key Definitions ................................................................................................................... 25 
 
Missing Data ....................................................................................................................... 27 
 
Primary Endpoint Data ................................................................................................ 27 
 
Other Efficacy Data ..................................................................................................... 28 
 
Safety Data .................................................................................................................. 28 
 
Visit Windows ..................................................................................................................... 29 
 
Pooling of Centres ............................................................................................................. 29 
 
Subgroups .......................................................................................................................... 30 
 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION .. 31 
 
Subject Disposition and Withdrawals .............................................................................. 31 
 
Demographic and Other Baseline Characteristics ......................................................... 32 
 
Medical History and Concomitant Diseases ................................................................... 32 
 
Medication .......................................................................................................................... 32 
 
Prior Medication .......................................................................................................... 33 
 
Concomitant Medication .............................................................................................. 33 
 
EFFICACY ............................................................................................................... 34 
 
Primary Efficacy Endpoint and Analysis ......................................................................... 34 
 
Primary Analysis of the Primary Efficacy Endpoint ..................................................... 34 
 
Sensitivity Analysis of the Primary Efficacy Endpoint ................................................. 36 
 
Multiplicity / Control of Type I error rate ...................................................................... 37 
 
Secondary Efficacy Endpoint(s) and Analyses .............................................................. 38 
 
Frequency of Pulmonary Exacerbations ..................................................................... 38 
 
Time to First Pulmonary Exacerbation ........................................................................ 39 
 
Change from Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Scores 
at Weeks 4, 12, and 20 ................................................................................................................. 39 
 
Chronic Respiratory Symptom Score (CFRSD-CRISS) scores at Weeks 4, 12, and 20
 
43 
 
Relative Change from Baseline in FEV1 Percent Predicted at Weeks 4, 12, and 20 . 46 
 
Number of Successful Response Cycles a Subject Achieves over Period 1 ............. 47 


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
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Area under the FEV1–time Profile ............................................................................... 48 
 
Exploratory Efficacy Endpoint and Analyses ................................................................. 48 
 
Changes from Baseline in EQ-5D-5L/EQ-5Dy Scores................................................ 48 
 
Change from Baseline in Body Weight ....................................................................... 49 
 
Minimum Inhibitory Concentration (MIC) for Vancomycin .......................................... 49 
 
MRSA Sputum Density ............................................................................................... 49 
 
Emergence of Additional Pathogens ........................................................................... 49 
 
Other Efficacy Analyses .................................................................................................... 50 
 
Pulmonary Function Tests (PFT) ................................................................................ 50 
 
Severity and Duration of Exacerbations ...................................................................... 50 
 
Time to First Use of Other Antibiotics due to Respiratory Symptoms......................... 50 
 
Subgroup Analysis ............................................................................................................ 50 
 
ANALYSIS OF PHARMACOKINETICS ................................................................... 51 
 
PK sampling schedule....................................................................................................... 51 
 
Plasma PK endpoint .......................................................................................................... 51 
 
Sputum PK endpoint ......................................................................................................... 51 
 
Presentation of concentration data ................................................................................. 51 
 
Handling of Missing Data ............................................................................................ 51 
 
Listing and Presentation of Individual PK data ........................................................... 51 
 SAFETY ................................................................................................................... 52 
 
Extent of Exposure ............................................................................................................ 52 
 
Treatment Compliance ...................................................................................................... 52 
 
Adverse Events .................................................................................................................. 52 
 
Laboratory Evaluations ..................................................................................................... 54 
 
Vital Signs ........................................................................................................................... 55 
 
ECG ..................................................................................................................................... 55 
 
Physical Examination ........................................................................................................ 55 
 INTERIM ANALYSES .............................................................................................. 56 
 CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ........................................ 57 
 REFERENCE LIST .................................................................................................. 58 
 PROGRAMMING CONSIDERATIONS .................................................................... 59 


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
Syneos Health #1006732 
 
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General Considerations .................................................................................................... 59 
 
Table, Listing, and Figure Format .................................................................................... 59 
 
General ........................................................................................................................ 59 
 
Headers ....................................................................................................................... 60 
 
Display Titles ............................................................................................................... 60 
 
Column Headers ......................................................................................................... 60 
 
Body of the Data Display ............................................................................................. 61 
 
Footnotes .................................................................................................................... 63 
 QUALITY CONTROL ............................................................................................... 64 
 INDEX OF TABLES ................................................................................................. 65 
 INDEX OF FIGURES ............................................................................................... 90 
 INDEX OF LISTINGS ............................................................................................... 92 
 APPENDICES .......................................................................................................... 94 
Appendix A: Cystic Fibrosis Questionnaire-Revised (CFQ-R) Scoring Algorithm   and SAS® 
Code 
95 
Appendix B: Updated Primary and Secondary Efficacy Analysis to Account    for missing 
data due to the COVID-19 Pandemic ........................................................................................... 102 
B.1 
Primary Efficacy Endpoint and Analysis ....................................................................... 102 
B.1.1 
Primary Analysis of the Primary Efficacy Endpoint ....................................................... 102 
B.1.1.1 
Sensitivity Analysis of the Primary Efficacy Endpoint ............................................... 103 
B.2 
Secondary Efficacy Endpoint(s) and Analyses ............................................................ 104 
B.2.1 
Frequency of pulmonary exacerbations ........................................................................ 104 
B.2.2 
Time to first pulmonary exacerbation ............................................................................ 104 
B.2.3 
Number of successful response cycles a subject achieves over Period 1 .................... 104 
B.2.4 
Relative change from Baseline in FEV1 percent predicted at Weeks 4, 12, and 20..... 104 
B.2.5 
Change from Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) scores at 
Weeks 4, 12, and 20 ................................................................................................................... 105 
B.2.6 
Chronic Respiratory Symptom Score (CFRSD-CRISS) scores at Weeks 4, 12, and 20
 
105 
B.2.7 
Area under the FEV1–time profile ................................................................................. 105 
B.2.8 
Exploratory and Other Efficacy Analyses ...................................................................... 106 
B.3 
Primary and Secondary efficacy Tables ........................................................................ 106 
 


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
Syneos Health #1006732 
 
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PREFACE 
In amendment 1, the analyses described here are those planned before the occurrence 
of the COVID-19 pandemic in early 2020.  Consequent to COVID-19, recruitment to the 
trial has been stopped prematurely and some changes to rules for handling missed visits 
(and resulting missing data) have been introduced. Where appropriate, the new rules 
for handling missing data will be applied to the primary and secondary efficacy analyses 
that may differ from the protocol.  For clarity, all changes resulting from COVID-19 
issues are described in Appendix B of this document.  For avoidance of doubt, the 
primary analyses will be based on the new rules for handling missing data (as described 
in Appendix B), and not necessarily as described in the original SAP text (as below) or in 
the protocol. 
In amendment 2, any Pulmonary Function Test that scored for reliability and 
repeatability with a grade of F shall not be used in analyses. In the Per Protocol 
analyses, results with grades of C or D will also be excluded. This was not specified in 
the protocol. 


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
Syneos Health #1006732 
 
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  Syneos Health 
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GLOSSARY OF ABBREVIATIONS 
 
Abbreviation 
Description 
ALT 
Alanine Transaminase 
AST 
Aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical 
BID 
Bis in die/twice daily  
BMI 
Body Mass Index 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFRSD-CRISS  
Cystic Fibrosis Respiratory Symptom Diary-Chronic Respiratory 
Symptom Score  
COVID-19 
Coronavirus disease 2019 
CV 
Coefficient of Variation 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FEV1 
Forced expiratory volume in 1 second  
ICH 
International Conference on Harmonization 
ITT 
Intent-to-treat 
i.v. 
Intravenous 
IWRS 
Interactive Web Response System 


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Abbreviation 
Description 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum Inhibitory Concentration 
MIC50 
The MIC that inhibits 50% of the tested isolates 
MIC90 
The MIC that inhibits 90% of the tested isolates 
MMRM 
Mixed Model for Repeated Measures 
MRSA 
Methicillin-resistant Staphylococcus aureus  
N/A 
Not Applicable 
PFT 
Pulmonary function test  
PK 
Pharmacokinetic 
PP 
Per Protocol Population 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TLF 
Table, Listing and Figure 
ULN 
Upper Limit Normal 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
 


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PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables, and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives.   
 
RESPONSIBILITIES 
Syneos Health will perform the statistical analyses and is responsible for the production 
and quality control of all tables, figures, and listings on behalf of Savara Inc., the study 
sponsor. 
 
TIMINGS OF ANALYSES 
An independent Data Monitoring Committee (DMC) will review periodic descriptive 
summaries of safety, subject disposition, and limited efficacy data during the course of 
the study.  Further description of the DSMB timing and analyses can be found in the DMC 
Statistical Analysis Plan Version 1.0 dated 25-Oct-2017 and the -DSMB charter Version 
2.0 dated 24-Nov-2017. An unblinded team from Syneos Health biostatistics will perform 
the analyses for the DSMB to maintain the blinding of the study. 
When 100% of subjects have completed Period 1 of the protocol or terminated early, 
the study will be unblinded as per Section 3.6. The primary analysis of safety and 
efficacy will be completed at that time. 
Additional analyses of safety and efficacy will also be conducted after all subjects 
complete the final study visit in Period 2 (open-label), or terminate early from the 
study. 


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STUDY OBJECTIVES 
 
PRIMARY OBJECTIVE 
The primary objective of the study is to evaluate the efficacy of AeroVanc in improving 
lung function of CF patients ≤ 21 years of age with persistent MRSA lung infection.  
 
SECONDARY OBJECTIVE(S) 
The secondary objectives of the study are: 
• 
To evaluate the time to first pulmonary exacerbation requiring use of another 
antibiotic medication (oral, intravenous, and/or inhaled) and the frequency of 
pulmonary exacerbations. 
• 
To evaluate the efficacy of AeroVanc in the reduction of respiratory symptoms 
and improvement in quality of life. 
• 
To evaluate the safety and tolerability of AeroVanc during 3 treatment cycles (24 
weeks). 
 
BRIEF DESCRIPTION 
SAV005-04 is a Phase III, randomized, multicenter, double-blind, placebo-controlled, 
parallel-group study to examine the safety and efficacy of AeroVanc in the treatment of 
persistent MRSA lung infection in subjects diagnosed with cystic fibrosis. 
After the Screening period (up to 42 days) to confirm study eligibility, subjects will be 
randomly assigned in a blinded fashion to receive either AeroVanc 30 mg twice daily 
(BID), or placebo BID (1:1 active to placebo) by inhalation for 24 weeks or 3 dosing 
cycles (Period 1). Upon completion of Period 1, subjects will receive open-label 
AeroVanc 30 mg BID for an additional 24 weeks or 3 dosing cycles (Period 2), to evaluate 
long-term safety of AeroVanc. 
A dosing cycle is defined as 28 days of treatment followed by 28 days of observation. 
Subjects meeting the inclusion / exclusion criteria will be stratified upon randomization 
on the basis of (a) age (6–21; > 21), (b) Baseline FEV1 (≥60%; <60%), (c) prior 
exacerbations treated with antibiotics during the previous 12 months (1-2; ≥ 3) and (d) 
P. aeruginosa treatment (not treated; treated). 
Subjects on a 28-day cyclical on/off anti-Pseudomonal antibiotic regimen will enter the 
Screening period at a time such that the Baseline visit coincides with the end of their 
anti-Pseudomonas antibiotic cycle. Study drug will thereby be administered during the 
off-cycle, and subjects can then resume anti-Pseudomonal therapy during the 28-day 


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observation period (Week 5 through Week 8). Subjects continuing alternating anti-
Pseudomonal therapy can continue their treatment during the study drug 
administration, and observation periods. The primary efficacy and safety parameters 
will be measured during the 3-cycle, double-blind treatment portion of the study 
(Period 1). Upon completion of the double-blind portion, subjects will have the option 
to continue into an open-label portion in which subjects will receive AeroVanc 30 mg 
BID for 3, 28-day dosing cycles (Period 2). 
 
Note: Period 2 dosing ends at Week 44 not Week 48 as indicated in the figure above. There is a 4 week 
follow-up until Week 48, 
200 subjects (150 subjects ≤ 21 years old, 50 subjects > 21 years old) 
 
SUBJECT SELECTION 
 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate 
in the study:  
1. Subjects ≥ 6 years of age at time of Informed Consent Form (ICF) or Assent Form 
signing.  
2. Confirmed diagnosis of CF, determined by having clinical features consistent 
with the CF phenotype, plus 1 of the following: 
a. Positive sweat chloride test (value ≥ 60 mEq/L),  
b. Genotype with 2 mutations consistent with CF (ie, a mutation in each of 
the cystic fibrosis transmembrane conductance regulator [CFTR] genes).  
3. Positive sputum culture or a throat swab culture for MRSA at Screening.  


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4. In addition to the Screening sample, have at least 2 prior sputum or throat swab 
cultures positive for MRSA, of which at least 1 sample is more than 6 months 
prior to Screening. At least 50% of all MRSA cultures (sputum or throat swab 
culture) collected from the time of the first positive culture (in the previous 1 
year) must have tested positive for MRSA. (Note: Screening sample may count 
towards 50% positive count)   
5. Forced expiratory volume in 1 second (FEV1) ≥ 30% and ≤ 90% of predicted that is 
normal for age, gender, race, and height, using the Global Lung Function 
Initiative (GLI) equation.  
6. At least 1 episode of acute pulmonary infection treated with non-maintenance 
antibiotics within 12 months prior to the Baseline visit. (Initiation of treatment 
with intermittent inhaled anti-Pseudomonal therapy will not qualify as 
treatment with non-maintenance antibiotics).  
7. If female of childbearing potential, an acceptable method of contraception must 
be used during the study and must be combined with a negative pregnancy test 
obtained during Screening; sexually active male subjects of reproductive 
potential who are non-sterile (i.e., male who has not been sterilized by 
vasectomy for at least 6 months, and were not diagnosed with infertility through 
demonstration of azoospermia in a semen sample and/or absence of vas deferens 
through ultrasound) must be willing to use a barrier method of contraception, or 
their female partner must use an acceptable method of contraception, during 
the study. 
  
For purposes of this study, the Sponsor defines “acceptable methods of 
contraception” as:  
a. Oral birth control pills administered for at least 1 monthly cycle prior to 
administration of the study drug  
b. A synthetic progestin implanted rod (eg, Implanon®) for at least 1 
monthly cycle prior to the study drug administration but not beyond the 
4th successive year following insertion  
c. Intrauterine devices (IUDs), inserted by a qualified clinician for at least 1 
monthly cycle prior to study drug administration  
d. Medroxyprogesterone acetate (eg, Depo-Provera®) administered for a 
minimum of 1 monthly cycle prior to administration of the study drug and 
continuing through 1 month following study completion.  
e. Hysterectomy or surgical sterilization  


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f. Abstinence  
g. Double barrier method (diaphragm with spermicidal gel or condoms with 
contraceptive foam)  
NOTE: For subjects prescribed Orkambi: Orkambi may substantially decrease 
hormonal contraceptive exposure, reducing the effectiveness and increasing the 
incidence of menstruation-associated adverse reactions. Hormonal contraceptives, 
including oral, injectable, transdermal, and implantable, should not be relied upon 
as an effective method of contraception when co-administered with Orkambi.  
8. Able and willing to comply with the protocol, including availability for all 
scheduled study visits and be able to perform all techniques necessary to use the 
AeroVanc inhaler and measure lung function.  
9. Agree not to smoke during any part of the clinical trial (Screening visit through 
end of study).  
10. Subjects with a P. aeruginosa co-infection must either be stable on a regular 
suppression regimen of inhaled antibiotics or must be, in the opinion of the 
Investigator, stable despite the lack of such treatment.  
 
Exclusion Criteria 
In addition to those unable to meet the Inclusion Criteria, subjects who meet any of the 
following criteria will be excluded from participating in the study:  
1. Use of anti-MRSA treatments prescribed as maintenance therapy (IV or inhaled 
treatment within 28 days; oral treatment within 14 days) prior to the Baseline 
visit.  
2. Use of non-maintenance antibiotic for pulmonary infection or extrapulmonary 
MRSA infection (IV or inhaled antibiotic within 28 days; oral antibiotic within 14 
days) prior to the Baseline visit.  
3. History of previous allergies or sensitivity to vancomycin, or other component(s) 
of the study drug or placebo except for a history of red-man syndrome.  
4. Inability to tolerate inhaled products.  
5. First time sputum culture or throat swab culture yielding B. cepacia, or 
nontuberculous Mycobacteria in the previous 6 months to Screening.  


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6. History of lung or other solid organ transplantation or currently on the list to 
receive lung or other solid organ transplantation.  
7. Resistance to vancomycin at Screening (vancomycin resistant Staphylococcus 
aureus [VRSA], or vancomycin intermediate resistant Staphylococcus aureus 
[VISA], with minimum inhibitory concentration [MIC] ≥ 8 µg/mL). 
8. Oral corticosteroids in doses exceeding 10 mg prednisone per day or 20 mg 
prednisone every other day, or equipotent doses of other corticosteroids.  
9. Changes in antimicrobial, bronchodilator, anti-inflammatory, or corticosteroid 
medications within 14 days, or changes in CFTR modulators within 28 days, prior 
to the Baseline visit.  
10. Abnormal laboratory findings or other findings or medical history at Screening 
that, in the Investigator's opinion, would compromise the safety of the subject or 
the quality of the study data.  
11. Inability to tolerate inhalation of a short acting beta2 agonist.  
12. SpO2 <90% at Screening.  
13. Changes in physiotherapy technique or physiotherapy scheduled within 1 week of 
the Baseline visit.  
14. Administration of any investigational drug or device within 4 weeks prior to the 
Screening visit and during the course of the study  
15. Female with positive pregnancy test result during Screening, pregnant (or intends 
to become pregnant), lactating or intends to breastfeed during the course of the 
study.  
16. Renal insufficiency, defined as creatinine clearance < 50 mL/min using the 
Cockcroft-Gault equation for adults or Schwartz equation for children at the 
Screening visit.  
17. Abnormal liver function, defined as ≥ 4x upper limit of normal (ULN), of serum 
aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT), or 
known cirrhosis at Screening.  
18. Diagnosed with clinically significant hearing loss.  
19. History of positive result for human immunodeficiency virus (HIV), hepatitis B 
virus (HBV) or hepatitis C virus (HCV).  


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20. Planned hospitalizations for prophylaxis antibiotic treatment within 28 days prior 
to Baseline visit or during the open-label period (Period 1).  
 
DETERMINATION OF SAMPLE SIZE 
A total of 200 subjects will be enrolled into the study (150 subjects ≤ 21 years old, 50 
subjects > 21 years old). The primary analysis population will be the subjects ≤ 21 years 
of age. In the single cycle Phase II study, with missing data imputed using conservative 
rules adopted by the FDA, a difference in the mean absolute change in FEV1 percent 
predicted of 4.3% and a root mean square deviation of 6.3% were observed between the 
treatment arms in subjects < 21 years of age. Based on these numbers, a sample size of 
45 subjects per arm would provide 89% power to detect a statistically significant 
difference at alpha level of 0.05. To account for potential drop outs and/or smaller 
effect size in a three-cycle study, a sample size of 75 per arm will be enrolled in the 
primary analysis population, which if all completed would provide 90% power to detect 
a difference of 3.4% at 20 weeks assuming the same standard deviation of 6.3%. 
In addition, approximately 25 patients per arm in the over 21-year age group will be 
included. 
 
TREATMENT ASSIGNMENT & BLINDING 
After the Screening period (up to 42 days) to confirm study eligibility, subjects will be 
randomly assigned, using Interactive Web Response System (IWRS), in a blinded fashion 
to receive either AeroVanc 30 mg twice daily (BID), or placebo BID (1:1 active to 
placebo) by inhalation for 24 weeks or 3 dosing cycles (Period 1). Upon completion of 
Period 1, subjects will receive open-label AeroVanc 30 mg BID for an additional 24 
weeks or 3 dosing cycles (Period 2), to evaluate long-term safety of AeroVanc. 
A dosing cycle is defined as 28 days of treatment followed by 28 days of observation. 
Subjects meeting the inclusion/exclusion criteria will be stratified upon randomization 
on the basis of (a) age (6–21; > 21), (b) Baseline FEV1 percent predicted (≥60%; <60%), (c) 
prior exacerbations treated with antibiotics during the previous 12 months (1-2; ≥ 3) 
and (d) P. aeruginosa treatment (not treated; treated). 
During the course of the study, all personnel will remain blinded except for DSMB 
members, Syneos Health unblinded DSMB statistician, Syneos Health unblinded DSMB 
programmer, and Syneos Health unblinded Senior Statistical Reviewer. 


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The unblinding of the treatment code will occur and the data will be analyzed after all 
the following have been completed: 
 
• 
The last subject’s Week 20 visit has been completed or study discontinuation 
• 
The study database for the Period 1 Double-blind Treatment Period has been 
locked for the first reporting phase 
• 
The final SAP has been signed off and the subjects in the analysis populations have 
been identified  
 
 
ADMINISTRATION OF STUDY MEDICATION 
AeroVanc, 30 mg or matching placebo (2 capsules) BID will be administered using the 
reloadable, capsule inhaler. Subjects will be instructed to take a short-acting 
bronchodilator agent pre-treatment (2 puffs of the short acting bronchodilator 
albuterol, or equivalent) no less than 10 minutes and up to 45 minutes prior to study 
drug administration. A short-acting bronchodilator, such as albuterol may also be used 
as rescue medication in the event of bronchoconstriction caused by the study drug. 
 
STUDY PROCEDURES AND FLOWCHART 
This study will consist of up to 6 cycles over a total of 48 weeks. A dosing cycle is 
defined as 28 days of treatment followed by 28 days of observation.  
During Period 1, visits occur at the beginning and end of each cycle with an additional 
visit at Week 2. During Period 2, visits are scheduled at the beginning of each cycle, 
after Cycle 6 and a follow-up visit at Week 48. 
A Schedule of Events representing the required testing procedures to be performed for 
the duration of the study is presented in Table 1 Schedule of Events 


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Table 1 Schedule of Events 
 
 


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ENDPOINTS 
The primary efficacy endpoint is the mean absolute change from baseline in FEV1 
percent predicted based on the ITT population of all randomized subjects ≤ 21 years of 
age. The endpoint will be analyzed sequentially at Week 4 (end of Cycle 1), Week 12 
(end of Cycle 2), and at Week 20 (end of Cycle 3). 
If AeroVanc is superior to placebo after Cycle 1, then the mean change in the FEV1 
percent predicted after Cycle 2 will be analyzed and if AeroVanc is superior to placebo 
after Cycle 2, then the mean change in the FEV1 percent predicted after Cycle 3 will be 
analyzed. 
 
SECONDARY EFFICACY ENDPOINTS 
The following parameters will be analyzed as secondary efficacy endpoints based on the 
ITT population of all randomized subjects ≤ 21 years of age: 
• 
Time to first pulmonary exacerbation requiring use of another antibiotic 
medication (oral, IV, and/or inhaled).  
• 
Change from Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) scores 
at Weeks 4, 12, and 20. 
• 
Change from Baseline in the Cystic Fibrosis Respiratory Symptom Diary-Chronic 
Respiratory Symptom Score (CFRSD-CRISS) scores at Weeks 4, 12, and 20. 
• 
Relative change from Baseline in FEV1 percent predicted at Weeks 4, 12, and 20. 
• 
The number of successful response cycles a subject achieves over Period 1 
(Weeks 4, 12, and 20).  
• 
Frequency of pulmonary exacerbations. 
• 
Area under the FEV1 – time profile, i.e. the mean treatment difference in FEV1 
across all post-baseline visits. 
 
EXPLORATORY ENDPOINTS  
The following parameters will be analyzed as exploratory efficacy endpoints based on 
the ITT population of all randomized subjects ≤ 21 years of age: 
• 
Changes from Baseline in EQ-5D-5L/EQ-5Dy scores at Weeks 4, 12, and 20. 


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• 
Change from Baseline in MRSA sputum density at Weeks 4, 12, and 20. 
• 
Change from Baseline in body weight at Weeks 8, 16 and 24. 
• 
Change from Baseline in MIC for Vancomycin at Weeks 4, 12 and 20. 
• 
Emergence of additional pathogens in sputum. 
 
PHARMACOKINETIC ENDPOINTS 
Pharmacokinetics will be studied as a sub-study of approximately 100 subjects, with 
trough plasma and sputum samples collected as per the Schedule of Events. 
 
SAFETY ENDPOINTS  
To evaluate safety and tolerability, safety assessments will be conducted on the safety 
population including analysis of all adverse events (AEs), as well as standard 
hematology, biochemistry, and urine analyses, vital signs, physical examination, 
spirometry, pulmonary function tests (PFT) and electrocardiogram (ECG).  
 
 
 


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ANALYSIS POPULATIONS 
 
ALL ENROLLED POPULATION 
The All Enrolled Population will include all subjects who signed informed consent and 
were screened. Unless specified otherwise, this population will be used for subject 
listings and for summaries of subject disposition. 
 
SAFETY POPULATION  
The Safety Population will include all subjects who were administered at least one dose 
of study medication. Subjects will be analyzed according to treatment received.  The 
Safety Population will be used for all analyses of safety endpoints and for the 
presentation of subjects in all subject listings except where noted. The Safety 
population may also be split out by age (≤ 21 years, > 21 years). 
 
INTENT-TO-TREAT POPULATION  
The Intent-to-Treat (ITT) Population will include all randomized subjects. Subjects will 
be analyzed according to randomized treatment.  The ITT population will also be split 
out by age (≤ 21 years, > 21 years). The ITT Population of subjects ≤ 21 years will be 
used for all main analyses of efficacy endpoints. 
 
PER PROTOCOL POPULATION 
The Per Protocol Population (PP) will include all ITT subjects who adhere to all key 
protocol procedures. As with the ITT population, the PP population will also be split out 
by age (≤ 21 years, >21 years). Subjects will be analyzed according to randomized 
treatment.  Criteria for exclusion from the PP include the following: 
• 
Study drug compliance of less than 80% during Period 1.  
• 
Any other criteria deemed to affect the primary efficacy analysis in some 
meaningful way. Criteria and subjects will be identified during a review of 
protocol violations during a population selection meeting to be held prior to 
database lock and unblinding but after all subjects have terminated the study. 
Inclusion in the PP, along with all other populations, will be determined prior to 
database lock.  
 


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PHARMACOKINETIC POPULATION   
The Pharmacokinetic (PK) Population will include all subjects who received at least one 
dose of the study drug and have at least one PK concentration measured. 
PK concentrations are listed for all subjects in PK population.  
 
 
PROTOCOL DEVIATIONS 
Protocol Deviations will be collected and classified on the eCRF. Subjects with protocol 
deviations listed in Section 5.4 will be excluded from the PP population. All other 
protocol deviations will be reviewed to identify other subjects to be excluded from the 
PP population. If necessary, a Blind Data Review Meeting will be held to review the 
protocol deviation to identify subjects to be included or excluded from the PP 
population. 
Protocol Deviations related to telemedicine or missed visits due to COVID-19 epidemic 
will be used to identify missing data as COVID-19 missing. COVID-19 missing data will be 
imputed differently than originally planned. Analysis of efficacy data using missing data 
due to COVID-19 is detailed in Appendix B.  


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GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
 
GENERAL METHODS 
This section describes analysis issues that relate to all or some of the analysis sections 
that follow.  It describes general guidelines for analysis as well as the following items:  
• 
SAS version 9.3 or later will be used. 
• 
Unless otherwise specified, summaries will be presented for each treatment. For 
Period 2, summaries will be presented based on the treatment group to which 
patients were randomized in Period 1. 
• 
All statistical testing will be two-sided and will be performed at the 0.05 
significance level. 
• 
Continuous variables will be summarized with means, standard deviations, 
medians, minimums, and maximums. For primary and secondary endpoints, the 
25th and 75th percentile will be include for the non-supporting analyses 
summaries. Categorical variables will be summarized by counts and by 
percentage of subjects in corresponding categories. 
• 
All relevant subject data will be included in listings. All subjects entered into 
the database will be included in subject data listings. 
• 
The nominal visit data will be used for analysis.  
• 
Visits will be assigned to Period 1 when the visit date or assessment date is on or 
after the date of first dose of study medication and on or prior to the date of 
completion/early discontinuation of Period 1 as identified on the eCRF. Visits 
will be assigned to Period 2 when the visit date or assessment date is on or after 
the date of first dose of study medication after the end date of Period 1 and on 
or prior to the date of completion/early discontinuation of Period 2 as identified 
on the eCRF. 
 
KEY DEFINITIONS 
Study Day 1 and First dose date for Period 1: Date of randomization and first dose of 
study medication respectively. 
Last dose date for Period 1: Date as indicated for “Date of Period 1 last double-blind 
study drug dose” on the eCRF page Period 1: End of Treatment. 


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First dose date for Period 2: Date of first dose of study medication after completion 
date of Period 1. 
Last dose date for Period 2: Date as indicated on the eCRF page Period 2: End of Study. 
In case of no date available then use last study medication dispense date for the 
purpose of the end of Period 2 data analysis. 
The onset of a pulmonary exacerbation is defined as the date after randomization 
where both an antibiotic concomitant medication and pulmonary exacerbation adverse 
event occur concurrently in the subject at one point in time. An antibiotic concomitant 
medication is defined as any concomitant medication from classes 9 (ANTIBACTERIALS 
FOR SYSTEMIC USE) or 20 (ANTIMYCOBACTERIALS) as found in the variable CMDECOD, 
prescribed for a pulmonary infection indication, and indexed to the pulmonary 
exacerbation adverse event with a route of administration equal to "ORAL", "G TUBE",  
"GASTROSTOMY TUBE", "THROUGH G TUBE" , "INTRA VENOUS", or "RESPIRATORY 
(INHALATION)"). The use of study drug is not included in the definition of antibiotic 
concomitant medication. A pulmonary exacerbation adverse event is defined as an 
affirmative response to the corresponding eCRF question (“Is this a pulmonary 
exacerbation?” = “Yes”). 
The end of a pulmonary exacerbation is defined as the last date of concurrent 
pulmonary exacerbation adverse event and antibiotic concomitant medication, 
regardless of the number of different consecutive antibiotic treatments required.  
Intervals of < 14 days between periods of concurrent antibiotic concomitant medication 
and pulmonary exacerbation adverse event, will be considered a relapse of the same 
event. Intervals of >= 14 days between periods of concurrent antibiotic concomitant 
medication and pulmonary exacerbation adverse event will be counted as a new event. 
The onset of a first pulmonary exacerbation is defined as the earliest date after 
randomization where both an antibiotic concomitant medication and pulmonary 
exacerbation adverse event occur concurrently in the subject at one point in time. An 
antibiotic concomitant medication is defined as any concomitant medication from 
classes 9 (ANTIBACTERIALS FOR SYSTEMIC USE) or 20 (ANTIMYCOBACTERIALS), prescribed 
for a pulmonary infection indication, and indexed to the pulmonary exacerbation 
adverse event with a route of administration equal to "ORAL", "G TUBE", "GASTROSTOMY 
TUBE", "THROUGH G TUBE" , "INTRA VENOUS", or "RESPIRATORY (INHALATION)"). The use 
of study drug is not included in the definition of antibiotic concomitant medication. A 
pulmonary exacerbation adverse event is defined as an affirmative response to the 
corresponding eCRF question (“Is this a pulmonary exacerbation?” = “Yes”). 


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MISSING DATA 
 
 Primary Endpoint Data 
Sensitivity analyses of the primary endpoint will be conducted where missing data will be 
imputed in different ways.  These will include: 
• 
Worst reasonable case analysis: subjects in the AeroVanc group with a missing 
FEV1 percent predicted will be assigned the visit median for the placebo group 
and subjects in the placebo group with a missing FEV1 percent predicted will 
be assigned the visit median for the AeroVanc group. 
• 
Best reasonable case analysis: subjects in the AeroVanc group with a missing 
FEV1 percent predicted will be assigned the visit median for the AeroVanc 
group and subjects in the placebo group with a missing FEV1 percent predicted 
will be assigned the visit median for the placebo group. 
• 
Tipping point analysis: In the event that statistical significance in favor of 
AeroVanc is determined from the primary analysis, subjects in the AeroVanc 
group with a missing FEV1 percent predicted will be assigned successively more 
extreme values, whilst subjects in the placebo group with a missing FEV1 
percent predicted will be assigned successively less extreme values, to find 
the point at which statistical significance is lost (i.e. the 2-sided P-value 
becomes greater than 0.05). 
Monotone missing data occurs when the result of a variable is missing for a particular 
individual and this implies that all subsequent results are missing for that individual. 
Alternatively, when a result is observed for a particular individual, it is assumed that all 
previous results are also observed for that individual. Non-monotone missing occurs when 
result of a variable is missing for a particular individual but this does not imply that all 
subsequent results are missing for that individual and at least one subsequent result is 
not missing. 
The tipping point analysis will be implemented using the steps delineated below: 
Step 1: Non-monotone missing data in AeroVanc treatment and placebo groups will be 
imputed using the Markov Chain Monte Carlo (MCMC) method within each treatment 
group. 
Step 2: Monotone missing data will be imputed using the regression method on the basis 
of the predicted future pattern for the same treatment group. The regression model will 
use treatment, visit, Baseline FEV1 percent predicted, age, age group (6–21; > 21), 
Baseline FEV1 (≥60%; <60%), prior exacerbations treated with antibiotics during the 
previous 12 months (1-2; ≥ 3), and P. aeruginosa treatment (not treated; treated) as the 
independent variables. Week 4 values will be imputed first, without visit in the model. 
Then Week 8 values will be imputed using all Week 4 values. Finally, Week 12 values will 


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be imputed using all values for Weeks 4 and 8. 
Step 3: The imputed values for the AeroVanc treatment group will be subtracted 
progressively by a delta = k (0%, 10%, 20%, …, 100%) * LSMeans estimate for treatment 
difference in the primary analysis (xtipping point = ximputed – (LSMeans *k)). The imputed values 
for the placebo treatment group will be held fixed (xtipping point = ximputed). 
Step 3 will be repeated iteratively while increasing the penalty (e.g., 10%, 20%, …, 100%) 
for the missing data in the AeroVanc treatment group and keeping all the other imputed 
data unchanged, until the tipping point value (i.e., where p-value > 0.05) is identified. 
Step 4: One hundred (100) imputed datasets will be generated for each MI analysis. Each 
imputed dataset is analyzed separately using the Mixed Model for Repeated Measures 
(MMRM) model specified in Section 8.1.1. The final estimate of treatment difference will 
be the average of the estimates based on the 100 individual imputed datasets. The pooling 
of the individual estimates and inferences based on the combined estimate will be 
handled by SAS procedure MIANALYZE. 
Analyses using each of these imputation methods are described in Section 8.1.2. 
 
Other Efficacy Data 
Several subjects missed collecting their baseline values for CFRSD-CRISS and CFQ-R 
because they lacked the device to collect the questionnaire at that time. For subjects 
without any baseline visit data for either of these questionnaires the baseline will be 
imputed using the median scores of the subjects meeting the same strata criteria as 
identified for randomization. 
All other missing data associated with various scores and scales will be handled as 
prescribed by the respective scoring methodology. These details are described in the 
related sub-section of 8.2 below. 
 
Safety Data 
Complete dates will be imputed from partial dates of medications solely for the purpose 
of defining prior/concomitant status for medications.  Dates will be defined using the 
hierarchy of derivations below. 
Concomitant Medications 
If the start date of a concomitant medication is missing, then the start date will be set 
to the first dose date. If the stop date of a concomitant medication is missing, then the 
medication will be treated as ongoing. Missing or incomplete dates will be defined using 
the hierarchy of derivations below. 


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• 
For missing start day where month and year are present, the start day will be set 
to the 1st of the month, unless the month and year are the same as the first dose 
month and year and the 1st of the month is before the first dose date, in which 
case, the start date will be set to the first dose date. 
• 
For missing start day and month where year is present, the start day and month 
will be set to January 1st, unless the year is the same as the first dose year and 
January 1st is before the first dose date, in which case, the start date will be set 
to the first dose date.  
• 
For missing end day where month and year are present, the end day will be set to 
the last day of the month, unless the month and year are the same as the trial 
termination month and year, in which case, the end date will be set to the trial 
termination date. 
• 
For missing end day and month, where year is present, the end date will be set to 
the trial termination date if the years are the same.  If the trial termination year 
is greater than the end year, the end day and month will be set to December 31st. 
  
 
VISIT WINDOWS 
The Cystic Fibrosis Respiratory Symptom Diary – Chronic Respiratory Infection Symptom 
Score (CFRSD-CRISS) is scheduled to be collected weekly. The visit week window will be 
the expected date ±3 days with the exception of Week 1. For example Week 2 data 
should be collected on Day 15. The visit window for Week 2 will be Day 12 through Day 
18. For Week 1, the window will include Day1 through Day 11. If 2 questionnaires are 
collected in a given window, the visit closest to the expected collection day will be 
used for analysis. If both questionnaires are equidistant from the expected collection 
day, the earlier of the 2 questionnaires will be used in the analyses. 
The Cystic Fibrosis questionnaire - revised (CFQ-R) is scheduled to be collected every 2 
weeks. The visit window will be the expected date -7 days through +6 days with the 
exception of Week 2. For example, Week 4 data should be collected on Day 29. The visit 
window for Week 4 will be Day 22 through Day 35. For Week 2, the window will include 
Day1 through Day 21. If 2 questionnaires are collected in a given window, the visit 
closest to the expected collection day will be used for analysis. If both questionnaires 
are equidistant from the expected collection day, the earlier of the 2 questionnaires 
will be used in the analyses. 
For all other data, nominal visit will be used. 
 
POOLING OF CENTRES 
Not applicable since center effects are not included in any analyses. 


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SUBGROUPS 
The primary efficacy population is the 6-21 years age group. All efficacy analyses, 
excluding sensitivity analyses, will also be repeated using the >21 years age group. All 
efficacy summary tables will be provided separately by age group.  Subjects will be 
assigned to either 6–21 years or > 21 years.  
Efficacy summary tables, for all primary, secondary and exploratory endpoints, will also 
be provided by other stratification factors (Baseline FEV1 (≥60%; <60%), prior 
exacerbations treated with antibiotics during the previous 12 months (1-2; ≥ 3), P. 
aeruginosa treatment (not treated; treated)). With the FDA approval for Trikafta 
(elexacaftor/tezacaftor/ivacaftor and ivacaftor), primary and secondary efficacy 
variables, along with demographics will be summarized for subjects who received 
Trikafta and those subjects who did not receive Trikafta at baseline or during Period 
1.Subjects who receive intravenous (i.v.) vancomycin during Period 1 will also be 
identified. Efficacy analyses, for all primary, secondary and exploratory endpoints will 
also be provided for those who did and did not receive i.v. vancomycin during Period 1. 


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DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition will be presented for all subjects by age group and overall, which 
include the following: 
• 
Number of subjects in the All Enrolled Population 
• 
Number (%) of subjects randomized by Period 1 treatment 
Among the randomized subjects, the following will be summarized by Period 1 
treatment 
• 
Number (%) of subjects in the Safety Population 
• 
Number (%) of subjects in the ITT Population 
• 
Number (%) of subjects in the Per-Protocol Population 
• 
Number (%) of subjects in the PK Population 
• 
Number (%) of subjects who completed Period 1 
• 
Number (%) of subjects who discontinued treatment in Period 1 and their reason 
• 
Number (%) of subjects who entered Period 2 
• 
Number (%) of subjects who completed Period 1 but choose not to enter Period 
and their reason 
• 
Number (%) of subjects who completed Period 2 
• 
Number (%) of subjects who discontinued from the study early in Period 2 and 
their reason 
• 
Number (%) of subjects ongoing in Period 2 (End of Period 1 Analysis only) 
A separate by-subject listing of subject disposition and withdrawal will also be 
provided. Subjects who screen failed will be listed along with the date and reason for 
the screen failure. 


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Protocol deviations will also be summarized and listed. Randomized subjects not 
included in the Per Protocol population and their reason for exclusion will be listed. 
 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographics and other baseline characteristics will be summarized for the Safety 
Population by age group, Trikafta use at baseline or during Period 1, and overall, and 
Period 1 treatment. Summary statistics and by-subject listings will be provided. 
Demographics and baseline characteristics will include age, age group (6-21 years, >21 
years), sex, ethnicity, race, weight height, body mass index (BMI), Pseudomonas 
aeruginosa infection present at Screening, Pseudomonas aeruginosa treatment (treated, 
not treated), number of pulmonary infections in the last year, prior exacerbations 
treated with antibiotics - previous 12 Months (1-2, ≥3), baseline FEV1 and baseline FEV1 
group (≥60%, <60%). 
Age = (informed consent date - date of birth + 1) / 365.25 and truncated to complete years. 
Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs.) * 0.4536 
BMI (kg/m2) = Weight (kg)/[Height(m)2] 
 
MEDICAL HISTORY AND CONCOMITANT DISEASES 
Previous diseases/conditions will be sorted alphabetically by system organ class and 
preferred term. History of MRSA and Cystic Fibrosis will be collected for all subjects. 
A summary table of the number and percentage of subjects by medical history, 
including MRSA and Cystic Fibrosis, system organ class (SOC) and preferred term will be 
produced for the Safety Population. Medical history will be sorted alphabetically by SOC 
and in descending order of subjects per preferred term with each SOC.  
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.0 or higher.  
A separate by-subject listing of medical history will also be provided. 
 
MEDICATION 
All prescription and non-prescription medications taken within 6 months prior to 
Baseline through the follow-up visit will be documented in the eCRF. 


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All prior and concomitant medications will be classified using the Anatomical 
Therapeutic Chemical (ATC) classification and preferred drug name from the World 
Health Organization Drug Dictionary, version MAR 2017, or later. 
A separate by-subject listing of medications will also be provided. 
 
Prior Medication 
Prior medications will be defined as medication on the eCRF as starting prior or ending 
prior to the first dose of study medication. Prior medications will be summarized by ATC 
level 2 and preferred drug name for the Safety Population. 
Prior medications which continue after first dose of study medication may also be 
classified as a concomitant medication. 
 
Concomitant Medication 
Concomitant medications will be defined as medication on the eCRF as starting prior to 
the first dose of study medication and ongoing at the time of first dose of study 
medication or started after first dose of study medication. Concomitant medications 
will be summarized by ATC level 2 and preferred drug name for the Safety Population. 


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EFFICACY 
The efficacy analyses described here are those planned before the occurrence of the 
COVID-19 pandemic in early 2020.  Consequent to the outbreak of COVID-19, 
recruitment to the trial has been stopped prematurely and some changes to rules for 
handling missed visits (and resulting missing data) have been introduced.  Where 
appropriate, the new rules for handling missing data will be applied to the primary and 
secondary analyses.  For clarity, all changes resulting from COVID-19 issues are 
described in Appendix B of this document.  For avoidance of doubt, the primary 
analyses will be based on the new rules for handling missing data (as described in 
Appendix B), and not necessarily as described in the original SAP text (as below) or in 
the protocol. 
For the purposes of transparency, in addition to the revised analysis, the primary and 
affected secondary efficacy analyses described here will be provided, but not the 
associated sensitivity analyses. Changes in the sensitivity analyses will be detailed in 
Appendix B. 
Each set of PFTs are scored for reliability and repeatability. Scores consist of letter 
grades of A, B, C, D, and F. All PFT results with a grade of F will be treated as missing 
for all analyses except for baseline F grade PFT measurements – in this instance, the F 
grade baseline PFT measurements will be replaced by the most recent previous 
acceptable and reproducible screening value (grade not equal to F). 
For the Per-Protocol analyses, only results with a grade of A or B will be used. All other 
grade PFTs will be treated as missing, except for baseline C, D, or F grade PFT 
measurements – in this instance, the C, D, or F grade baseline PFT measurements will 
be replaced by the most recent previous A or B grade screening value.  
 
The main analysis will only be performed using the 6-21 year age group. Strata for the 
primary and secondary analyses will be based on strata identified for randomization. 
Supportive summaries and analyses will be performed on the >21 year age group. 
 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
 
Primary Analysis of the Primary Efficacy Endpoint  
The primary efficacy endpoint is the mean absolute change from baseline in FEV1 
percent predicted. The primary analysis will be based on the ITT population of ≤ 21 
years of age using all observed data with a PFT scoring grade of A, B, C, or D, at Weeks 
4, 12, and 20. 


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All subjects will undergo standardized pulmonary function testing FEV1. Pulmonary 
function testing will be performed according to American Thoracic Society (ATS) 
guidelines (2005). Subjects will be tested using the same spirometry equipment 
provided by the Sponsor. Up to 8 efforts should be performed to obtain 3 acceptable 
and reproducible test results. The best results from the  acceptable and reproducible 
efforts for PFTs will be recorded in the Biomedical Systems (BMS) spirometry system and 
transferred to the clinical database, - and a copy of the spirometry reports will be 
retained with the subject’s source documents. 
For any subjects who have one or more missing FEV1 result(s) (whether that be because 
they withdrew early from the trial, or for any other reason), their missing FEV1 will be 
imputed using the least favorable group visit median change from baseline.  This 
imputation can occur for more than one visit (if necessary); in such cases, the “least 
favorable group” will be determined on a visit-by-visit basis (i.e. the “least favorable” 
group could be different at weeks 4, 12 and 20). 
The absolute change from baseline in FEV1 percent predicted will be analyzed using a 
Mixed Model for Repeated Measures (MMRM) with the absolute change from baseline in 
FEV1 percent predicted for a given visit as the dependent variable. Treatment, visit, 
treatment by visit interaction, Baseline FEV1 percent predicted, age, Baseline FEV1 
(≥60%; <60%), prior exacerbations treated with antibiotics during the previous 12 
months (1-2; ≥ 3), and P. aeruginosa treatment (not treated; treated) will be the 
independent variables.  The Kenward-Roger approximation will be used to adjust the 
denominator degrees of freedom. An unstructured (general) covariance structure will be 
assumed initially to model the within-subject errors. If the model fails to run properly, 
the following corrective actions will be take in order; drop Baseline FEV1 percent 
predicted, then other covariance structure (ie, AR(1), CS) will be tested and used in the 
final model as appropriate. 
The absolute change from baseline in FEV1 percent predicted will be tested sequentially 
at Week 4 (end of Cycle 1), Week 12 (end of Cycle 2), and at Week 20 (end of Cycle 3) 
using the MMRM model stated above. If a statistically significant difference is observed 
in favor of AeroVanc compared to placebo after Cycle 1, then the change from baseline 
in the FEV1 percent predicted -after Cycle 2 will be tested. Similarly, if the effect after 
Cycle 2 is statistically significant, then the analysis of Baseline to end of Cycle 3 will be 
tested. 
As a supportive analysis, three Analysis of Covariance (ANCOVA) models (one at each of 
weeks 4, 12 and 20) with the absolute change from baseline in FEV1 percent predicted 
for a given visit as the dependent variable will be performed. Treatment, Baseline FEV1 
percent predicted, age, Baseline FEV1 (≥60%; <60%), prior exacerbations treated with 
antibiotics during the previous 12 months (1-2; ≥ 3) and P. aeruginosa treatment (not 
treated; treated) will be used as independent variables. If an ANCOVA model fails to run 
properly, the variable Baseline FEV1 percent predicted will be dropped.  The same 


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missing value imputation strategy as for the primary analysis (i.e. imputing least 
favorable group visit mean change from baseline) will be used to allow clearer 
comparisons between analysis strategies. 
All analyses will be performed for Period 1 only.  
Absolute change from baseline in FEV1 percent predicted will be summarized using 
descriptive statistics by other stratification factors (Baseline FEV1 (≥60%; <60%), prior 
exacerbations treated with antibiotics during the previous 12 months (1-2; ≥ 3), P. 
aeruginosa treatment (not treated; treated)). Figures will be provided for mean in FEV1 
percent predicted and mean absolute change from baseline in FEV1 percent predicted 
during Period 1 by other stratification factors. A by-subject listing will be included with 
the listing of pulmonary function tests. 
 
Sensitivity Analysis of the Primary Efficacy Endpoint  
For confirmation of the primary endpoint, sensitivity analyses will be performed where 
missing data will be imputed using worst reasonable case analysis, best reasonable case 
analysis, and tipping point analysis as described in Section 6.3 .  
An additional sensitivity analysis will be performed using the Per-Protocol Population in 
place of the ITT and including only results with a PFT scoring grade of A or B. 
Given the FDA approval of Trikafta, sensitivity analyses will be performed for subjects 
who did not use Trikafta at baseline or during Period 1. 
Sensitivity analyses will be performed to assess the effect of actual stratification as 
based on eCRF data, instead of strata reported at time of randomization. These 
analyses will be repeated for all primary supportive analyses. Since P. aeruginosa 
treatment is not directly collected, if a subject has reported using one of the following 
antibiotics, based on ATC3 coding, and route of administration of Respiratory 
(Inhalation) prior to start of study medication, they will be considered as receiving P. 
aeruginosa treatment. 
• 
Aztreonam 
• 
Aztreonam Lysine 
• 
Colistimethate Sodium 
• 
Colistin 
• 
Gentamicin 


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• 
Tobramycin 
A sensitivity analyses will also be provided for those who did and did not receive i.v. 
vancomycin during Period 1. 
All sensitivity analyses will be performed using the same analysis methodology as the 
primary analysis (Section 8.1.1). 
 
Multiplicity / Control of Type I error rate  
The sequence of statistical testing will be as follows: 
• 
Age group 6–21: 
o Primary endpoint (mean absolute change from Baseline in FEV1 percent 
predicted) at 4 weeks, then 12 weeks, then 20 weeks. 
o Secondary endpoints: 
 
Frequency of pulmonary exacerbations requiring use of another 
antibiotic medication (oral, IV, and/or inhaled. 
 
Time to first pulmonary exacerbation requiring use of another 
antibiotic medication (oral, IV, and/or inhaled).  
 
Change from Baseline in the Cystic Fibrosis Questionnaire-Revised 
(CFQ-R) scores at Weeks 4, 12, and 20. 
 
Change from Baseline in the Cystic Fibrosis Respiratory Symptom 
Diary-Chronic Respiratory Symptom Score (CFRSD-CRISS) scores at 
Weeks 4, 12, and 20. 
 
Relative change from Baseline in FEV1 percent predicted at Weeks 
4, 12, and 20. 
 
The number of successful response cycles a subject achieves over 
Period 1 (Weeks 4, 12, and 20).  
 
Area under the FEV1 – time profile, i.e. the mean treatment 
difference in FEV1 across all post-baseline visits. 
The statistical decision rule for moving to each analysis will be based on the sequence 
listed above and each cycle within each parameter. The testing order with each 
parameter will proceed from Week 4 (Cycle 1) to Week 12 (Cycle 2) then to Week 20 


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(Cycle 3 prior to advancing to the next parameter. Statistical testing will stop when the 
threshold of P < 0.05 is not reached.  Sensitivity analyses will not impact on the decision 
to move forward or stop testing. Subgroup analyses for the stratification factors (other 
than age group) are for descriptive and supportive purposes and will not impact the 
decision to move forward or stop testing. 
Although the above sequence is implemented to control type I error, results of all the 
analyses will be included in the final report. 
In addition to the above, all analyses will be repeated in the group of patients > 21 
years of age and using strata as identified on the eCRF.  Estimates of treatment effects 
and 95% confidence intervals will be produced.  Nominal p-values will also be produced 
but only for descriptive purposes.  No Type I error control will be implemented for the 
patients >21 years of age or the eCRF based strata analyses. 
 
SECONDARY EFFICACY ENDPOINT(S) AND ANALYSES 
 
Frequency of Pulmonary Exacerbations 
The Generalized Linear Model, based on the negative binomial distribution, will use the 
number of pulmonary exacerbations requiring use of another antibiotic medication 
(oral, IV, and/or inhaled) as the dependent variable and will include treatment group 
and the stratification factors (Baseline FEV1 (≥60%; <60%), prior exacerbations treated 
with antibiotics during the previous 12 months (1-2; ≥ 3), P. aeruginosa treatment (not 
treated; treated)) as fixed effects. The analysis will be adjusted for each subject’s 
length of follow-up in Period 1 defined as last dose Period 1- first dose Period 1 + 28 
days. The risk ratio (AeroVanc group: placebo) of treatment effect will be derived from 
the model along with the 95% 2-sided Confidence Interval for the risk ratio. Model 
adjusted mean rates for each treatment group will be derived and their 95% 2-sided 
confidence interval; calculated.   
A descriptive summary will be provided by age group, and other stratification factors 
(Baseline FEV1 (≥60%; <60%), prior exacerbations treated with antibiotics during the 
previous 12 months (1-2; ≥ 3), P. aeruginosa treatment (not treated; treated)). A 
separate by-subject listing will also be provided. 
Secondary analysis will be performed using subjects ≤21 years old. Subjects >21 years 
old, subjects not using Trikafta at baseline or during Period 1 will be analyzed 
separately as supportive analyses. An additional supportive analysis using eCRF-
identified strata in place of strata identified at randomization will also be provided. A 
supportive analyses will also be provided for those who did and did not receive i.v. 
vancomycin during Period 1. 


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Time to First Pulmonary Exacerbation 
The distributions of time to first pulmonary exacerbation will be compared between the 
treatment arms using a Cox proportional hazards regression model including the effects 
of treatment group, age, and the stratification factors for Period 1 except for age 
group. The hazard ratio and the associated 95% confidence interval will be provided 
along with the associated log-rank test p-value.  
The number of days from the date of randomization until the date of the first 
pulmonary exacerbation will be calculated and summarized for Period 1 using a Kaplan-
Meier life table presentation and Kaplan-Meier curves for subjects in each age group 
separately. Subjects who do not experience an exacerbation prior to discontinuation 
from the study will be censored at the date of their study drug discontinuation.  
A descriptive summary will be provided by age group and other stratification factors 
(Baseline FEV1 (≥60%; <60%), prior exacerbations treated with antibiotics during the 
previous 12 months (1-2; ≥ 3), P. aeruginosa treatment (not treated; treated)). A 
separate by-subject listing will also be provided. 
Secondary analysis will be performed using subjects ≤21 years old. Subjects >21 years 
old, subjects not using Trikafta at baseline or during Period 1 will be analyzed 
separately as supportive analyses. An additional supportive analysis using eCRF-
identified strata in place of strata identified at randomization will also be provided. A 
supportive analyses will also be provided for those who did and did not receive i.v. 
vancomycin during Period 1. 
 
Change from Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-
R) Scores at Weeks 4, 12, and 20 
The CFQ-R is a disease-specific health-related quality of life measure for children, 
adolescents, and adults with CF. The CFQ-R measures functioning in a variety of 
domains, including Physical Functioning, Vitality, Health Perceptions, Respiratory 
Symptoms, Treatment Burden, Role Functioning  (teen/adult version only), Emotional 
Functioning, Social Functioning (teen/adult version only), Body, Eat, Weight, Digest, 
and School (parent version only).  A parent version of the CFQ-R will be used for 
subjects ≤ 13 years and the teen/adult version for subjects ≥ 14 years. 
Score each question based on the responses to the question: 
Very True = 1, Mostly True = 2, Somewhat True = 3, Not at all True = 4 
Always = 1, Often = 2, Sometimes = 3, Never = 4 


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When an item is indicted to be reverse-coded the numeric values are reversed from 
what is indicated above (derived as 5 – item score). Missing values are replaced with the 
median value for the responses within a given domain within each treatment group. If 
the median would end in a value of .5, round the imputed value to the next higher 
value. If more than half of the values within a domain are missing then leave the 
domain score as missing.  
In creation of the electronic diary (eDiary) used for the collection of the CFQ-R 
questionnaire, question 27 (“People are afraid I am contagious”) had the question text 
replace with the text from question 26 (“I feel bad about my personal appearance”) for 
some early versions of the eDiary. These values will be flagged in the data by the 
vendor (CRF Health). For calculations, summaries, analyses, and data presentations, 
these values will be treated as missing and the general rules for missing data (impute 
least favorable group mean will not be used in these cases). 
 
 


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Table 2 CFQ-R Scoring 
Domain 
Parent CFQ-R 
Question 
Numbers 
Parent CFQ-R 
Scaled Score 
Teen/Adult 
CFQ-R 
Question 
Numbers 
Teen/Adult CFQ-R 
Scaled Score 
Physical 
Functioning 
 
1 
2 
3 
4 
5 
14 
15* 
16 
if number miss ≤ 4 
then physical = 
(mean (1, 2, 3, 4, 
5, 14, 15*, 16)-
1)/3*100; 
 
1 
2 
3 
4 
5 
13* 
19 
20 
if number miss ≤ 4 
then physical = 
(mean (1, 2, 3, 4, 
5, 13*, 19, 20)-
1)/3*100; 
Vitality 
 
8 
9 
10* 
11 
12* 
if number miss  ≤ 2 
then vitality = 
(mean (8, 9, 10*, 
11, 12)-1)/3*100; 
6* 
9 
10* 
11 
if number miss  
≤ 2 then vitality = 
(mean (6*, 9, 10*, 
11)-1)/3*100; 
Health 
Perceptions 
22* 
24* 
32* 
if number miss  ≤ 1 
then health = 
(mean (22*, 24*, 
32*)-1)/3*100; 
18* 
32* 
34* 
if number miss ≤ 1 
then health = 
(mean (18*, 32*, 
34*)-1)/3*100; 
Respiratory 
Symptoms 
 
34 
35 
36 
38 
39 
40 
if number miss  ≤ 3 
then respirat = 
(mean (34, 35, 36, 
38, 39, 40)-
1)/3*100; 
40 
41 
42 
44 
45 
46 
if number miss  ≤ 
3 then respirat = 
(mean (40, 41, 42, 
44, 45, 46)-
1)/3*100; 
Treatment 
Burden 
18 
30 
31* 
if number miss  ≤ 1 
then treat = (mean 
(18, 30, 31*)-
1)/3*100; 
15* 
16 
17* 
if number miss  ≤ 
1 then treat = 
(mean (15*, 16, 
17*)-1)/3*100; 
Role 
Functioning 
-- 
-- 
35* 
36 
37 
38 
if number miss ≤ 2 
then role = (mean 
(35*,36, 37, 38)-
1)/3*100; 
Emotional 
Functioning  
 
6* 
7 
23 
25 
26 
if number miss ≤ 2 
then emotion = 
(mean (6*, 7, 23, 
25, 26)-1)/3*100; 
7 
8 
12 
31 
33 
if number miss  ≤ 
2 then 
emotion = (mean 
(7, 8, 12, 31, 33)-
1)/3*100; 


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Domain 
Parent CFQ-R 
Question 
Numbers 
Parent CFQ-R 
Scaled Score 
Teen/Adult 
CFQ-R 
Question 
Numbers 
Teen/Adult CFQ-R 
Scaled Score 
Social 
Functioning 
-- 
-- 
22 
23* 
27 
28* 
29 
30* 
if number miss  ≤ 
3 then social = 
(mean (22, 23*, 
27, 28*, 29, 30*)-
1)/3*100; 
Body 
19 
20 
21 
if number miss  ≤ 1 
then body = 
(mean(19, 20, 21)-
1)/3*100; 
24 
25 
26 
if number miss  ≤ 
1 then body = 
(mean (24, 25, 
26)-1)/3*100; 
Eat 
17 
44 
if number miss  ≤0 
then eat = 
(mean(17, 44)-
1)/3*100; 
14 
21 
50 
if number miss  ≤ 
1 then eat = 
(mean (14, 21, 
50)-1)/3*100; 
Weight 
33 
if number miss  ≤ 0 
then weight = 
(mean (33)-
1)/3*100; 
39 
if number miss  = 
0 then weight= 
(mean (39)-
1)/3*100; 
 
Digest 
41 
42 
43 
if number miss  ≤ 1 
then digest = 
(mean (41, 42, 43)-
1)/3*100; 
47 
48 
49 
if number miss ≤ 1 
then digest = 
(mean (47, 48, 
49)-1)/3*100; 
run; 
School  
13 
27 
28* 
29 
if number miss  ≤ 2 
then school = 
(mean (13, 27, 28*, 
29)-1)/3*100; 
-- 
-- 
• 
Items that are reversed coded prior to calculating score. Reverse coding will 
be performed by using 5-response as the value used to generate the scaled 
scores. 
 
CFQ-R is recorded every 14 days in the trial and has a recall period of 14 days.   
The scaled score for each domain of the CFQ-R will be analyzed the same as the primary 
efficacy analysis, including the same rules for missing domain values at each scheduled 


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collection time point (See Section 8.1.1) using the domain baseline value instead of the 
baseline FEV1 result in the model for subjects <13 years old, subjects 14-21 years old, 
and subjects >21 years old. Additionally, the respiratory domain, domain of primary 
interest, will also be analyzed by combining the results of both the CFQ-R (Teen/Adult 
Version) and CFQ-R (Parents Version) for all subjects ≤ 21 years old, subjects not using 
Trikafta at baseline or during Period 1. An additional supportive analysis using eCRF-
identified strata in place of strata identified at randomization will also be provided. A 
supportive analyses will also be provided for those who did and did not receive i.v. 
vancomycin during Period 1. 
Summary tables will also be provided by period and age group, Trikafta use at baseline 
or during Period 1, and by other stratification factors (Baseline FEV1 (≥60%; <60%), prior 
exacerbations treated with antibiotics during the previous 12 months (1-2; ≥ 3), P. 
aeruginosa treatment (not treated; treated)). Summary figures will be provided for 
mean change from baseline in the Respiratory Domain for each period. 
A separate by-subject listing will also be provided. 
 
Chronic Respiratory Symptom Score (CFRSD-CRISS) scores at Weeks 4, 12, 
and 20 
The CFRSD-CRISS is an 8-item patient-reported outcome (PRO) symptom measure that is 
part of the Cystic Fibrosis Respiratory Symptom Diary (CFRSD). The CFRSD-CRISS is 
designed to evaluate the effect of treatment on the severity of symptoms of respiratory 
infection in subjects with Cystic Fibrosis (CF). Assessments in the CFRSD-CRISS comprise 
the 8 symptom items of the CFRSD: difficulty breathing, cough, cough up mucus, chest 
tightness, wheeze, feeling feverish, tired, and chills/sweats. 
The Rasch-derived CFRSD-CRISS is computed by rescoring the eight respiratory symptom 
items of the CFRSD, summing the rescored items, and converting to a 0 to 100 scale. 
The CFRSD-CRISS should not be calculated if more than one item response is missing.  
The rescaling schema and conversion table are provided below. Rescore item responses 
as follows:  
 
 


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 Q1.                                                               Q2. 
 
 
 
 
 
 
Q3.                                                               Q4. 
 
 
 
 
Q5.                                                               Q6. 
 
Response  
Raw 
Score 
Item 
Score 
None  
0 
0 
A little  
1 
1 
Somewhat  
2 
1 
A good deal  
3 
1 
A great deal  
4 
2 
Response  
Raw 
Score 
Item 
Score 
None  
0 
0 
A little  
1 
1 
Somewhat  
2 
1 
A good deal  
3 
2 
A great deal  
4 
3 
Response  
Raw 
Score 
Item 
Score 
None  
0 
0 
A little  
1 
1 
Somewhat  
2 
1 
A good deal  
3 
2 
A great deal  
4 
3 
Response  
Raw 
Score 
Item 
Score 
None  
0 
0 
Slightly 
1 
1 
Moderately 
2 
1 
Very 
3 
2 
Extremely 
4 
3 
Response  
Raw 
Score 
Item 
Score 
None  
0 
0 
Slightly 
1 
1 
Moderately 
2 
2 
Very 
3 
3 
Extremely 
4 
4 
Response  
Raw 
Score 
Item 
Score 
None  
0 
0 
A little  
1 
1 
Somewhat  
2 
2 
A good deal  
3 
3 
A great deal  
4 
4 


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Q7.                                                               Q8. 
 
 
Sum the item scores. Then convert the summed score to the CFRSD_CRISS score as 
indicated below. 
 
 
Response  
Raw 
Score 
Item 
Score 
None  
0 
0 
A little  
1 
1 
Somewhat  
2 
1 
A good deal  
3 
2 
A great deal  
4 
3 
Response  
Raw 
Score 
Item 
Score 
None  
0 
0 
Slightly 
1 
1 
Moderately 
2 
1 
Very 
3 
1 
Extremely 
4 
2 


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Table 3 Conversion of Raw Summed Score to CFRSD-CRISS. 
Raw Summed Score 
CFRSD-CRISS 
 
Raw Summed Score 
CFRSD-CRISS 
0 
0 
 
13 
59 
1 
14 
 
14 
61 
2 
23 
 
15 
63 
3 
29 
 
16 
65 
4 
34 
 
17 
68 
5 
37 
 
18 
70 
6 
41 
 
19 
73 
7 
44 
 
20 
76 
8 
46 
 
21 
80 
9 
49 
 
22 
85 
10 
52 
 
23 
91 
11 
54 
 
24 
100 
12 
56 
 
 
 
 
CFRSD-CRISS is recorded every 7 days at home on the ePRO diary.  It has a recall period 
of 7 days.   
The CFRSD-CRISS will be analyzed using the same methods as the primary efficacy 
analysis, including the same rules for missing CFRSD-CRISS values at each scheduled 
collection time point (See Section 8.1.1) using the CFRSD-CRISS baseline value instead 
of the baseline FEV1 result in the model. Summary tables will also be provided by period 
and age group, and by other stratification factors (Baseline FEV1 (≥60%; <60%), prior 
exacerbations treated with antibiotics during the previous 12 months (1-2; ≥ 3), P. 
aeruginosa treatment (not treated; treated)). A supportive analyses will also be 
provided for those who did and did not receive i.v. vancomycin during Period 1. 
Summary figures will be provided for mean change from baseline for each period. 
An additional supportive analysis using eCRF-identified strata in place of strata 
identified at randomization will also be provided. 
A separate by-subject listing will also be provided. 
 
Relative Change from Baseline in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 
Relative change from Baseline in FEV1 percent predicted is defined as (Visit FEV1 
percent predicted – Baseline FEV1 percent predicted)/Baseline FEV1 percent predicted. 


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Relative change from Baseline in FEV1 percent predicted will be analyzed using the 
same methods as the primary efficacy analysis, including the same rules for missing 
values (See Section 8.1.1). Summary tables will also be provided by age group and other 
stratification factors (Baseline FEV1 (≥60%; <60%), prior exacerbations treated with 
antibiotics during the previous 12 months (1-2; ≥ 3), P. aeruginosa treatment (not 
treated; treated)). 
Secondary analysis will be performed using subjects ≤21 years old. Subjects >21 years 
old, subjects not using Trikafta at baseline or during Period 1 will be analyzed 
separately as supportive analyses. An additional supportive analysis using eCRF-
identified strata in place of strata identified at randomization will also be provided. A 
supportive analyses will also be provided for those who did and did not receive i.v. 
vancomycin during Period 1. 
A separate by-subject listing will also be provided. 
 
Number of Successful Response Cycles a Subject Achieves over Period 1 
A response in a cycle is defined by at least a 5% relative improvement from baseline in 
FEV1 percent predicted at the end of each cycle. If the relative FEV1 improvement is 
less than 5%, the subject is considered a failure in that cycle, but the failure does not 
preclude success in future cycles. If a subject experiences an exacerbation, and 
concomitant antibiotic therapy is given, the subject is considered a failure in that cycle 
but not subsequent cycles. 
The number of successful response cycles each subject achieves over the 3 cycles of 
therapy will be used to create a 2 × 4 contingency table consisting of the 2 treatments 
(AeroVanc and Placebo) and the counts of all Subjects across the 4 levels of response (0, 
1, 2, or 3 successful treatment cycles). Summary tables will be provided by age group 
and other stratification factors (Baseline FEV1 (≥60%; <60%), prior exacerbations treated 
with antibiotics during the previous 12 months (1-2; ≥ 3), P. aeruginosa treatment (not 
treated; treated)). 
The number of successful response cycles in Period 1 will be analyzed using the Wald 
Chi-squared test based on an Ordinal logistic regression with treatment as the 
independent variable and number of cycles as the dependent variable.  
Secondary analysis will be performed using subjects ≤21 years old. Subjects >21 years 
old, subjects not using Trikafta at baseline or during Period 1 will be analyzed 
separately as supportive analyses. An additional supportive analysis using eCRF-
identified strata in place of strata identified at randomization will also be provided. A 
supportive analyses will also be provided for those who did and did not receive i.v. 
vancomycin during Period 1. 


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Area under the FEV1–time Profile 
Area under the FEV1–time profile will be calculated for each subject over the course of 
each period. The area will be the sum of each FEV1 multiplied by the duration of 
representative time period. The beginning of each time period will be either the 
beginning of the period or the midpoint between the time of the FEV1 measurement and 
the previous FEV1 measurement. The end of each time period will be either the end of 
the period or the midpoint between the time of the FEV1 measurement and the 
following FEV1 measurement. Duration will be calculated as (end of time period – start 
of time period) as measured in days. 
Area under the FEV1–time profile will be analyzed using a Generalized Linear Model with 
the Area under the FEV1–time profile for a given period as the dependent variable, and 
using the same rules for missing values as for the primary variable. Treatment, Baseline 
FEV1 percent predicted, age, Baseline FEV1 (≥60%; <60%), prior exacerbations treated 
with antibiotics during the previous 12 months (1-2; ≥ 3), and P. aeruginosa treatment 
(not treated; treated) will be the independent variables. A supportive analyses will also 
be provided for those who did and did not receive i.v. vancomycin during Period 1. If 
the model fails to run properly, age will be dropped, then Baseline FEV1 percent 
predicted will be dropped if necessary.  
 
A separate by-subject listing will also be provided. 
 
EXPLORATORY EFFICACY ENDPOINT AND ANALYSES 
 
Changes from Baseline in EQ-5D-5L/EQ-5Dy Scores  
EQ-5D is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic 
appraisal.1 The EQ-5D-5L include five levels of severity in each of the existing five EQ-
5D dimensions along with a 20 cm visual analog scale (VAS) to collect how good or bad 
the subject’s health is today, with 0 - worst health you can image and 100 – best you 
can image. 
The EQ-5D Youth (EQ-5Dy) is the youth version of the EQ-5D developed specifically for 
children and adolescents aged 8-15 years. 
The EQ-5D-5L/EQ-5Dy will be given at each visit starting at the Baseline visit. Results 
will be summarized as categorical results for the 5 dimensions at each visit. Summaries 
will be by measure and age group (EQ-5Dy age/≤15 years, EQ-5D-5L/age ≤21 years, EQ-
5D-5L/age >21 years). A shift from baseline table will be provided for Weeks 4 and 20. 
Additionally a by subject listing will be provided. 


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The VAS scores and their change from baseline will be summarized at each visit as 
continuous variables by measure and age group. Summary tables will also be provided 
by measure and other stratification factors (Baseline FEV1 (≥60%; <60%), prior 
exacerbations treated with antibiotics during the previous 12 months (1-2; ≥ 3), P. 
aeruginosa treatment (not treated; treated)). 
 
Change from Baseline in Body Weight 
Body weight is collected at the Screening Visit, Baseline Visit, and every visit starting at 
Week 4. Body weight and the change from baseline will be summarized at each visit as a 
continuous variable by age group and other stratification factors (Baseline FEV1 (≥60%; 
<60%), prior exacerbations treated with antibiotics during the previous 12 months (1-2; 
≥ 3), P. aeruginosa treatment (not treated; treated)). 
 
Minimum Inhibitory Concentration (MIC) for Vancomycin  
Sputum samples are collected at the Screening Visit, Baseline Visit, and every visit 
starting at Week 4. Based on these sputum samples, MIC for Vancomycin will be 
determined. These results will be summarized at each visit as a categorical variable 
along with the MIC50 and MIC90 (50th and 90th percentile) values by age group and other 
stratification factors (Baseline FEV1 (≥60%; <60%), prior exacerbations treated with 
antibiotics during the previous 12 months (1-2; ≥ 3), P. aeruginosa treatment (not 
treated; treated)). A summary table of the shift from Baseline to each visit will be 
provided. 
 
MRSA Sputum Density  
Methicillin resistant Staphylococcus aureus (MRSA) sputum density will be determined at 
all visits except Week 2 and Week 36 visits. MRSA sputum density will be summarized 
and listed for a subset of subjects. The MRSA sputum density summary will consist of 
mean, standard deviation, median, 25th percentile, 75th percentile, minimum, and 
maximum by age group. If multiple MRSA isolates are available at any visit then only the 
maximum values will be used for the descriptive statistics. 
 
 Emergence of Additional Pathogens 
Emergence of additional pathogens during and after the study drug administration will 
be monitored in sputum or throat swab microbiology cultures already being collected. 
The presence of the following pathogens will be determined at Baseline, Week 20, and 
Week 44: Pseudomonas aeruginosa, Achromobacter xylosoxidans, Aspergillus fumigatus, 
Burkholderia cepacia complex, and Stenotrophomonas maltophilia.  
Emergence of additional pathogens will be summarized at each scheduled visit by group 
and by other stratification factors (Baseline FEV1 (≥60%; <60%), prior exacerbations 


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treated with antibiotics during the previous 12 months (1-2; ≥ 3), P. aeruginosa 
treatment (not treated; treated)). 
 
 
OTHER EFFICACY ANALYSES 
 
Pulmonary Function Tests (PFT) 
All subjects will undergo standardized pulmonary function testing to determine their 
forced vital capacity (FVC), peak expiratory flow rate (PEFR), forced expiratory flow 
(FEF) between 25% and 75% of FVC (FEF25-75) and FEV1. Pulmonary Function Tests will be 
performed at each visit prior to the subject administering the bronchodilator pre-
treatment and study drug (AeroVanc/placebo). 
For all PFTs, their results and associated change from baseline will be summarized at 
each visit as a continuous variable by age group and by other stratification factors 
(Baseline FEV1 (≥60%; <60%), prior exacerbations treated with antibiotics during the 
previous 12 months (1-2; ≥ 3), P. aeruginosa treatment (not treated; treated)). 
 
Severity and Duration of Exacerbations 
Exacerbations are recorded as adverse events and reported as part of the AE 
summaries.  Additionally, summary statistics will be presented of the distribution of 
severity of exacerbations and duration of exacerbations (duration as determined from 
the AE start and end dates). 
 
Time to First Use of Other Antibiotics due to Respiratory Symptoms 
Time to first use of other antibiotics due to respiratory symptoms in Period 1 will be 
provided as a Kaplan-Meier plot by age group. 
 
SUBGROUP ANALYSIS 
All efficacy measures will be summarized at each visit by age group and other 
stratification factors (Baseline FEV1 (≥60%; <60%), prior exacerbations treated with 
antibiotics during the previous 12 months (1-2; ≥ 3), P. aeruginosa treatment (not 
treated; treated)) using the ITT population. 
With the FDA approval for Trikafta, primary and secondary efficacy measures, along 
with demographics will be summarized for subject who received Trikafta and those 
subjects who did not receive Trikafta at baseline or during Period 1. Similarly, primary 
and secondary efficacy variables will be summarized by use of IV vancomycin during 
each period. 


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ANALYSIS OF PHARMACOKINETICS 
 
PK SAMPLING SCHEDULE  
Pharmacokinetics (PK) will be studied as a sub-study of approximately 100 subjects, 
with trough plasma and sputum samples collected. Plasma vancomycin trough samples 
and sputum PK samples will be collected at the Week 2 visit.  
 
PLASMA PK ENDPOINT 
Vancomycin plasma PK trough levels at Week 2 will be summarized and listed for a 
subset of subject. The PK summary will consist of mean, standard deviation, geometric 
mean, CV, median, minimum, and maximum by age group.  
 
SPUTUM PK ENDPOINT  
Sputum PK trough values will be determined at Week 2 and Week 36 visits. These values 
will be summarized and listed for a subset of subjects. The sputum PK summary will 
consist of mean, standard deviation, geometric mean, CV, median, minimum, and 
maximum by age group.  
 
PRESENTATION OF CONCENTRATION DATA 
 
Handling of Missing Data  
No imputation of missing PK concentrations will be done. 
 
Listing and Presentation of Individual PK data 
All related individual PK data will be listed. 
 


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SAFETY 
The population used for safety analyses will be the Safety Population.  Safety will be 
assessed on the basis of adverse event (AE) reports, clinical laboratory data (ie, 
hematology, serum chemistries, and urinalysis), ECG parameters, physical examinations, 
and vital signs. All safety measures will be summarized, unless otherwise stated. 
 
EXTENT OF EXPOSURE 
Exposure to each cycle is defined as (last dose date of the cycle – first dose date of the 
cycle + 1) / 7, rounded to one decimal place. For each period, the exposure of each 
cycle will be added together to calculate the total exposure for the period. The 
cumulative exposure will be the sum of periods’ exposures for subjects assigned 
AeroVanc 30 mg BID in period 1. For Subjects assigned Placebo in Period 1, then the 
cumulative exposure will equal their exposure in Period 2 only. If the last dose date is 
not available for a cycle, such as for the end of Period 1 analysis, then the last dose 
date will be set to the last known dose date. 
Study treatment exposure will be summarized using the Safety Population for each 
period and overall by Period 1 treatment. Exposure will be calculated for each Period by 
the summation of exposure in each cycle. Exposure will be summarized as a continuous 
variable. Additionally, a categorical summary will be provided with exposure broken 
into 4 week periods (ie, 0 - 4 weeks, >4 weeks – 8 weeks, >8 weeks – 12 weeks). 
 
TREATMENT COMPLIANCE  
Treatment compliance is defined as (actual number of capsules used / expected number 
of capsules used) * 100 for a period or overall and will be presented as a percentage. 
Actual number of capsules used in a cycle is the number of capsules dispensed (128) - 
number of unused capsules returned. Actual number of capsules used in a cycle is added 
together for each period and overall as appropriate. Expected number of capsules per 
cycle is defined as the minimum of (date returned – date dispensed, 28) * 4 capsules. 
Expected number of capsules used in a cycle is added together for each period and 
overall as appropriate. 
Treatment compliance, actual number of capsules used and expected number of 
capsules used will be listed and summarized using the Safety Population for each period 
and overall by Period 1 treatment. 
 
ADVERSE EVENTS  
An adverse event is any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug-related. All adverse events (AEs) will be 


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coded using the MedDRA version 20.0 or higher. The following listings of AEs will be 
provided by subjects:  
• 
All AEs, 
• 
Study drug-related AEs,  
• 
Serious adverse events (SAEs) 
• 
AEs leading to death 
• 
AEs leading to study discontinuation 
Adverse Events will be included in summary tables by Period 1 treatment and overall for 
each period. An overall summary table of AEs will be produced for the following 
categories:  
• 
Any AE 
• 
Severe or Life-threatening AEs 
• 
Study drug-related AEs 
• 
Serious AEs  
• 
Study drug-related Serious AEs 
• 
AEs leading to study discontinuation  
• 
AEs leading to death  
All AEs will be classified by SOC and PT. Frequency count of AEs, the number of unique 
subjects experiencing an AE, and percentage of unique subjects experiencing an AE will 
be tabulated by Period 1 treatment. Subjects who experienced more than one TEAE will 
be counted only once in each category. For percentages, Clopper–Pearson 95% 
confidence intervals will be tabulated by treatment group, system organ class, and 
preferred term. For the number of unique subjects reporting, if a subject reported 
more than one AE that was coded to the same SOC or PT, the subject will be counted 
only once for that specific SOC or PT.  
The following summaries of AEs will also be provided: 
• 
AEs by SOC and PT  


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• 
AEs by SOC, PT and maximum severity 
• 
AEs by SOC, PT and causality relationship 
• 
Severe or Life-threatening AEs by SOC and PT 
• 
Severe or Life-threatening treatment-related AEs by SOC and PT 
• 
Serious AEs by SOC and PT 
• 
Serious treatment-related AEs by SOC and PT 
• 
AEs leading to study discontinuation by SOC and PT 
• 
AEs leading to death by SOC and PT 
• 
AEs by PT 
 
For AEs presented by relationship to study treatment, the strongest relationship to 
study treatment(s) during the clinical trial will be presented for each subject if coded 
to the same SOC or PT. For AEs presented by severity, the worst severity during the 
clinical trial will be presented for each subject if coded to the same SOC or PT. If either 
relationship or severity is missing, then the strongest relationship (related) or worst 
severity (life-threatening) will be assigned. 
 
LABORATORY EVALUATIONS 
Blood samples for hematology and biochemistry are to be collected at screening, 
Baseline, on Weeks 4, 12 and 20 during Period 1, on Weeks 28, 36, and 44 of Period 2, 
and at the Week 48 follow-up visit. Urine for urinalysis is to be collected at screening, 
Baseline, on Weeks 12 and 20 of Period 1, on Weeks 24, 36 and 44 of Period 2, and at 
the Week 48 follow-up visit.  
Descriptive statistics will be provided for each test parameter and for change from 
baseline by Period 1 treatment for each period. Shift tables (ie, low-normal-high at 
Baseline versus low-normal-high at each post-baseline visit in a 3-by-3 contingency 
table) will be provided to assess changes from Baseline in laboratory values by visit for 
each Period. Summary figures will be provided for mean change from baseline will be 
provided for each test parameter and each period. 
Separate listings will be provided for all laboratory evaluations (hematology, 
biochemistry, urinalysis, and serum pregnancy results). 


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VITAL SIGNS  
Vital signs consist of body temperature, systolic and diastolic blood pressure, pulse, 
pulse oxygenation (SpO2), weight, and respirations. Vital signs are collected at 
Screening, on Weeks 4,8,12,16 and 20 of Period 1, on Weeks 24, 28, 36, and 44 of 
Period 2, and at the Week 48 follow-up visit. 
Vital signs will be summarized using descriptive statistics at Baseline and at each post-
Baseline visit by Period 1 treatment. Changes from Baseline will also be summarized. 
Summary figures will be provided for mean change from baseline for systolic and 
diastolic blood pressure, pulse, and respirations in each period. 
Separate listings will be provided for all vital sign results. 
 
ECG  
A 12-lead ECG will be performed during the study at Screening, at Baseline, on Week 20 
of Period 1, and on Week 44 of Period 2. Electrocardiogram parameters will be 
summarized using descriptive statistics at Baseline and at each post-Baseline visit where 
an ECG assessment was made by Period 1 treatment.   Changes from Baseline will also 
be summarized. In addition, shift tables (ie, normal, abnormal not clinically significant 
[NCS], abnormal clinically significant [CS]) at Baseline versus normal, abnormal NCS, 
abnormal CS at each post-baseline visit in a 3-by-3 contingency table) will be provided 
to assess changes from Baseline. 
Clinically significant findings, not present during the Baseline visit, should be recorded 
as an AE. 
Separate listings will be provided for all ECG results. 
 
PHYSICAL EXAMINATION 
A complete physical examination will be performed at Screening, on Weeks 12 and 20 of 
Period 1, and Week 44 of Period 2. Complete physical examinations will include a 
minimum of a review of the subject’s general appearance, head, eyes, ears, nose, and 
throat (HEENT), neck, heart, lungs, abdomen, extremities, skin, and general 
neurological system.   
Symptom-oriented or brief physical examinations will be performed at Baseline, on 
Weeks 4, 8, and 16 of Period 1, and Weeks 24, 28, and 36 of Period 2. New abnormal 
physical exam findings not present during the baseline visits should be recorded as AEs.  
Physical examination data is presented in a data listing only. 


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INTERIM ANALYSES 
When 100% of subjects have completed Period 1 of the protocol or terminated early, 
the study will be unblinded. The analysis of safety and efficacy for Period 1 will be 
completed at that time. Given Period 2 is strictly an open-label period and only 
summaries will be provided, there will be no adjustment to the Period 1 p-values due to 
repeated testing. Following the end of Period 2 for all subjects, a full set of tables, 
figures, and listings will be provided. 


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CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
The protocol states, with respect to in FEV1 percent predicted, “A linear regression 
model will be fitted using subjects with observed values for the endpoint (Week 4, 12 
and 20, respectively), the covariates Baseline FEV1 percent predicted, and earlier on-
treatment measurements of FEV1 percent predicted that are available (if any), and the 
stratification factors. Full details will be included in the SAP.”  In the SAP, post-baseline 
FEV1 percent predicted analysis using prior visit results as covariates. 
While not explicitly stated in the protocol, the order of the secondary endpoints in the 
protocol was planned as the order of analysis. The frequency of pulmonary 
exacerbations is now moved from the sixth position within the secondary analyses to the 
first position within the secondary analyses to be the first secondary endpoint to be 
tested. 
With the FDA approval for Trikafta, analysis of the primary and secondary efficacy 
measures will be performed for subjects who did not receive Trikafta at baseline or 
during Period 1. Summaries of the primary and secondary efficacy measures will be 
performed separately for subjects who received Trikafta and subjects who did not 
receive Trikafta at baseline or during Period 1. 
Consequent to COVID-19, recruitment to the trial has been stopped prematurely and 
some changes to rules for handling missed visits (and resulting missing data) have been 
introduced. Where appropriate, the new rules for handling missing data will be applied 
to the primary and secondary efficacy analyses.  For clarity, all changes resulting from 
COVID-19 issues are described in Appendix B of this document.  For avoidance of doubt, 
the primary analyses will be based on the new rules for handling missing data (as 
described in Appendix B), and not necessarily as described in the original SAP text 
(Section 8) or in the protocol. 
The definition of pulmonary exacerbations are clarified, including Updates to the 
definitions of exacerbations, antibiotics to be considered for an exacerbation, and the 
time interval required between one event in order to be considered a separate 
exacerbation. 
Any Pulmonary Function Test that scored for reliability and repeatability with a grade of 
F shall not be used in analyses. In the Per Protocol analyses, results with grades of C or 
D will also be excluded. This was not specified in the protocol. 
 
 


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REFERENCE LIST 
1. The EuroQol Group (1990). EuroQol-a new facility for the measurement of 
health-related quality of life. Health Policy 16(3):199-208. 
 


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PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using 
SAS® for Windows, Release 9.3 (SAS® Institute Inc., Cary, NC, USA). Computer-
generated table, listing, and figure output will adhere to the following specifications.   
 
GENERAL CONSIDERATIONS 
The following items need to be clarified upfront with the sponsor and Medical Writing 
and modified as per study requirements. 
• 
A separate SAS program will be created for each output. 
• 
Each output will be stored in a separate file. 
• 
Output files will be delivered in Word format. 
• 
Numbering of TLFs will follow ICH E3 guidance  
 
 
TABLE, LISTING, AND FIGURE FORMAT 
 
General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size 8  
• 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
• 
Headers and footers for figures will be in Courier New font, size 8. 
• 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 


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Headers 
All output should have the following header at the top of each page:  
Savara, Inc.  
 
 
 
 
 
Draft/Final 
Protocol SAV-005-04   
            
  
 
Page n of N 
• 
TLFs should be internally paginated in relation to the total length (i.e., the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the table). 
• 
The date output was generated should appear along with the program name as a 
footer on each page. 
 
 
Display Titles 
• 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination. A decimal system (x.y and x.y.z) should be 
used to identify TLFs with related contents. The title is centered. The analysis 
population should be identified on the line immediately following the title. The title 
and table designation are single spaced. A solid line spanning the margins will 
separate the display titles from the column headers. There will be 1 blank line 
between the last title and the solid line. 
 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Population 
 
 
Column Headers 
• 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values may be presented under the total column or in separate p-value column (if 
applicable). Within-treatment comparisons may have p-values presented in a row 
beneath the summary statistics for that treatment. 
• 
For numeric variables, include “unit” in column or row heading when appropriate. 
• 
Analysis population sizes will be presented for each treatment group in the column 
heading as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ 


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used for the descriptive statistics representing the number of subjects in the 
analysis population. 
• 
The order of treatments in the tables and listings will be Placebo first followed by 
Active, followed by a total column (if applicable). 
 
Body of the Data Display 
14.2.5.1. General Conventions 
• 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
 
14.2.5.2. Table Conventions 
• 
Units will be included where available 
• 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
• 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 
• 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
• 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 


Statistical Analysis Plan 
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N 
  XX 
Mean 
XXX.X 
Std Dev 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
• 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
value is returned as >0.999 then present as >0.999 
• 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to 
display values that round down to 0.0.  A common convention is to display as '<0.1', 
or as appropriate with additional decimal places. Unless otherwise noted, for all 
percentages, the number of subjects in the analysis population for the treatment 
group who have an observation will be the denominator. Percentages after zero 
counts should not be displayed and percentages equating to 100% should be 
presented as 100%, without any decimal places.  
• 
Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of adverse event data should be presented by the body system, 
treatment class, or SOC with the highest occurrence in the active treatment group 
in decreasing order, assuming all terms are coded. Within the body system, drug 
class and SOC, medical history (by preferred term), drugs (by ATC1 code), and 
adverse events (by preferred term) should be displayed in decreasing order. If 
incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics or p-values which cannot be estimated 
should be reported as “-”. 
• 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis 
population presented. However, careful consideration is required in many instances 
due to the complicated nature of selecting the denominator, usually the appropriate 
number of subjects exposed. Describe details of this in footnotes or programming 
notes. 
• 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
• 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page.  The overall summary statistics for the subheading should only be 
output on the first relevant page. 


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14.2.5.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 
• 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
• 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
• 
Units will be included where available 
 
14.2.5.4. Figure Conventions 
• 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis. 
 
Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
• 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
• 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
• 
Subject specific footnotes should be avoided, where possible. 
• 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page.  
• 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


Statistical Analysis Plan 
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QUALITY CONTROL 
SAS programs are developed to produce output such as analysis data populations, 
summary tables, data listings, figures or statistical analyses. Syneos Health SOP 3906.00 
and 3907.00 or later versions provide an overview of the development of such SAS 
programs. 
Syneos Health SOP 3908.00 or later version describes the quality control procedures that 
are performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs 
produce the output by checking for their logic, efficiency and commenting and by 
review of the produced output.   
 
 
 
 


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INDEX OF TABLES 
Table Number 
Table Title 
Population 
14.1.1.1 
Subject Disposition 
All Enrolled 
Subjects 
14.1.1.2 
Subject Disposition 
Subjects ≤ 21 Years 
All Enrolled 
Subjects 
14.1.1.3 
Subject Disposition 
Subjects > 21 Years 
All Enrolled 
Subjects 
14.1.2.1 
Demographics and Baseline Characteristics 
Safety 
Population 
14.1.2.2 
Demographics and Baseline Characteristics 
Subjects ≤ 21 Years 
Safety 
Population 
14.1.2.3 
Demographics and Baseline Characteristics 
Subjects > 21 Years 
Safety 
Population 
14.1.2.4 
Demographics and Baseline Characteristics by 
Trikafta use at Baseline or During Period 1 
Subjects ≤ 21 Years 
Safety 
Population 
14.1.2.5 
Demographics and Baseline Characteristics by 
Trikafta use at Baseline or During Period 1 
Subjects > 21 Years  
Safety 
Population 
14.1.3 
Medical History 
Safety 
Population 
14.1.4 
Exposure to Study Treatments by Period  
Safety 
Population 
14.1.5 
Study Treatment Compliance by Period 
Safety 
Population 
14.1.6 
Summary of Protocol Deviations by Period 
Safety 
Population 
14.1.7 
Summary of Prior Medications 
Safety 
Population 
14.1.8.1 
Summary of Concomitant Medications During Period 
1 
Safety 
Population 
14.1.8.2 
Summary of Concomitant Medications During Period 
2 
Safety 
Population 
14.2.1.1.1 
Analysis of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20 
Subjects ≤ 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.1.1.1.1 
Analysis of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20 using 
Strata as Reported in Database 
Subjects ≤ 21 Years 
ITT Population 
14.2.1.1.2 
Analysis of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20 
Subjects > 21 Years 
ITT Population 
14.2.1.1.3 
Analysis of Imputed Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 
Worst Reasonable Case Analysis 
Subjects ≤ 21 Years 
ITT Population 
14.2.1.1.3.1 
Analysis of Imputed Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 
Worst Reasonable Case Analysis using Strata as 
Reported in Database 
Subjects ≤ 21 Years 
ITT Population 
14.2.1.1.4 
Analysis of Imputed Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 
Best Reasonable Case Analysis 
Subjects ≤ 21 Years  
ITT Population 
14.2.1.1.4.1 
Analysis of Imputed Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 
Best Reasonable Case Analysis using Strata as 
Reported in Database 
Subjects ≤ 21 Years  
ITT Population 
14.2.1.1.5 
Analysis of Imputed Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 
Tipping Point Analysis 
Subjects ≤ 21 Years 
ITT Population 
14.2.1.1.5.1 
Analysis of Imputed Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 
Tipping Point Analysis using Strata as Reported in 
Database 
Subjects ≤ 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.1.1.6 
Analysis of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted Weeks 4, 12, and 20 
Subjects ≤ 21 Years 
Per-Protocol 
Population  
14.2.1.1.6.1 
Analysis of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted Weeks 4, 12, and 20 using 
Strata as Reported in Database 
Subjects ≤ 21 Years 
Per-Protocol 
Population  
14.2.1.1.7 
Analysis of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20 by  
Subjects ≤ 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.1.1.8 
Analysis of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20  
Subjects > 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.1.1.9 
Analysis of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20 by 
i.v. Vancomycin use during Period 1  
Subjects ≤ 21 Years 
ITT Population 
14.2.1.1.10 
Analysis of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20 by 
i.v. Vancomycin use during Period 1  
Subjects > 21 Years 
ITT Population 
14.2.1.2.1 
Summary of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20 by 
Baseline FEV1 
Subjects ≤ 21 Years 
ITT Population 
14.2.1.2.2 
Summary of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20 by 
Baseline FEV1 
Subjects > 21 Years 
ITT Population 
14.2.1.3.1 
Summary of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20 by 
Prior Exacerbations Treated with Antibiotics During 
the Previous 12 Months 
Subjects ≤ 21 Years 
ITT Population 
14.2.1.3.2 
Summary of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20 by 
Prior Exacerbations Treated with Antibiotics During 
the Previous 12 Months 
Subjects > 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.1.4.1 
Summary of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20 by P. 
Aeruginosa Treatment 
Subjects ≤ 21 Years 
ITT Population 
14.2.1.4.2 
Summary of Mean Absolute Change from Baseline in 
FEV1 Percent Predicted at Weeks 4, 12, and 20 by P. 
Aeruginosa Treatment 
Subjects > 21 Years 
ITT Population 
14.2.2.1.1 
Analysis of Frequency of Pulmonary Exacerbation 
During Period 1 
Subjects ≤ 21 Years 
ITT Population 
14.2.2.1.1.1 
Analysis of Frequency of Pulmonary Exacerbation 
During Period 1 using Strata as Reported in Database 
Subjects ≤ 21 Years 
ITT Population 
14.2.2.1.2 
Analysis of Frequency of Pulmonary Exacerbation 
During Period 1 
Subjects > 21 Years 
ITT Population 
14.2.2.1.3 
Analysis of Frequency of Pulmonary Exacerbation 
During Period 1 
Subjects ≤ 21 Years 
Per-Protocol 
Population 
14.2.2.1.4 
Analysis of Frequency of Pulmonary Exacerbation 
During Period 1 by Trikafta use 
Subjects ≤ 21 Years 
ITT Population 
14.2.2.1.5 
Analysis of Frequency of Pulmonary Exacerbation 
During Period 1 
Subjects > 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.2.1.6 
Analysis of Frequency of Pulmonary Exacerbation 
During Period 1 by i.v. Vancomycin use during Period 
1 
Subjects <= 21 Years 
ITT Population 
14.2.2.1.7 
Analysis of Frequency of Pulmonary Exacerbation 
During Period 1 by i.v. Vancomycin use during Period 
1 
Subjects > 21 Years 
ITT Population 
14.2.2.2.1 
Summary of Frequency of Pulmonary Exacerbation by 
Period  
Subjects ≤ 21 Years  
ITT Population 
14.2.2.2.2 
Summary of Frequency of Pulmonary Exacerbation by 
Period  
Subjects > 21 Years  
ITT Population 


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Table Number 
Table Title 
Population 
14.2.2.3.1 
Summary of Frequency of Pulmonary Exacerbation by 
Period and Trikafta use at Baseline or During Period 
1 
Subjects ≤ 21 Years  
ITT Population 
14.2.2.3.2 
Summary of Frequency of Pulmonary Exacerbation by 
Period and Trikafta use at Baseline or During Period 
1 
Subjects > 21 Years  
ITT Population 
14.2.2.4.1 
Summary of Frequency of Pulmonary Exacerbation by 
Period and Baseline FEV1 
Subjects ≤ 21 Years  
ITT Population 
14.2.2.4.2 
Summary of Frequency of Pulmonary Exacerbation by 
Period and Baseline FEV1 
Subjects > 21 Years  
ITT Population 
14.2.2.5.1 
Summary of Frequency of Pulmonary Exacerbation by 
Period and Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months 
Subjects ≤ 21 Years  
ITT Population 
14.2.2.5.2 
Summary of Frequency of Pulmonary Exacerbation by 
Period and Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months  
Subjects > 21 Years  
ITT Population 
14.2.2.6.1 
Summary of Frequency of Pulmonary Exacerbation by 
Period and P. Aeruginosa Treatment 
Subjects ≤ 21 Years  
ITT Population 
14.2.2.6.2 
Summary of Frequency of Pulmonary Exacerbation by 
Period and P. Aeruginosa Treatment 
Subjects > 21 Years  
ITT Population 
14.2.3.1.1 
Analysis of Time to First Pulmonary Exacerbation 
During Period 1 
Subjects ≤ 21 Years 
ITT Population 
14.2.3.1.1.1 
Analysis of Time to First Pulmonary Exacerbation 
During Period 1 using Strata as Reported in Database 
Subjects ≤ 21 Years 
ITT Population 
14.2.3.1.2 
Analysis of Time to First Pulmonary Exacerbation 
During Period 1 
Subjects > 21 Years 
ITT Population 
14.2.3.1.3 
Analysis of Time to First Pulmonary Exacerbation 
During Period 1 
Subjects ≤ 21 Years 
Per-Protocol 
Population 


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Table Number 
Table Title 
Population 
14.2.3.1.4 
Analysis of Time to First Pulmonary Exacerbation 
During Period 1  
Subjects ≤ 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.3.1.5 
Analysis of Time to First Pulmonary Exacerbation 
During Period 1 
Subjects > 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.3.1.6 
Analysis of Time to First Pulmonary Exacerbation 
During Period 1 by i.v. Vancomycin use during Period 
1 
Subjects ≤ 21 Years  
ITT Population 
14.2.3.1.7 
Analysis of Time to First Pulmonary Exacerbation 
During Period 1 by i.v. Vancomycin use during Period 
1 
Subjects > 21 Years  
ITT Population 
14.2.3.1.8 
Kaplan-Meier Life Table for Time to First Pulmonary 
Exacerbation During Period 1 
Subjects ≤ 21 Years 
ITT Population 
14.2.3.1.9 
Kaplan-Meier Life Table for Time to First Pulmonary 
Exacerbation During Period 1 
Subjects > 21 Years 
ITT Population 
14.2.3.2.1 
Summary of Time to First Pulmonary Exacerbation 
During Period 1 
Subjects ≤ 21 Years 
ITT Population 
14.2.3.2.2 
Summary of Time to First Pulmonary Exacerbation 
During Period 1 
Subjects > 21 Years 
ITT Population 
14.2.3.3.1 
Summary of Time to First Pulmonary Exacerbation 
During Period 1 by Trikafta use at Baseline or During 
Period 1 
Subjects ≤ 21 Years 
ITT Population 
14.2.3.3.2 
Summary of Time to First Pulmonary Exacerbation 
During Period 1 by Trikafta use at Baseline or During 
Period 1 
Subjects > 21 Years 
ITT Population 
14.2.3.4.1 
Summary of Time to First Pulmonary Exacerbation 
During Period 1 by Baseline FEV1 
Subjects ≤ 21 Years 
ITT Population 
14.2.3.4.2 
Summary of Time to First Pulmonary Exacerbation 
During Period 1 by Baseline FEV1 
Subjects > 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.3.5.1 
Summary of Time to First Pulmonary Exacerbation 
During Period 1 by Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months 
Subjects ≤ 21 Years 
ITT Population 
14.2.3.5.2 
Summary of Time to First Pulmonary Exacerbation 
During Period 1 by Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months 
Subjects > 21 Years 
ITT Population 
14.2.3.6.1 
Summary of Time to First Pulmonary Exacerbation 
During Period 1 by P. Aeruginosa Treatment 
Subjects ≤ 21 Years 
ITT Population 
14.2.3.6.2 
Summary of Time to First Pulmonary Exacerbation 
During Period 1 by P. Aeruginosa Treatment 
Subjects > 21 Years 
ITT Population 
14.2.4.1.1 
Analysis of  Number of Successful Response Cycles 
During Period 1 
Subjects ≤ 21 Years 
ITT Population 
14.2.4.1.1.1 
Analysis of  Number of Successful Response Cycles 
During Period 1 using Strata as Reported in Database 
Subjects ≤ 21 Years 
ITT Population 
14.2.4.1.2 
Analysis of Number of Successful Response Cycles 
During Period 1 
Subjects > 21 Years 
ITT Population 
14.2.4.1.3 
Analysis of Number of Successful Response Cycles 
During Period 1 
Subjects ≤ 21 Years 
Per-Protocol 
Population 
14.2.4.1.4 
Analysis of  Number of Successful Response Cycles 
During Period 1  
Subjects ≤ 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.4.1.5 
Analysis of Number of Successful Response Cycles 
During Period 1  
Subjects > 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.4.1.6 
Analysis of  Number of Successful Response Cycles 
During Period 1 by i.v. Vancomycin use during Period 
1 
Subjects ≤ 21 Years 
ITT Population 
14.2.4.1.7 
Analysis of  Number of Successful Response Cycles 
During Period 1 by i.v. Vancomycin use during Period 
1 
Subjects > 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.4.2.1 
Summary of Number of Successful Response Cycles 
During Period 1 by Baseline FEV1 
Subjects ≤ 21 Years 
ITT Population 
14.2.4.2.2 
Summary of Number of Successful Response Cycles 
During Period 1 by Baseline FEV1 
Subjects > 21 Years  
ITT Population 
14.2.4.3.1 
Summary of Number of Successful Response Cycles 
During Period 1 by Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months 
Subjects ≤ 21 Years  
ITT Population 
14.2.4.3.2 
Summary of Number of Successful Response Cycles 
During Period 1 by Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months  
Subjects > 21 Years 
ITT Population 
14.2.4.4.1 
Summary of Number of Successful Response Cycles 
During Period 1 by P. Aeruginosa Treatment 
Subjects ≤ 21 Years  
ITT Population 
14.2.4.4.2 
Summary of Number of Successful Response Cycles 
During Period 1 by P. Aeruginosa Treatment 
Subjects > 21 Years 
ITT Population 
14.2.5.1.1 
Analysis of Relative Change from Baseline in FEV1 
Percent Predicted at Week 4, 12, and Week 20 
Subjects ≤ 21 Years 
ITT Population 
14.2.5.1.1.1 
Analysis of Relative Change from Baseline in FEV1 
Percent Predicted at Week 4, 12, and Week 20 using 
Strata as Reported in Database 
Subjects ≤ 21 Years 
ITT Population 
14.2.5.1.2 
Analysis of Relative Change from Baseline in FEV1 
Percent Predicted at Week 4, 12, and Week 20 
Subjects > 21 Years 
ITT Population 
14.2.5.1.3 
Analysis of Relative Change from Baseline in FEV1 
Percent Predicted at Week 4, 12, and Week 20 
Subjects ≤ 21 Years 
Per-Protocol 
Population 
14.2.5.1.4 
Analysis of Relative Change from Baseline in FEV1 
Percent Predicted at Week 4, 12, and Week 20  
Subjects ≤ 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.5.1.5 
Analysis of Relative Change from Baseline in FEV1 
Percent Predicted at Week 4, 12, and Week 20  
Subjects > 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.5.1.6 
Analysis of Relative Change from Baseline in FEV1 
Percent Predicted at Week 4, 12, and Week 20 by 
i.v. Vancomycin use during Period 1 
Subjects ≤ 21 Years  
ITT Population 
14.2.5.1.7 
Analysis of Relative Change from Baseline in FEV1 
Percent Predicted at Week 4, 12, and Week 20 by 
i.v. Vancomycin use during Period 1 
Subjects > 21 Years 
ITT Population 
14.2.5.2.1 
Summary of Relative Change from Baseline in FEV1 
Percent Predicted at Weeks 4, 12, and 20 by 
Baseline FEV1 
Subjects ≤ 21 Years 
ITT Population 
14.2.5.2.2 
Summary of Relative Change from Baseline in FEV1 
Percent Predicted at Weeks 4, 12, and 20 by 
Baseline FEV1 
Subjects > 21 Years 
ITT Population 
14.2.5.3.1 
Summary of Relative Change from Baseline in FEV1 
Percent Predicted at Weeks 4, 12, and 20 by Prior 
Exacerbations Treated with Antibiotics During the 
Previous 12 Months 
Subjects ≤ 21 Years 
ITT Population 
14.2.5.3.2 
Summary of Relative Change from Baseline in FEV1 
Percent Predicted at Weeks 4, 12, and 20 by Prior 
Exacerbations Treated with Antibiotics During the 
Previous 12 Months 
Subjects > 21 Years 
ITT Population 
14.2.5.4.1 
Summary of Relative Change from Baseline in FEV1 
Percent Predicted at Weeks 4, 12, and 20 by P. 
Aeruginosa Treatment 
Subjects ≤ 21 Years 
ITT Population 
14.2.5.4.2 
Summary of Relative Change from Baseline in FEV1 
Percent Predicted at Weeks 4, 12, and 20 by P. 
Aeruginosa Treatment 
Subjects > 21 Years 
ITT Population 
14.2.6.1.1 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Parent Scaled Scores 
and Teen/Adult Scaled Scores at Weeks 4, 12, and 20 
Subjects ≤ 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.6.1.1.1 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Parent Scaled Scores 
and Teen/Adult Scaled Scores at Weeks 4, 12, and 20 
using Strata as Reported in Database 
Subjects ≤ 21 Years 
ITT Population 
14.2.6.1.2 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Parent Scaled Scores 
at Weeks 4, 12, and 20 
Subjects ≤ 13 Years 
ITT Population 
14.2.6.1.3 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult Scaled 
Scores  at Weeks 4, 12, and 20 
13 Years < Subjects ≤ 21 Years 
ITT Population 
14.2.6.1.4 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult Scaled 
Scores at Weeks 4, 12, and 20 
Subjects > 21 Years 
ITT Population 
14.2.6.1.5 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Parent Scaled Scores 
and Teen/Adult Scaled Scores at Weeks 4, 12, and 20 
Subjects ≤ 21 Years 
Per-Protocol 
Population 
14.2.6.1.6 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Parent Scaled Scores 
at Weeks 4, 12, and 20 
Subjects ≤ 13 Years 
Per-Protocol 
Population 
14.2.6.1.7 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult Scaled 
Scores  at Weeks 4, 12, and 20 
13 Years < Subjects ≤ 21 Years 
Per-Protocol 
Population 
14.2.6.1.8 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Parent Scaled Scores 
and Teen/Adult Scaled Scores at Weeks 4, 12, and 20 
Subjects ≤ 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.6.1.9 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Parent Scaled Scores 
at Weeks 4, 12, and 20  
Subjects ≤ 13 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.6.1.10 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult Scaled 
Scores  at Weeks 4, 12, and 20  
13 Years < Subjects ≤ 21 Years with no Trikafta use 
at Baseline or During Period 1 
ITT Population 
14.2.6.1.11 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult Scaled 
Scores at Weeks 4, 12, and 20 
Subjects > 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.6.1.12 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult Scaled 
Scores  at Weeks 4, 12, and 20 by i.v. Vancomycin 
use during Period 1 
Subjects ≤ 13 Years 
ITT Population 
14.2.6.1.13 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult Scaled 
Scores  at Weeks 4, 12, and 20 by i.v. Vancomycin 
use during Period 1 
13 Years < Subjects ≤ 21 Years 
ITT Population 
14.6.1.14 
Analysis of Change from Baseline in the Respiratory 
Symptoms Domain of the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult Scaled 
Scores  at Weeks 4, 12, and 20 by i.v. Vancomycin 
use during Period 1 
Subjects > 21 Years 
ITT Population 
14.2.6.2.1 
Analysis of Change from Baseline in the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) Parent Scaled 
Scores and Teen/Adult Scaled Scores at Weeks 4, 12, 
and 20 
Subjects ≤ 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.6.2.2 
Analysis of Change from Baseline in the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) Parent Scaled 
Scores at Weeks 4, 12, and 20 
Subjects ≤ 13 Years 
ITT Population 
14.2.6.2.3 
Analysis of Change from Baseline in the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores  at Weeks 4, 12, and 20 
13 Years < Subjects ≤ 21 Years 
ITT Population 
14.2.6.2.4 
Analysis of Change from Baseline in the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores  at Weeks 4, 12, and 20 
Subjects > 21 Years 
TT Population 
14.2.6.3.1 
Analysis of Change from Baseline in the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) Parent Scaled 
Scores and Teen/Adult Scaled Scores at Weeks 4, 12, 
and 20  
Subjects ≤ 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.6.3.2 
Analysis of Change from Baseline in the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) Parent Scaled 
Scores at Weeks 4, 12, and 20  
Subjects ≤ 13 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.6.3.3 
Analysis of Change from Baseline in the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores  at Weeks 4, 12, and 20  
13 Years < Subjects ≤ 21 Years with no Trikafta use 
at Baseline or During Period 1 
ITT Population 
14.2.6.3.4 
Analysis of Change from Baseline in the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores  at Weeks 4, 12, and 20 
Subjects > 21 Years with no Trikafta use at Baseline 
or During Period 1 
TT Population 
14.2.6.4.1 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Scores  by Period 
Subjects ≤ 13 Years 
ITT Population 
14.2.6.4.2 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores by Period 
13 Years < Subjects ≤ 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.6.4.3 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores by Period 
Subjects > 21 Years 
TT Population 
14.2.6.5.1 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Scores  by Period and Trikafta use at 
Baseline or During Period 1 
Subjects ≤ 13 Years 
ITT Population 
14.2.6.5.2 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores by Period and Trikafta use 
at Baseline or During Period 1 
13 Years < Subjects ≤ 21 Years 
ITT Population 
14.2.6.5.3 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores by Period and Trikafta use 
at Baseline or During Period 1 
Subjects > 21 Years 
TT Population 
14.2.6.6.1 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Scores  by Period and Baseline FEV1 
Subjects ≤ 13 Years 
ITT Population 
14.2.6.6.2 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores by Period and Baseline 
FEV1 
13 Years < Subjects ≤ 21 Years 
ITT Population 
14.2.6.6.3 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores by Period and Baseline 
FEV1 
Subjects > 21 Years 
TT Population 
14.2.6.7.1 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Scores  by Period and Prior 
Exacerbations Treated with Antibiotics during the 
Previous 12 Months 
Subjects ≤ 13 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.6.7.2 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores by Prior Exacerbations 
Treated with Antibiotics during the Previous 12 
Months 
13 Years < Subjects ≤ 21 Years 
ITT Population 
14.2.6.7.3 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores by Period and Prior 
Exacerbations Treated with Antibiotics during the 
Previous 12 Months 
Subjects > 21 Years 
TT Population 
14.2.6.8.1 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Scores  by Period and P. aeruginosa 
Treatment 
Subjects ≤ 13 Years 
ITT Population 
14.2.6.8.2 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores by Period and P. 
aeruginosa Treatment 
13 Years < Subjects ≤ 21 Years 
ITT Population 
14.2.6.8.3 
Summary of Actual and of Change from Baseline in 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores by Period and P. 
aeruginosa Treatment 
Subjects > 21 Years 
TT Population 
14.2.7.1.1 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) Scores at 
Weeks 4, 12, and 20 
Subjects ≤ 21 Years 
ITT Population 
14.2.7.1.1.1 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) Scores at 
Weeks 4, 12, and 20 using Strata as Reported in 
Database 
Subjects ≤ 21 Years 
ITT Population 
14.2.7.1.2 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) Scores at 
Weeks 4, 12, and 20 
Subjects > 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.7.1.3 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) Scores at 
Weeks 4, 12, and 20 
Subjects ≤ 21 Years 
Per-Protocol 
Population 
14.2.7.1.4 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) Scores at 
Weeks 4, 12, and 20  
Subjects ≤ 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.7.1.5 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) Scores at 
Weeks 4, 12, and 20  
Subjects > 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.7.1.6 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) Scores at 
Weeks 4, 12, and 20 by i.v. Vancomycin use during 
Period 1 
Subjects ≤ 21 Years  
ITT Population 
14.2.7.1.7 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) Scores at 
Weeks 4, 12, and 20 by i.v. Vancomycin use during 
Period 1 
Subjects> 21 Years 
ITT Population 
14.2.7.2.1 
Summary of Actual and Change from Baseline in 
Chronic Respiratory Symptom Score (CFRSD-CRISS) 
Scores by Period  
Subjects ≤ 21 Years  
ITT Population 
14.2.7.2.2 
Summary of Actual and Change from Baseline in 
Chronic Respiratory Symptom Score (CFRSD-CRISS) 
Scores by Period  
Subjects > 21 Years  
ITT Population 
14.2.7.3.1 
Summary of Actual and Change from Baseline in 
Chronic Respiratory Symptom Score (CFRSD-CRISS) 
Scores by Period and Trikafta use at Baseline or 
During Period 1 
Subjects ≤ 21 Years  
ITT Population 
14.2.7.3.2 
Summary of Actual and Change from Baseline in 
Chronic Respiratory Symptom Score (CFRSD-CRISS) 
Scores by Period and Trikafta use at Baseline or 
During Period 1 
Subjects > 21 Years  
ITT Population 


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Table Number 
Table Title 
Population 
14.2.7.4.1 
Summary of Actual and Change from Baseline in 
Chronic Respiratory Symptom Score (CFRSD-CRISS) 
Scores by Period and Baseline FEV1 
Subjects ≤ 21 Years 
ITT Population 
14.2.7.4.2 
Summary of Actual and Change from Baseline in 
Chronic Respiratory Symptom Score (CFRSD-CRISS) 
Scores by Period and Baseline FEV1 
Subjects > 21 Years 
ITT Population 
14.2.7.5.1 
Summary of Actual and Change from Baseline in 
Chronic Respiratory Symptom Score (CFRSD-CRISS) 
Scores by Period and Prior Exacerbations Treated 
with Antibiotics During the Previous 12 Months 
Subjects ≤ 21 Years 
ITT Population 
14.2.7.5.2 
Summary of Actual and Change from Baseline in 
Chronic Respiratory Symptom Score (CFRSD-CRISS) 
Scores by Period and Prior Exacerbations Treated 
with Antibiotics During the Previous 12 Months 
Subjects > 21 Years 
ITT Population 
14.2.7.6.1 
Summary of Actual and Change from Baseline in 
Chronic Respiratory Symptom Score (CFRSD-CRISS) 
Scores by Period and P. Aeruginosa Treatment 
Subjects ≤ 21 Years 
ITT Population 
14.2.7.6.2 
Summary of Actual and Change from Baseline in 
Chronic Respiratory Symptom Score (CFRSD-CRISS) 
Scores by Period and P. Aeruginosa Treatment 
Subjects > 21 Years 
ITT Population 
14.2.8.1.1 
Analysis of Area Under the FEV1–time Profile 
Subjects ≤ 21 Years 
ITT Population 
14.2.8.1.1.1 
Analysis of Area Under the FEV1–time Profile using 
Strata as Reported in Database 
Subjects ≤ 21 Years 
ITT Population 
14.2.8.1.2 
Analysis of Area Under the FEV1–time Profile 
Subjects > 21 Years 
ITT Population 
14.2.8.1.3 
Analysis of Area Under the FEV1–time Profile 
Subjects ≤ 21 Years 
Per-Protocol 
Population 
14.2.8.1.4 
Analysis of Area Under the FEV1–time Profile  
Subjects ≤ 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 
14.2.8.1.5 
Analysis of Area Under the FEV1–time Profile  
Subjects > 21 Years with no Trikafta use at Baseline 
or During Period 1 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.8.1.6 
Analysis of Area Under the FEV1–time Profile by i.v. 
Vancomycin use during Period 1 
Subjects ≤ 21 Years  
ITT Population 
14.2.8.1.7 
Analysis of Area Under the FEV1–time Profile by i.v. 
Vancomycin use during Period 1 
Subjects > 21 Years 
ITT Population 
14.2.8.2.1 
Summary of Area Under the FEV1–time Profile by 
Period  
Subjects ≤ 21 Years  
ITT Population 
14.2.8.2.2 
Summary of Area Under the FEV1–time Profile by 
Period  
Subjects > 21 Years  
ITT Population 
14.2.8.3.1 
Summary of Area Under the FEV1–time Profile by 
Period and Trikafta use at Baseline or During Period 
1 
Subjects ≤ 21 Years  
ITT Population 
14.2.8.3.2 
Summary of Area Under the FEV1–time Profile by 
Period and Trikafta use at Baseline or During Period 
1 
Subjects > 21 Years  
ITT Population 
14.2.8.4.1 
Summary of Area Under the FEV1–time Profile by 
Period and Baseline FEV1 
Subjects ≤ 21 Years  
ITT Population 
14.2.8.4.2 
Summary of Area Under the FEV1–time Profile by 
Period and Baseline FEV1 
Subjects > 21 Years  
ITT Population 
14.2.8.5.1 
Summary of Area Under the FEV1–time Profile by 
Period and Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months 
Subjects ≤ 21 Years  
ITT Population 
14.2.8.5.2 
Summary of Area Under the FEV1–time Profile by 
Period and Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months  
Subjects > 21 Years  
ITT Population 
14.2.8.6.1 
Summary of Area Under the FEV1–time Profile by 
Period and P. Aeruginosa Treatment 
Subjects ≤ 21 Years  
ITT Population 
14.2.8.6.2 
Summary of Area Under the FEV1–time Profile by 
Period and P. Aeruginosa Treatment 
Subjects > 21 Years  
ITT Population 


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Table Number 
Table Title 
Population 
14.2.9.1.1 
Summary of Actual and Change from Baseline in 
EQ-5D Youth (EQ-5Dy) by Period 
Subjects ≤ 15 Years 
ITT Population 
14.2.9.1.2 
Summary of Actual and Change from Baseline in 
EQ-5D-5L by Period 
15 Years < Subjects ≤ 21 Years 
ITT Population 
14.2.9.1.3 
Summary of Actual and Change from Baseline in 
EQ-5D-5L by Period 
Subjects > 21 Years 
ITT Population 
14.2.9.2.1 
Summary of Actual and Change from Baseline in 
EQ-5D Youth (EQ-5Dy) by Period and Baseline FEV1 
Subjects ≤ 15 Years 
ITT Population 
14.2.9.2.2 
Summary of Actual and Change from Baseline in 
EQ-5D-5L by Period and Baseline FEV1 
15 Years < Subjects ≤ 21 Years 
ITT Population 
14.2.9.2.3 
Summary of Actual and Change from Baseline in 
EQ-5D-5L by Period and Baseline FEV1 
Subjects >21 Years 
ITT Population 
14.2.9.3.1 
Summary of Actual and Change from Baseline in 
EQ-5D Youth (EQ-5Dy) by Period and Prior 
Exacerbations Treated with Antibiotics During the 
Previous 12 Months 
Subjects ≤ 15 Years 
ITT Population 
14.2.9.3.2 
Summary of Actual and Change from Baseline in 
EQ-5D-5L by Period and Prior Exacerbations Treated 
with Antibiotics During the Previous 12 Months  
15 Years < Subjects ≤ 21 Years 
ITT Population 
14.2.9.3.3 
Summary of Actual and Change from Baseline in 
EQ-5D-5L by Period and Prior Exacerbations Treated 
with Antibiotics During the Previous 12 Months 
Subjects >21 Years 
ITT Population 
14.2.9.4.1 
Summary of Actual and Change from Baseline in 
EQ-5D Youth (EQ-5Dy) by Period and P. Aeruginosa 
Treatment  
Subjects ≤ 15 Years 
ITT Population 
14.2.9.4.2 
Summary of Actual and Change from Baseline in 
EQ-5D-5L by Period and P. Aeruginosa Treatment  
15 Years < Subjects ≤ 21 Years 
ITT Population 
14.2.9.4.3 
Summary of Actual and Change from Baseline in 
EQ-5D-5L by Period and P. Aeruginosa Treatment  
Subjects >21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.9.5.1 
Shift in EQ-5D Youth (EQ-5Dy) by Period 
Subjects ≤15 Years 
ITT Population 
14.2.9.5.2 
Shift in EQ-5D-5L by Period 
15 Years < Subjects ≤21 Years 
ITT Population 
14.2.9.5.3 
Shift in EQ-5D-5L by Period 
Subjects >21 Years 
ITT Population 
14.2.10.1.1 
Summary of Actual and Change from Baseline in Body 
Weight by Period  
Subjects ≤ 21 Years 
ITT Population 
14.2.10.1.2 
Summary of Actual and Change from Baseline in Body 
Weight by Period  
Subjects > 21 Years 
ITT Population 
14.2.10.2.1 
Summary of Actual and Change from Baseline in Body 
Weight by Period and Baseline FEV1 
Subjects ≤ 21 Years 
ITT Population 
14.2.10.2.2 
Summary of Actual and Change from Baseline in Body 
Weight by Period and Baseline FEV1 
Subjects > 21 Years 
ITT Population 
14.2.10.3.1 
Summary of Actual and Change from Baseline in Body 
Weight by Period and Prior Exacerbations Treated 
with Antibiotics During the Previous 12 Months 
Subjects ≤ 21 Years 
ITT Population 
14.2.10.3.2 
Summary of Actual and Change from Baseline in Body 
Weight by Period and Prior Exacerbations Treated 
with Antibiotics During the Previous 12 Months 
Subjects > 21 Years 
ITT Population 
14.2.10.4.1 
Summary of Actual and Change from Baseline in Body 
Weight by Period and P. Aeruginosa Treatment 
Subjects ≤ 21 Years 
ITT Population 
14.2.10.4.2 
Summary of Actual and Change from Baseline in Body 
Weight by Period and P. Aeruginosa Treatment 
Subjects > 21 Years 
ITT Population 
14.2.11.1.1 
Summary of Minimum Inhibitory Concentration (MIC) 
for Vancomycin  
Subjects ≤ 21 Years 
ITT Population 
14.2.11.1.2 
Summary of Minimum Inhibitory Concentration (MIC) 
for Vancomycin  
Subjects > 21 Years 
ITT Population 
14.2.11.2.1 
Summary of Shift from Baseline in Minimum 
Inhibitory Concentration (MIC) for Vancomycin  
Subjects ≤ 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.11.2.2 
Summary of Shift from Baseline in Minimum 
Inhibitory Concentration (MIC) for Vancomycin  
Subjects > 21 Years 
ITT Population 
14.2.11.3.1 
Summary of Minimum Inhibitory Concentration (MIC) 
for Vancomycin by Baseline FEV1 
Subjects ≤ 21 Years 
ITT Population 
14.2.11.3.2 
Summary of Minimum Inhibitory Concentration (MIC) 
for Vancomycin by Baseline FEV1 
Subjects > 21 Years 
ITT Population 
14.2.11.4.1 
Summary of Minimum Inhibitory Concentration (MIC) 
for Vancomycin by Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months 
Subjects ≤ 21 Years 
ITT Population 
14.2.11.4.2 
Summary of Minimum Inhibitory Concentration (MIC) 
for Vancomycin by Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months 
Subjects > 21 Years 
ITT Population 
14.2.11.5.1 
Summary of Minimum Inhibitory Concentration (MIC) 
for Vancomycin by P. Aeruginosa Treatment 
Subjects ≤ 21 Years 
ITT Population 
14.2.11.5.2 
Summary of Minimum Inhibitory Concentration (MIC) 
for Vancomycin by P. Aeruginosa Treatment 
Subjects > 21 Years 
ITT Population 
14.2.12.1.1 
Summary of Actual and Change from Baseline in 
MRSA Sputum Density by Period 
Subjects ≤ 21 Years 
ITT Population 
14.2.12.1.2 
Summary of Actual and Change from Baseline in 
MRSA Sputum Density by Period 
Subjects > 21 Years 
ITT Population 
14.2.12.1.3 
Summary of Actual and Change from Baseline in 
MRSA Throat Swap Density by Period 
Subjects ≤ 21 Years 
ITT Population 
14.2.12.1.4 
Summary of Actual and Change from Baseline in 
MRSA Throat Swap Density by Period 
Subjects > 21 Years 
ITT Population 
14.2.12.2.1 
Summary of Actual and Change from Baseline in 
MRSA Sputum Density by Period and Baseline FEV1 
Subjects ≤ 21 Years 
ITT Population 
14.2.12.2.2 
Summary of Actual and Change from Baseline in 
MRSA Sputum Density by Period and Baseline FEV1 
Subjects > 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.12.2.3 
Summary of Actual and Change from Baseline in 
MRSA Throat Swap Density by Period and Baseline 
FEV1 
Subjects ≤ 21 Years 
ITT Population 
14.2.12.2.4 
Summary of Actual and Change from Baseline in 
MRSA Throat Swap Density by Period and Baseline 
FEV1 
Subjects > 21 Years 
ITT Population 
14.2.12.3.1 
Summary of Actual and Change from Baseline in 
MRSA Sputum Density by Period and Prior 
Exacerbations Treated with Antibiotics During the 
Previous 12 Months 
Subjects ≤ 21 Years 
ITT Population 
14.2.12.3.2 
Summary of Actual and Change from Baseline in 
MRSA Sputum Density by Period and Prior 
Exacerbations Treated with Antibiotics During the 
Previous 12 Months 
Subjects > 21 Years 
ITT Population 
14.2.12.3.3 
Summary of Actual and Change from Baseline in 
MRSA Throat Swap Density by Period and Prior 
Exacerbations Treated with Antibiotics During the 
Previous 12 Months 
Subjects ≤ 21 Years 
ITT Population 
14.2.12.3.4 
Summary of Actual and Change from Baseline in 
MRSA Throat Swap Density by Period and Prior 
Exacerbations Treated with Antibiotics During the 
Previous 12 Months 
Subjects > 21 Years 
ITT Population 
14.2.12.4.1 
Summary of Actual and Change from Baseline in 
MRSA Sputum Density by Period and P. Aeruginosa 
Treatment 
Subjects ≤ 21 Years 
ITT Population 
14.2.12.4.2 
Summary of Actual and Change from Baseline in 
MRSA Sputum Density by Period and P. Aeruginosa 
Treatment 
Subjects > 21 Years 
ITT Population 
14.2.12.4.3 
Summary of Actual and Change from Baseline in 
MRSA Throat Swap Density by Period and P. 
Aeruginosa Treatment 
Subjects ≤ 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.12.4.4 
Summary of Actual and Change from Baseline in 
MRSA Throat Swap Density by Period and P. 
Aeruginosa Treatment 
Subjects > 21 Years 
ITT Population 
14.2.13.1.1 
Summary of Actual and Change from Baseline in 
Pulmonary Function Tests by Period  
Subjects ≤ 21 Years 
ITT Population 
14.2.13.1.2 
Summary of Actual and Change from Baseline in 
Pulmonary Function Tests by Period 
Subjects > 21 Years 
ITT Population 
14.2.13.2.1 
Summary of Pulmonary Function Tests by Actual and 
Change from Baseline in Period and Baseline FEV1 
Subjects ≤ 21 Years 
ITT Population 
14.2.13.2.2 
Summary of Actual and Change from Baseline in 
Pulmonary Function Tests by Period and Baseline 
FEV1 
Subjects > 21 Years 
ITT Population 
14.2.13.3.1 
Summary of Actual and Change from Baseline in 
Pulmonary Function Tests by Period and Prior 
Exacerbations Treated with Antibiotics During the 
Previous 12 Months 
Subjects ≤ 21 Years 
ITT Population 
14.2.13.3.2 
Summary of Actual and Change from Baseline in 
Pulmonary Function Tests by Period and Prior 
Exacerbations Treated with Antibiotics During the 
Previous 12 Months 
Subjects > 21 Years 
ITT Population 
14.2.13.4.1 
Summary of Actual and Change from Baseline in 
Pulmonary Function Tests by Period and P. 
Aeruginosa Treatment 
Subjects ≤ 21 Years 
ITT Population 
14.2.13.4.2 
Summary of Actual and Change from Baseline in 
Pulmonary Function Tests by Period and P. 
Aeruginosa Treatment 
Subjects > 21 Years 
ITT Population 
14.2.14.1.1 
Summary of Emergence of Additional Pathogens  
Subjects ≤ 21 Years 
ITT Population 
14.2.14.1.2 
Summary of Emergence of Additional Pathogens  
Subjects > 21 Years 
ITT Population 
14.2.14.2.1 
Summary of Emergence of Additional Pathogens by 
Baseline FEV1  
Subjects ≤ 21 Years 
ITT Population 


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Table Number 
Table Title 
Population 
14.2.14.2.2 
Summary of Emergence of Additional Pathogens by 
Baseline FEV1 
Subjects > 21 Years 
ITT Population 
14.2.14.3.1 
Summary of Emergence of Additional Pathogens by 
Prior Exacerbations Treated with Antibiotics During 
the Previous 12 Months  
Subjects ≤ 21 Years 
ITT Population 
14.2.14.3.2 
Summary of Emergence of Additional Pathogens by 
Prior Exacerbations Treated with Antibiotics During 
the Previous 12 Months 
Subjects > 21 Years 
ITT Population 
14.2.14.4.1 
Summary of Emergence of Additional Pathogens by 
P. Aeruginosa Treatment 
Subjects ≤ 21 Years 
ITT Population 
14.2.14.4.2 
Summary of Emergence of Additional Pathogens by 
P. Aeruginosa Treatment 
Subjects > 21 Years 
ITT Population 
14.3.1.1.1 
Overall Summary of Adverse Events During Period 1 
Safety 
Population 
14.3.1.1.2 
Overall Summary of Adverse Events During Period 2 
Safety 
Population 
14.3.1.2.1 
Summary of Adverse Events by System Organ Class 
and Preferred Term During Period 1 
Safety 
Population 
14.3.1.2.2 
Summary of Adverse Events by System Organ Class 
and Preferred Term During Period 2 
Safety 
Population 
14.3.1.3.1 
Summary of Adverse Events by Preferred Term 
During Period 1 
Safety 
Population 
14.3.1.3.2 
Summary of Adverse Events by Preferred Term 
During Period 2 
Safety 
Population 
14.3.1.4.1 
Summary of Adverse Event by System Organ Class, 
Preferred Term and Maximum Severity During Period 
1 
Safety 
Population 
14.3.1.4.2 
Summary of Adverse Event by System Organ Class, 
Preferred Term and Maximum Severity During Period 
2 
Safety 
Population 
14.3.1.5.1 
Summary of Adverse Event by System Organ Class, 
Preferred Term and Relationship to 
Study Drug During Period 1 
Safety 
Population 
14.3.1.5.2 
Summary of Adverse Event by System Organ Class, 
Preferred Term and Relationship to 
Study Drug During Period 2 
Safety 
Population 


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Table Number 
Table Title 
Population 
14.3.1.6.1 
Summary of Severe or Life-Threatening Adverse 
Event by System Organ Class and Preferred Term 
During Period 1 
Safety 
Population 
14.3.1.6.2 
Summary of Severe or Life-Threatening Adverse 
Event by System Organ Class and Preferred Term 
During Period 2 
Safety 
Population 
14.3.1.7.1 
Summary of Treatment-related Severe or Life-
Threatening Adverse Event by System Organ Class 
and Preferred Term During Period 1 
Safety 
Population 
14.3.1.7.2 
Summary of Treatment-related Severe or Life-
Threatening Adverse Event by System Organ Class 
and Preferred Term During Period 2 
Safety 
Population 
14.3.1.8.1 
Summary of Pulmonary Exacerbation  by Severity 
During Period 1 
Safety 
Population 
14.3.1.8.2 
Summary of Pulmonary Exacerbation  by Severity 
During Period 2 
Safety 
Population 
14.3.1.9.1 
Summary of Pulmonary Exacerbation Duration During 
Period 1 
Safety 
Population 
14.3.1.9.2 
Summary of Pulmonary Exacerbation Duration During 
Period 2 
Safety 
Population 
14.3.2.1.1 
Summary of Serious Adverse Event by System Organ 
Class and Preferred Term During Period 1 
Safety 
Population 
14.3.2.1.2 
Summary of Serious Adverse Event by System Organ 
Class and Preferred Term During Period 2 
Safety 
Population 
14.3.2.1.3 
Listing of Serious Adverse Event 
Safety 
Population 
14.3.2.2.1 
Summary of Treatment-related Serious Adverse 
Event by System Organ Class and Preferred Term 
During Period 1 
Safety 
Population 
14.3.2.2.2 
Summary of Treatment-related Serious Adverse 
Event by System Organ Class and Preferred Term 
During Period 2 
Safety 
Population 
14.3.2.3.1 
Summary of Adverse Event Leading to Study 
Discontinuation by System Organ Class 
and Preferred Term During Period 1 
Safety 
Population 
14.3.2.3.2 
Summary of Adverse Event Leading to Study 
Discontinuation by System Organ Class 
and Preferred Term During Period 2 
Safety 
Population 
14.3.2.4 
Listing of Adverse Event Leading to Death 
Safety 
Population 
14.3.4.1.1 
Summary of Actual and Change from Baseline in 
Hematology Results by Period  
Safety 
Population 


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Table Number 
Table Title 
Population 
14.3.4.1.2 
Summary of Shift from Baseline in Hematology 
Results by Period  
Safety 
Population 
14.3.4.2.1 
Summary of Actual and Change from Baseline in  
Blood Chemistry Results by Period  
Safety 
Population 
14.3.4.2.2 
Summary of Shift from Baseline in Blood Chemistry 
Results by Period  
Safety 
Population 
14.3.4.3 
Summary of Shift from Baseline in Urinalysis Results 
by Period  
Safety 
Population 
14.3.5.1 
Summary of Actual and Change from Baseline in Vital 
Signs by Period  
Safety 
Population 
14.3.6.1 
Summary of Actual and Change from Baseline in 12-
Lead ECG Results by Period  
Safety 
Population 
14.3.6.2 
Summary of Shift from Baseline in 12-Lead ECG 
Results by Period  
Safety 
Population 
14.4.1 
Summary of Vancomycin Plasma Pharmacokinetic 
Trough Levels by Age Group 
Pharmacokinetic 
Population 
14.4.2 
Summary of Vancomycin Sputum Pharmacokinetic 
Trough Levels by Age Group  
Pharmacokinetic 
Population 


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INDEX OF FIGURES 
Figure 
Number 
Figure Title 
Population 
14.2.1.1.1 
Mean (± SD) FEV1 Percent Predicted During Period 1 
by Age Group 
ITT Population 
14.2.1.1.2 
Mean (± SD) Absolute Change from Baseline in FEV1 
Percent Predicted During Period 1 by Age Group 
ITT Population 
14.2.1.2.1 
Mean (± SD) FEV1 Percent Predicted During Period 1 
by Baseline FEV1 
ITT Population 
14.2.1.2.2 
Mean (± SD) FEV1 Percent Predicted During Period 1 
by Prior Exacerbations Treated with Antibiotics 
During the Previous 12 Months 
ITT Population 
14.2.1.2.3 
Mean (± SD) FEV1 Percent Predicted During Period 1 
by P. Aeruginosa Treatment 
ITT Population 
14.2.1.2.4 
Mean (± SD) Absolute Change from Baseline in FEV1 
Percent Predicted by Baseline FEV1 
ITT Population 
14.2.1.2.5 
Mean (± SD)  Absolute Change from Baseline in FEV1 
Percent Predicted During Period 1 by Prior 
Exacerbations Treated with Antibiotics During the 
Previous 12 Months 
ITT Population 
14.2.1.2.6 
Mean (± SD)  Absolute Change from Baseline in FEV1 
Percent Predicted During Period 1 by P. Aeruginosa 
Treatment 
ITT Population 
14.2.2.1 
Kaplan Meier Curves of Time to First Pulmonary 
Exacerbation During Period 1 
ITT Population 
14.2.6.4.4 
Mean Change from Baseline in Respiratory Domain 
from the Cystic Fibrosis Questionnaire-Revised (CFQ-
R) Parent Version and Teen/Adult Version during 
Period 1 by Age Group 
ITT Population 
14.2.7.4.3 
Mean Change from Baseline in Cystic Fibrosis 
Respiratory Symptom Diary-Chronic Respiratory 
Symptom Score (CFRSD-CRISS) during Period 1 by Age 
Group 
ITT Population 
14.2.15 
Kaplan-Meier Life Table of Time to First Use of Other 
Antibiotics due to Respiratory Symptoms during 
Period 1 by Age Group 
ITT Population 
14.3.4.1.3 
Mean Change from Baseline in Hematology Results 
during Period 1 
Safety 
Population 
14.3.4.1.4 
Mean Change from Baseline in Hematology Results 
during Period 2 
Safety 
Population 


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Figure 
Number 
Figure Title 
Population 
14.3.4.2.3 
Mean Change from Baseline in Chemistry Results 
during Period 1 
Safety 
Population 
14.3.4.2.4 
Mean Change from Baseline in Chemistry Results 
during Period 2 
Safety 
Population 
14.3.5.2 
Mean Change from Baseline in Vital Signs during 
Period 1 
Safety 
Population 
14.3.5.3 
Mean Change from Baseline in Vital Signs during 
Period 2 
Safety 
Population 
 


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INDEX OF LISTINGS 
Listing 
Number 
Listing Title 
Population 
16.2.1 
Subject Disposition 
All Enrolled Subjects 
16.2.2 
Protocol Deviations 
All Randomized 
Subjects 
16.2.3.1 
Analysis Populations 
All Randomized 
Subjects 
16.2.3.2 
Inclusion and Exclusion Criteria Violations 
All Randomized 
Subjects 
16.2.3.3 
Screen Failures 
All Screen Failure 
Subjects 
16.2.4.1 
Demography 
Safety Population 
16.2.4.2 
Baseline Characteristics 
Safety Population 
14.2.4.3 
Medical History 
Safety Population 
16.2.4.4 
Prior and Concomitant Medications 
Safety Population 
16.2.5.1 
Study Drug Exposure and Treatment 
Compliance 
Safety Population 
16.2.5.2 
Vancomycin Plasma Concentration 
Pharmacokinetic 
Population 
16.2.5.3 
Vancomycin Sputum Concentrations 
Pharmacokinetic 
Population 
14.2.6.1 
Pulmonary Function Tests 
Safety Population 
16.2.6.2 
Pulmonary Exacerbations 
Safety Population 
16.2.6.3 
Non-maintenance Antibiotic Therapy due to 
Pulmonary Infection 
Safety Population 
16.2.6.4.1 
Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Item Scores 
Safety Population 
16.2.6.4.2 
Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Item Scores 
Safety Population 
16.2.6.4.3 
Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
Domain Scores 
Safety Population 
16.2.6.5 
Chronic Respiratory Symptom Score (CFRSD-
CRISS)  
Safety Population 
16.2.6.6 
EQ-5D/EQ-5D-5L 
Safety Population 
16.2.6.7 
MRSA Swab and Sputum Density and Minimum 
Inhibitory Concentration (MIC) for 
Vancomycin 
Safety Population 
16.2.6.8 
Additional Pathogens 
Safety Population 
16.2.7.1 
Adverse Events 
Safety Population 
16.2.7.2 
Treatment-related Adverse Events  
Safety Population 


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Listing 
Number 
Listing Title 
Population 
16.2.7.3 
Adverse Events Leading to Study 
Discontinuation 
Safety Population 
16.2.8.1 
Hematology Results 
Safety Population 
16.2.8.2 
Blood Chemistry Results 
Safety Population 
16.2.8.3 
Urinalysis Results 
Safety Population 
16.2.8.4 
Serum Pregnancy Results 
Safety Population 
16.2.9 
Vital Sign Results 
Safety Population 
16.2.10 
12-Lead Electrocardiogram (ECG) Results 
Safety Population 
16.2.11 
Physical Exam Findings 
Safety Population 
16.2.12 
Vancomycin Plasma Pharmacokinetic Trough 
Levels 
Pharmacokinetic 
Population 
 
 


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APPENDICES 
 
 


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APPENDIX A: CYSTIC FIBROSIS QUESTIONNAIRE-REVISED (CFQ-R) SCORING ALGORITHM 
  AND SAS® CODE 
General Scoring Instructions 
For ease of interpretation, the questions on the CFQ-R are labeled according to the 
number on the questionnaire and the domain they are designed to measure. The domain 
label precedes the question number. For example the first question on the 
questionnaire is designed to measure a physical symptom and its label is “Phys1.” The 
complete labeling for each version of the CFQ-R is presented under the section entitled 
“Question Labels”.  
The following scoring codes were written to be used with CFQ-R data that was entered 
into a database/spreadsheet where each question is a unique variable. The variable 
names should match the question labels listed in the “Question Labels” section.  Values 
for each question range from 1 to 4. For questions with responses listed horizontally 
(left to right) the left response category should be assigned a value of 1, the second 
category should be assigned a 2, the third a 3, and the rightmost category should be 
assigned a 4.  
Here is an example. 
1. Performing vigorous activities such as running or playing sports……    . 1    2    3    4 
For questions that are listed vertically (top to bottom), the top category should be 
assigned a value of 1, the next a 2, the third a 3, and the bottom category a 4. 
Here is an example. 
13. To what extent do you have difficulty walking? Scoring Values 
 
1.  You can walk a long time without getting tired  
(1) 
 
2.  You can walk a long time but you get tired 
 
(2) 
 
3.  You cannot walk a long time because you get tired quickly 
 
(3) 
 
4.  You avoid walking whenever possible because it’s too tiring for you 
 
(4) 
 
It is important that you assign the values according to these rules for each question. 
Some of the questions will be phrased in a positive direction (like Question 13 listed 
above) and the values may seem inappropriate. The scoring codes reverse the ordering 
for these positively phrased questions. Do not reverse the coding when you are entering 
the scores into your database/spreadsheet. We have found it to be more accurate to let 
the scoring procedures address the reverse coding.   


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Please note that question 43 (resp43) on the Teen/Adult version and question 37 
(resp37) on the Parent version have one extra category (don’t know) we typically assign 
a value of 5 to that category. This question is not included in the scoring of the 
respiratory scale.  
Question Labels 
CFQ-R Teen/Adult Version  CFQ-R Parent Version 
CFQ-R Child Version 
Question 1 = phys1 
Question 2 = phys2 
Question 3 = phys3 
Question 4 = phys4 
Question 5 = phys5 
Question 6 = vital6 
Question 7 = emot7 
Question 8 = emot8 
Question 9 = vital9 
Question 10 = vital10 
Question 11 = vital11 
Question 12 = emot12 
Question 13 = phys13 
Question 14 = eat14 
Question 15 = treat15 
Question 16 = treat16 
Question 17 = treat17 
Question 18 = health18 
Question 19 = phys19 
Question 20 = phys20 
Question 21 = eat21 
Question 22 = social22 
Question 23 = social23 
Question 24 = body24 
Question 25 = body25 
Question 26 = body26 
Question 27 = social27 
Question 28 = social28 
Question 29 = social29 
Question 30 = social30 
Question 31 = emot31 
Question 32 = health32 
Question 33 = emot33 
Question 1 = phys1 
Question 2 = phys2 
Question 3 = phys3 
Question 4 = phys4 
Question 5 = phys5 
Question 6 = emot6 
Question 7 = emot7 
Question 8 = vital8 
Question 9 = vital9 
Question 10 = vital10 
Question 11 = vital11 
Question 12 = vital12 
Question 13 = school13 
Question 14 = phys14 
Question 15 = phys15 
Question 16 = phys16 
Question 17 = eat17 
Question 18 = treat18 
Question 19 = body19 
Question 20 = body20 
Question 21 = body21 
Question 22 = health22 
Question 23 = emot23 
Question 24 = health24 
Question 25 = emot25 
Question 26 = emot26 
Question 27 = school27 
Question 28 = school28 
Question 29 = school29 
Question 30 = treat30 
Question 31 = treat31 
Question 32 = health32 
Question 33 = weight33 
Question 1 = phys1 
Question 2 = phys2 
Question 3 = phys3 
Question 4 = phys4 
Question 5 = phys5 
Question 6 = phys6 
Question 7 = emot7 
Question 8 = emot8 
Question 9 = emot9 
Question 10 = emot10 
Question 11 = emot11 
Question 12 = emot12 
Question 13 = emot13 
Question 14 = emot14 
Question 15 = eat15 
Question 16 = treat16 
Question 17 = eat17 
Question 18 = treat18 
Question 19 = eat19 
Question 20 = social20 
Question 21 = social21 
Question 22 = social22 
Question 23 = social23 
Question 24 = social24 
Question 25 = social25 
Question 26 = social26 
Question 27 = body27 
Question 28 = body28 
Question 29 = body29 
Question 30 = treat30 
Question 31 = resp31 
Question 32 = resp32 
Question 33 = resp33 


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CFQ-R Teen/Adult Version  CFQ-R Parent Version 
CFQ-R Child Version 
Question 34 = health34 
Question 35 = role35 
Question 36 = role36 
Question 37 = role37 
Question 38 = role38 
Question 39 = weight39 
Question 40 = resp40 
Question 41 = resp41 
Question 42 = resp42 
Question 43 = resp43 
Question 44 = resp44 
Question 45 = resp45 
Question 46 = resp46 
Question 47 = digest47 
Question 48 = digest48 
Question 49 = digest49 
Question 50 = eat50 
Question 34 = resp34 
Question 35 = resp35 
Question 36 = resp36 
Question 37 = resp37 
Question 38 = resp38 
Question 39 = resp39 
Question 40 = resp40 
Question 41 = digest41 
Question 42 = digest42 
Question 43 = digest43 
Question 44 = eat44  
Question 34 = resp34 
Question 35 = digest35 
  
 
 


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SAS Program Codes for Scoring the CFQ-R Teen/Adult Version 
/*This scoring program requires that the data be imported into a SAS table titled 
"CFQR_TA" and that the variable names in the table match those listed below.*/ 
Data CFQR_TA; set CFQR_TA; 
/* Recoding Some Variables */ 
vital6  
= 
5-vital6; 
vital10  
= 
5-vital10; 
phys13  
= 
5-phys13; 
treat15 
= 
5-treat15; 
treat17 
= 
5-treat17; 
health18 
= 
5-health18; 
social23 
= 
5-social23; 
social28 
= 
5-social28; 
social30 
= 
5-social30; 
health32 
= 
5-health32; 
health34 
= 
5-health34; 
role35  
= 
5-role35; 
resp43  
= 
5-resp43;      
 
/* Calculating Scores */ 
if nmiss (phys1, phys2, phys3, phys4, phys5, phys13, phys19, phys20) ≤ 4 then 
physical = (mean (phys1, phys2, phys3, phys4, phys5, phys13, phys19, phys20)-1)/3*100; 
 
if nmiss (role35, role36, role37, role38) ≤ 2 then 
role = (mean (role35, role36, role37, role38)-1)/3*100; 
 
if nmiss (vital6, vital9, vital10, vital11) ≤ 2 then 
vitality = (mean (vital6, vital9, vital10, vital11)-1)/3*100; 
 
if nmiss (emot7, emot8, emot12, emot31, emot33) ≤ 2 then 
emotion = (mean (emot7, emot8, emot12, emot31, emot33)-1)/3*100; 
 
if nmiss (social22, social23, social27, social28, social29, social30) ≤ 3 then 
social = (mean (social22, social23, social27, social28, social29, social30)-1)/3*100; 
 
if nmiss (body24, body25, body26) ≤ 1 then 
body = (mean (body24, body25, body26)-1)/3*100; 
 


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if nmiss (eat14, eat21, eat50) ≤ 1 then 
eat = (mean (eat14, eat21, eat50)-1)/3*100; 
 
if nmiss (treat15, treat16, treat17) ≤ 1 then 
treat = (mean (treat15, treat16, treat17)-1)/3*100; 
 
if nmiss (health18, health32, health34) ≤ 1 then 
health = (mean (health18, health32, health34)-1)/3*100; 
 
if nmiss (weight39) = 0 then 
weight= (mean (weight39)-1)/3*100; 
 
if nmiss (resp40, resp41, resp42, resp44, resp45, resp46) ≤ 3 then 
respirat = (mean (resp40, resp41, resp42, resp44, resp45, resp46)-1)/3*100; 
 
if nmiss (digest47, digest48, digest49) ≤ 1 then 
digest = (mean (digest47, digest48, digest49)-1)/3*100; 
run; 
 
SAS Program Codes for Scoring the CFQ-R Parent Version 
/*This scoring program requires that the data be imported into a SAS table titled 
"CFQR_P" and that the variable names in the table match those listed below.*/ 
Data CFQR_P; set CFQR_P; 
/* Recoding Some Variables */ 
emot6 = 
5- emot6; 
vital10  
= 
5-vital10; 
vital12  
= 
5- vital12 
phys15  
= 
5-phys15; 
treat31 
= 
5-treat31; 
health22 
= 
5-health22; 
health24 
= 
5-health24; 
health32 
= 
5-health32; 
school28 
= 
5-school28; 
resp37 = 
5- resp37; 
 
/* Calculating Scores */ 
 
if nmiss (phys1, phys2, phys3, phys4, phys5, phys14, phys15, phys16) ≤ 4 then 


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physical = (mean (phys1, phys2, phys3, phys4, phys5, phys14, phys15, phys16)-1)/3*100; 
 
if nmiss (emot6, emot7, emot23, emot25, emot26) ≤ 2 then 
emotion = (mean (emot6, emot7, emot23, emot25, emot26)-1)/3*100; 
 
if nmiss (vital8, vital9, vital10, vital11, vital12) ≤ 2 then 
vitality = (mean (vital8, vital9, vital10, vital11, vital12)-1)/3*100; 
 
if nmiss (school13, school27, school28, school29) ≤ 2 then 
school = (mean (school13, school27, school28, school29)-1)/3*100; 
 
if nmiss (eat17, eat44) = 0 then 
eat = (mean(eat17, eat44)-1)/3*100; 
 
if nmiss (body19, body20, body21) ≤ 1 then 
body = (mean(body19, body20, body21)-1)/3*100; 
 
if nmiss (treat18, treat30, treat31) ≤ 1 then 
treat = (mean (treat18, treat30, treat31)-1)/3*100; 
 
if nmiss (health22, health24, health32) ≤ 1 then 
health = (mean (health22, health24, health32)-1)/3*100; 
 
if nmiss (resp34, resp35, resp36, resp38, resp39, resp40) ≤ 3 then 
respirat = (mean (resp34, resp35, resp36, resp38, resp39, resp40)-1)/3*100; 
 
if nmiss (digest41, digest42, digest43) ≤ 1 then 
digest = (mean (digest41, digest42, digest43)-1)/3*100; 
 
if nmiss (weight33) = 0 then 
weight = (mean (weight33)-1)/3*100; 
 
run; 
 
SAS Program Codes for Scoring the CFQ-R Child Version 
/*This scoring program requires that the data be imported into a SAS table titled 
"CFQR_Ch" and that the variable names in the table match those listed below.*/ 
Data CFQR_Ch; set CFQR_Ch; 
/* Recoding Some Variables */ 


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phys1  
= 
5-phys1; 
phys2  
= 
5-phys2; 
phys3  
= 
5-phys3; 
phys4  
= 
5-phys4; 
phys5  
= 
5-phys5; 
emot14 
= 
5-emot14; 
treat18 
= 
5-treat18; 
eat19  
= 
5-eat19; 
social20 
= 
5- social20; 
social22 
= 
5- social22; 
social24 
= 
5- social24; 
social26 
= 
5- social26; 
 
/* Calculating Scores */ 
 
if nmiss (phys1, phys2, phys3, phys4, phys5, phys6) ≤ 3 then 
physical = (mean (phys1, phys2, phys3, phys4, phys5, phys6)-1)/3*100; 
 
if nmiss (emot7, emot8, emot9, emot10, emot11, emot12, emot13, emot14) ≤ 4 then 
emotion = (mean (emot7, emot8, emot9, emot10, emot11, emot12, emot13, emot14)-
1)/3*100; 
 
if nmiss (social20, social21, social22, social23, social24, social25, social26) ≤ 3 then 
social = (mean (social20, social21, social22, social23, social24, social25, social26)-
1)/3*100; 
 
if nmiss (eat15, eat17, eat19) ≤ 1 then 
eat = (mean(eat15, eat17, eat19)-1)/3*100; 
 
if nmiss (body27, body28, body29) ≤ 1 then 
body = (mean(body27, body28, body29)-1)/3*100; 
 
if nmiss (treat16, treat18, treat30) ≤ 1 then 
treat = (mean (treat16, treat18, treat30)-1)/3*100; 
 
if nmiss (resp31, resp32, resp33, resp34) ≤ 2 then 
respirat = (mean (resp31, resp32, resp33, resp34)-1)/3*100; 
 
if nmiss (digest35) = 0 then 
digest = (mean (digest35)-1)/3*100; 
 
run; 
 
 


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APPENDIX B: UPDATED PRIMARY AND SECONDARY EFFICACY ANALYSIS TO ACCOUNT 
   FOR MISSING DATA DUE TO THE COVID-19 PANDEMIC 
The efficacy analyses described in Section 8 above are those planned before the 
occurrence of the COVID-19 pandemic in early 2020.  Consequent to the outbreak of 
COVID-19, recruitment to the trial has been stopped prematurely and some changes to 
rules for handling missed visits (and resulting missing data) have been introduced.  For 
clarity, all changes resulting from COVID-19 issues are described here.  For avoidance of 
doubt, the primary and affected analyses will be based on the new rules for handling 
missing data (as described below), and not necessarily as described in the original SAP 
text (Section 8) or in the protocol. 
Figures and listings will present actual results. No imputed data will be used. Thus no 
changes to the figures or listings will be made as part of Appendix B. 
A subject who has a visit skipped or performed via telemedicine, a protocol deviation 
will be recorded as either “Week X <<insert applicable week #>> performed via 
telemedicine due to COVID-19 pandemic.” or “Week X <<insert applicable week #>> 
missed due to COVID-19 pandemic.” respectively. When such a protocol deviation is 
reported, the missing data for that visit will be considered missing due to COVID-19. 
Otherwise it will be treated as normally missing data. 
B.1 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
B.1.1 
Primary Analysis of the Primary Efficacy Endpoint  
The primary efficacy endpoint is the absolute change from baseline in FEV1 percent 
predicted. The primary analysis will be based on the ITT population of ≤ 21 years of age 
using all observed data, with a PFT scoring grade of A, B, C, or D, at Weeks 4, 12, and 
20. 
For any subjects who have one or more missing FEV1 result(s) (whether that be because 
they withdrew early from the trial, or for any other reason not relating to the COVID-19 
pandemic), their missing FEV1 will be imputed using the least favorable group visit 
median change from baseline.  This imputation can occur for more than one visit (if 
necessary); in such cases, the “least favorable group” will be determined on a visit-by-
visit basis (i.e. the “least favorable” group could be different at weeks 4, 12 and 20). 
For any subject who has one or more missing FEV1 result(s) due to the COVID-19 
pandemic, data will be left missing in the ADaM dataset. After the COVID-19 unrelated 
missing data is imputed as specified above, multiple imputation will be applied using 
Markov Chain Monte Carlo methods, assuming these data to be missing at random. A 
total of 500 datasets will be created. Each dataset will be analyzed using the MMRM 
model listed below with the results used to determine the final results. 


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For each imputed dataset, absolute change from baseline in FEV1 percent predicted will 
be analyzed using same MMRM model as described in Section 8.1.1 above. The results of 
each dataset will then be combined into a single result using PROC MIANALYZE. 
The absolute change from baseline in FEV1 percent predicted will be tested sequentially 
at Week 4 (end of Cycle 1), Week 12 (end of Cycle 2), and at Week 20 (end of Cycle 3). 
If a statistically significant difference is observed in favor of AeroVanc compared to 
placebo after Cycle 1, then the mean change in the FEV1 percent predicted during Cycle 
2 will be tested. Similarly, if the effect after Cycle 2 is statistically significant, then the 
analysis of Baseline to end of Cycle 3 will be tested. 
As a supportive analysis three Analysis of Covariance (ANCOVA) models (one at each of 
weeks 4, 12 and 20) with the absolute change from baseline in FEV1 percent predicted 
for a given visit as the dependent variable will be performed. Treatment, Baseline FEV1 
percent predicted, age, Baseline FEV1 (≥60%; <60%), prior exacerbations treated with 
antibiotics during the previous 12 months (1-2; ≥ 3) and P. aeruginosa treatment (not 
treated; treated) will be used as independent variables. If an ANCOVA model fails to run 
properly, the variable Baseline FEV1 percent predicted will be dropped.  The same 
missing value multiple imputation strategies as for the primary analysis (i.e. missing for 
COVID-19 related or non-related reasons) will be used to allow clearer comparisons 
between analysis strategies. 
All analyses will be performed for Period 1 only.  
Summarization and listing of the change from baseline in FEV1 percent predicted will be 
provided as detailed in Section 8.1.1 above. 
B.1.1.1 
Sensitivity Analysis of the Primary Efficacy Endpoint  
For confirmation of the primary endpoint, sensitivity analyses will be performed where 
COVID-19 unrelated missing data will be imputed using worst reasonable case analysis, 
best reasonable case analysis, and tipping point analysis as described in Section 6.3. 
COVID-19 related missing data will be imputed using the same multiple imputation 
method describe in B.1.1 above. 
An additional sensitivity analysis will be performed using the Per-Protocol Population in 
place of the ITT and including results with a PFT scoring grade of A or B. 
Given the FDA approval of Trikafta, sensitivity analyses will be performed by Trikafta 
use during the study. 
Sensitivity analyses will be performed to assess the effect of actual stratification as 
based on eCRF data instead of strata reported at time of randomization. These analyses 
will be repeated for all primary supportive analyses. 


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All sensitivity analyses will be performed using the same analysis methodology and, 
unless otherwise specified, the same imputations methods as the primary analysis (B.1.1 
above). 
B.2 
SECONDARY EFFICACY ENDPOINT(S) AND ANALYSES 
B.2.1 
Frequency of pulmonary exacerbations 
Pulmonary exacerbations can be determined by the clinician during a telemedicine 
contact. Therefore, missing data cannot be strictly associated with COVID-19. Analysis 
of the frequency of pulmonary exacerbations will be performed as described in Section 
8.2.1 above. 
B.2.2 
Time to first pulmonary exacerbation 
Pulmonary exacerbations can be determined by the clinician during a telemedicine 
contact. Therefore, missing data cannot be strictly associated with COVID-19. Analysis 
of time to first pulmonary exacerbation will be performed as described in Section 8.2.2 
above. 
B.2.3 
Number of successful response cycles a subject achieves over Period 1 
Analysis of number of successful cycles a subject achieves across Period 1 will be 
performed as described in Section 8.2.6 above. 
B.2.4 
Relative change from Baseline in FEV1 percent predicted at Weeks 4, 12, 
and 20 
Relative change from Baseline in FEV1 percent predicted is defined as (Visit FEV1 
percent predicted – Baseline FEV1 percent predicted)/Baseline FEV1 percent predicted. 
Relative change from Baseline in FEV1 percent predicted will be analyzed using the 
same methods as the primary efficacy analysis, including the same rules for missing 
values (See B.1.1 above). Summary tables will also be provided by age group and other 
stratification factors (Baseline FEV1 (≥60%; <60%), prior exacerbations treated with 
antibiotics during the previous 12 months (1-2; ≥ 3), P. aeruginosa treatment (not 
treated; treated)). 
Secondary analysis will be performed using subjects ≤21 years old. Subjects >21 years 
old, subjects using Trikafta, and subjects not using Trikafta will be analyzed separately 
as supportive analyses. An additional supportive analysis using eCRF-identified strata in 
place of strata identified at randomization will also be provided. 
A sensitivity analysis of relative change from Baseline in FEV1 percent predicted will 
also be performed as originally planned (Section 8.2.4 above).  


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A separate by-subject listing will also be provided. 
B.2.5 
Change from Baseline in the Cystic Fibrosis Questionnaire-Revised 
(CFQ-R) scores at Weeks 4, 12, and 20 
The CFQ-R is able to be collected by a handheld device. The CFQ-R data is 
electronically captured and an office visit is not required for the questionnaire to be 
completed. Therefore, missing data cannot be strictly associated with COVID-19. 
Analysis of the change from baseline in CFQ-R will be performed as described in Section 
8.2.3 above. 
B.2.6 
Chronic Respiratory Symptom Score (CFRSD-CRISS) scores at Weeks 4, 12, 
and 20 
The CFRSD-CRISS is able to be collected by a handheld device. The CFQ-R data is 
electronically captured and an office visit is not required for the questionnaire to be 
completed. Therefore, missing data cannot be strictly associated with COVID-19. 
Analysis of the CFRSD-CRISS will be performed as described in Section 8.2.4 above. 
B.2.7 
Area under the FEV1–time profile 
Area under the FEV1–time profile will be calculated for each subject over the course of 
each period. The area will be the sum of each FEV1 multiplied by the duration of 
representative time period. The beginning of each time period will be either the 
beginning of the period or the midpoint between the time of the FEV1 measurement and 
the previous FEV1 measurement. The end of each time period will be either the end of 
the period or the midpoint between the time of the FEV1 measurement and the 
following FEV1 measurement. Duration will be calculated as (end of time period – start 
of time period) as measured in days. 
Area under the FEV1–time profile will be analyzed using a Generalized Linear Model with 
the Area under the FEV1–time profile for a given period as the dependent variable, and 
using the same rules and methods for missing values as for the primary variable (Section 
B.1.1 above). Treatment, Baseline FEV1 percent predicted, age, Baseline FEV1 (≥60%; 
<60%), prior exacerbations treated with antibiotics during the previous 12 months (1-2; 
≥ 3), and P. aeruginosa treatment (not treated; treated) will be the independent 
variables. If the model fails to run properly, age will be dropped, then Baseline FEV1 
percent predicted will be dropped if necessary.  
Summary tables will also be provided by period and age group, and by other 
stratification factors (Baseline FEV1 (≥60%; <60%), prior exacerbations treated with 
antibiotics during the previous 12 months (1-2; ≥ 3), P. aeruginosa treatment (not 
treated; treated)).  


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Secondary analysis will be performed using subjects ≤21 years old. Subjects >21 years 
old, subjects using Trikafta, and subjects not using Trikafta will be analyzed separately 
as supportive analyses. An additional supportive analysis using eCRF-identified strata in 
place of strata identified at randomization will also be provided. 
B.2.8 
Exploratory and Other Efficacy Analyses 
No changes to any exploratory or other efficacy analyses will be made. All summaries 
and analyses will be provided based on available data, as described in Sections 8.3 and 
8.4 above.  
B.3 
PRIMARY AND SECONDARY EFFICACY TABLES 
Tables 14.1.x, 14.3.x, 14.4.x, and exploratory and other efficacy tables are unaffected 
by the COVID-19 pandemic. These tables will be provided as stated in Section 16 above. 
Similarly, figures and listings present actual results without any imputations. Figures 
and listings will remain unchanged. 
 
Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.1.1.1 
Analysis of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 
Subjects ≤ 21 Years 
ITT 
Population 
Updated 
Analysis 
14.2.1.1.1.1 Analysis of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 using Strata as 
Reported in Database 
Subjects ≤ 21 Years 
ITT 
Population 
Updated 
Analysis 
14.2.1.1.1.2 Analysis of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20  
Original Planned Analysis  
Subjects ≤ 21 Years 
ITT 
Population 
New 
(Original 
14.2.1.1.1) 
14.2.1.1.2 
Analysis of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 
Subjects > 21 Years 
ITT 
Population 
Updated 
Analysis 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.1.1.3 
Analysis of Imputed Mean Absolute Change 
from Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 
Worst Reasonable Case Analysis 
Subjects ≤ 21 Years 
ITT 
Population 
Updated 
Analysis 
14.2.1.1.3.1 Analysis of Imputed Mean Absolute Change 
from Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 
Worst Reasonable Case Analysis using Strata 
as Reported in Database 
Subjects ≤ 21 Years 
ITT 
Population 
Updated 
Analysis 
14.2.1.1.4 
Analysis of Imputed Mean Absolute Change 
from Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 
Best Reasonable Case Analysis 
Subjects ≤ 21 Years  
ITT 
Population 
Updated 
Analysis 
14.2.1.1.4.1 Analysis of Imputed Mean Absolute Change 
from Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 
Best Reasonable Case Analysis using Strata 
as Reported in Database 
Subjects ≤ 21 Years  
ITT 
Population 
Updated 
Analysis 
14.2.1.1.5 
Analysis of Imputed Mean Absolute Change 
from Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 
Tipping Point Analysis 
Subjects ≤ 21 Years 
ITT 
Population 
Updated 
Analysis 
14.2.1.1.5.1 Analysis of Imputed Mean Absolute Change 
from Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 
Tipping Point Analysis using Strata as 
Reported in Database 
Subjects ≤ 21 Years 
ITT 
Population 
Updated 
Analysis 
14.2.1.1.6 
Analysis of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted Weeks 4, 
12, and 20 
Subjects ≤ 21 Years 
Per-
Protocol 
Population  
Updated 
Analysis 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.1.1.6.1 Analysis of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted Weeks 
4, 12, and 20 using Strata as Reported in 
Database 
Subjects ≤ 21 Years 
Per-
Protocol 
Population  
Updated 
Analysis 
14.2.1.1.7 
Analysis of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20  
Subjects ≤ 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
Updated 
Analysis 
14.2.1.1.8 
Analysis of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20  
Subjects > 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
Updated 
Analysis 
14.2.1.1.9 
Analysis of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 by i.v. Vancomycin use 
during Period 1  
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.1.1.10 
Analysis of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 by i.v. Vancomycin use 
during Period 1  
Subjects > 21 Years 
ITT 
Population 
 
14.2.1.2.1 
Summary of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 by Baseline FEV1 
Subjects ≤ 21 Years 
ITT 
Population 
  
14.2.1.2.2 
Summary of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 by Baseline FEV1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.1.3.1 
Summary of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 by Prior Exacerbations 
Treated with Antibiotics During the 
Previous 12 Months 
Subjects ≤ 21 Years 
ITT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.1.3.2 
Summary of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 by Prior Exacerbations 
Treated with Antibiotics During the 
Previous 12 Months 
Subjects > 21 Years 
ITT 
Population 
 
14.2.1.4.1 
Summary of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 by P. Aeruginosa 
Treatment 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.1.4.2 
Summary of Mean Absolute Change from 
Baseline in FEV1 Percent Predicted at 
Weeks 4, 12, and 20 by P. Aeruginosa 
Treatment 
Subjects > 21 Years 
ITT 
Population 
 
14.2.2.1.1 
Analysis of Frequency of Pulmonary 
Exacerbation During Period 1 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.2.1.1.1 Analysis of Frequency of Pulmonary 
Exacerbation During Period 1 using Strata as 
Reported in Database 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.2.1.2 
Analysis of Frequency of Pulmonary 
Exacerbation During Period 1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.2.1.3 
Analysis of Frequency of Pulmonary 
Exacerbation During Period 1 
Subjects ≤ 21 Years 
Per-
Protocol 
Population 
 
14.2.2.1.4 
Analysis of Frequency of Pulmonary 
Exacerbation During Period 1  
Subjects ≤ 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 
14.2.2.1.5 
Analysis of Frequency of Pulmonary 
Exacerbation During Period 1  
Subjects > 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.2.1.6 
Analysis of Frequency of Pulmonary 
Exacerbation During Period 1 by i.v. 
Vancomycin use during Period 1 
Subjects <= 21 Years 
ITT 
Population 
 
14.2.2.1.7 
Analysis of Frequency of Pulmonary 
Exacerbation During Period 1 by i.v. 
Vancomycin use during Period 1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.2.2.1 
Summary of Frequency of Pulmonary 
Exacerbation by Period  
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.2.2.2 
Summary of Frequency of Pulmonary 
Exacerbation by Period  
Subjects > 21 Years  
ITT 
Population 
 
14.2.2.3.1 
Summary of Frequency of Pulmonary 
Exacerbation by Period and Trikafta use at 
Baseline or During Period 1 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.2.3.2 
Summary of Frequency of Pulmonary 
Exacerbation by Period and Trikafta use at 
Baseline or During Period 1 
Subjects > 21 Years  
ITT 
Population 
 
14.2.2.4.1 
Summary of Frequency of Pulmonary 
Exacerbation by Period and Baseline FEV1 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.2.4.2 
Summary of Frequency of Pulmonary 
Exacerbation by Period and Baseline FEV1 
Subjects > 21 Years  
ITT 
Population 
 
14.2.2.5.1 
Summary of Frequency of Pulmonary 
Exacerbation by Period and Prior 
Exacerbations Treated with Antibiotics 
During the Previous 12 Months 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.2.5.2 
Summary of Frequency of Pulmonary 
Exacerbation by Period and Prior 
Exacerbations Treated with Antibiotics 
During the Previous 12 Months  
Subjects > 21 Years  
ITT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.2.6.1 
Summary of Frequency of Pulmonary 
Exacerbation by Period and P. Aeruginosa 
Treatment 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.2.6.2 
Summary of Frequency of Pulmonary 
Exacerbation by Period and P. Aeruginosa 
Treatment 
Subjects > 21 Years  
ITT 
Population 
 
14.2.3.1.1 
Analysis of Time to First Pulmonary 
Exacerbation During Period 1 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.3.1.1.1 Analysis of Time to First Pulmonary 
Exacerbation During Period 1 using Strata as 
Reported in Database 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.3.1.2 
Analysis of Time to First Pulmonary 
Exacerbation During Period 1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.3.1.3 
Analysis of Time to First Pulmonary 
Exacerbation During Period 1 
Subjects ≤ 21 Years 
Per-
Protocol 
Population 
 
14.2.3.1.4 
Analysis of Time to First Pulmonary 
Exacerbation During Period 1  
Subjects ≤ 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 
14.2.3.1.5 
Analysis of Time to First Pulmonary 
Exacerbation During Period 1 
Subjects > 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 
14.2.3.1.6 
Analysis of Time to First Pulmonary 
Exacerbation During Period 1 by i.v. 
Vancomycin use during Period 1 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.3.1.7 
Analysis of Time to First Pulmonary 
Exacerbation During Period 1 by i.v. 
Vancomycin use during Period 1 
Subjects > 21 Years  
ITT 
Population 
 
14.2.3.1.8 
Kaplan-Meier Life Table for Time to First 
Pulmonary Exacerbation During Period 1 
Subjects ≤ 21 Years 
ITT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.3.1.9 
Kaplan-Meier Life Table for Time to First 
Pulmonary Exacerbation During Period 1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.3.2.1 
Summary of Time to First Pulmonary 
Exacerbation During Period 1 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.3.2.2 
Summary of Time to First Pulmonary 
Exacerbation During Period 1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.3.3.1 
Summary of Time to First Pulmonary 
Exacerbation During Period 1 by Trikafta 
use at Baseline or During Period 1 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.3.3.2 
Summary of Time to First Pulmonary 
Exacerbation During Period 1 by Trikafta 
use at Baseline or During Period 1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.3.4.1 
Summary of Time to First Pulmonary 
Exacerbation During Period 1 by Baseline 
FEV1 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.3.4.2 
Summary of Time to First Pulmonary 
Exacerbation During Period 1 by Baseline 
FEV1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.3.5.1 
Summary of Time to First Pulmonary 
Exacerbation During Period 1 by Prior 
Exacerbations Treated with Antibiotics 
During the Previous 12 Months 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.3.5.2 
Summary of Time to First Pulmonary 
Exacerbation During Period 1 by Prior 
Exacerbations Treated with Antibiotics 
During the Previous 12 Months 
Subjects > 21 Years 
ITT 
Population 
 
14.2.3.6.1 
Summary of Time to First Pulmonary 
Exacerbation During Period 1 by P. 
Aeruginosa Treatment 
Subjects ≤ 21 Years 
ITT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.3.6.2 
Summary of Time to First Pulmonary 
Exacerbation During Period 1 by P. 
Aeruginosa Treatment 
Subjects > 21 Years 
ITT 
Population 
 
14.2.4.1.1 
Analysis of  Number of Successful Response 
Cycles During Period 1 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.4.1.1.1 Analysis of  Number of Successful Response 
Cycles During Period 1 using Strata as 
Reported in Database 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.4.1.1.2 Analysis of  Number of Successful Response 
Cycles During Period 1 
Original Planned Analysis 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.4.1.2 
Analysis of Number of Successful Response 
Cycles During Period 1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.4.1.3 
Analysis of Number of Successful Response 
Cycles During Period 1 
Subjects ≤ 21 Years 
Per-
Protocol 
Population 
 
14.2.4.1.4 
Analysis of  Number of Successful Response 
Cycles During Period 1  
Subjects ≤ 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 
14.2.4.1.5 
Analysis of Number of Successful Response 
Cycles During Period 1  
Subjects > 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 
14.2.4.2.1 
Summary of Number of Successful Response 
Cycles During Period 1 by Baseline FEV1 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.4.1.6 
Analysis of  Number of Successful Response 
Cycles During Period 1 by i.v. Vancomycin 
use during Period 1 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.4.1.7 
Analysis of  Number of Successful Response 
Cycles During Period 1 by i.v. Vancomycin 
use during Period 1 
Subjects > 21 Years 
ITT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.4.2.2 
Summary of Number of Successful Response 
Cycles During Period 1 by Baseline FEV1 
Subjects > 21 Years  
ITT 
Population 
 
14.2.4.3.1 
Summary of Number of Successful Response 
Cycles During Period 1 by Prior 
Exacerbations Treated with Antibiotics 
During the Previous 12 Months 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.4.3.2 
Summary of Number of Successful Response 
Cycles During Period 1 by Prior 
Exacerbations Treated with Antibiotics 
During the Previous 12 Months  
Subjects > 21 Years 
ITT 
Population 
 
14.2.4.4.1 
Summary of Number of Successful Response 
Cycles During Period 1 by P. Aeruginosa 
Treatment 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.4.4.2 
Summary of Number of Successful Response 
Cycles During Period 1 by P. Aeruginosa 
Treatment 
Subjects > 21 Years 
ITT 
Population 
 
14.2.5.1.1 
Analysis of Relative Change from Baseline in 
FEV1 Percent Predicted at Week 4, 12, and 
Week 20 
Subjects ≤ 21 Years 
ITT 
Population 
Updated 
Analysis 
14.2.5.1.1.1 Analysis of Relative Change from Baseline in 
FEV1 Percent Predicted at Week 4, 12, and 
Week 20 using Strata as Reported in 
Database 
Subjects ≤ 21 Years 
ITT 
Population 
Updated 
Analysis 
14.2.5.1.1.2 Analysis of Relative Change from Baseline in 
FEV1 Percent Predicted at Week 4, 12, and 
Week 20 
Original Planned Analysis 
Subjects ≤ 21 Years 
ITT 
Population 
New 
(Original 
14.2.5.1.1) 
14.2.5.1.2 
Analysis of Relative Change from Baseline in 
FEV1 Percent Predicted at Week 4, 12, and 
Week 20 
Subjects > 21 Years 
ITT 
Population 
Updated 
Analysis 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.5.1.3 
Analysis of Relative Change from Baseline in 
FEV1 Percent Predicted at Week 4, 12, and 
Week 20 
Subjects ≤ 21 Years 
Per-
Protocol 
Population 
Updated 
Analysis 
14.2.5.1.4 
Analysis of Relative Change from Baseline in 
FEV1 Percent Predicted at Week 4, 12, and 
Week 20  
Subjects ≤ 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
Updated 
Analysis 
14.2.5.1.5 
Analysis of Relative Change from Baseline in 
FEV1 Percent Predicted at Week 4, 12, and 
Week 20  
Subjects > 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
Updated 
Analysis 
14.2.5.1.6 
Analysis of Relative Change from Baseline in 
FEV1 Percent Predicted at Week 4, 12, and 
Week 20 by i.v. Vancomycin use during 
Period 1 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.5.1.7 
Analysis of Relative Change from Baseline in 
FEV1 Percent Predicted at Week 4, 12, and 
Week 20 by i.v. Vancomycin use during 
Period 1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.5.2.1 
Summary of Relative Change from Baseline 
in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 by Baseline FEV1 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.5.2.2 
Summary of Relative Change from Baseline 
in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 by Baseline FEV1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.5.3.1 
Summary of Relative Change from Baseline 
in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 by Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months 
Subjects ≤ 21 Years 
ITT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.5.3.2 
Summary of Relative Change from Baseline 
in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 by Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months 
Subjects > 21 Years 
ITT 
Population 
 
14.2.5.4.1 
Summary of Relative Change from Baseline 
in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 by P. Aeruginosa Treatment 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.5.4.2 
Summary of Relative Change from Baseline 
in FEV1 Percent Predicted at Weeks 4, 12, 
and 20 by P. Aeruginosa Treatment 
Subjects > 21 Years 
ITT 
Population 
 
14.2.6.1.1 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Scores and Teen/Adult Scaled 
Scores at Weeks 4, 12, and 20 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.6.1.1.1 Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Scores and Teen/Adult Scaled 
Scores at Weeks 4, 12, and 20 using Strata 
as Reported in Database 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.6.1.2 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Scores at Weeks 4, 12, and 20 
Subjects ≤ 13 Years 
ITT 
Population 
 
14.2.6.1.3 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores  at Weeks 4, 12, 
and 20 
13 Years < Subjects ≤ 21 Years 
ITT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.6.1.4 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores at Weeks 4, 12, 
and 20 
Subjects > 21 Years 
ITT 
Population 
 
14.2.6.1.5 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Scores and Teen/Adult Scaled 
Scores at Weeks 4, 12, and 20 
Subjects ≤ 21 Years 
Per-
Protocol 
Population 
 
14.2.6.1.6 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Scores at Weeks 4, 12, and 20 
Subjects ≤ 13 Years 
Per-
Protocol 
Population 
 
14.2.6.1.7 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores  at Weeks 4, 12, 
and 20 
13 Years < Subjects ≤ 21 Years 
Per-
Protocol 
Population 
 
14.2.6.1.8 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Scores and Teen/Adult Scaled 
Scores at Weeks 4, 12, and 20  
Subjects ≤ 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 
14.2.6.1.9 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Parent Scaled Scores at Weeks 4, 12, and 20  
Subjects ≤ 13 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.6.1.10 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores  at Weeks 4, 12, 
and 20  
13 Years < Subjects ≤ 21 Years with no 
Trikafta use at Baseline or During Period 1 
ITT 
Population 
 
14.2.6.1.11 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores at Weeks 4, 12, 
and 20  
Subjects > 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 
14.2.6.1.12 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores  at Weeks 4, 12, 
and 20 by i.v. Vancomycin use during Period 
1 
Subjects ≤ 13 Years 
ITT 
Population 
 
14.2.6.1.13 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores  at Weeks 4, 12, 
and 20 by i.v. Vancomycin use during Period 
1 
13 Years < Subjects ≤ 21 Years 
ITT 
Population 
 
14.6.1.14 
Analysis of Change from Baseline in the 
Respiratory Symptoms Domain of the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R) 
Teen/Adult Scaled Scores  at Weeks 4, 12, 
and 20 by i.v. Vancomycin use during Period 
1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.6.2.1 
Analysis of Change from Baseline in the 
Cystic Fibrosis Questionnaire-Revised (CFQ-
R) Parent Scaled Scores and Teen/Adult 
Scaled Scores at Weeks 4, 12, and 20 
Subjects ≤ 21 Years 
ITT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.6.2.2 
Analysis of Change from Baseline in the 
Cystic Fibrosis Questionnaire-Revised (CFQ-
R) Parent Scaled Scores at Weeks 4, 12, and 
20 
Subjects ≤ 13 Years 
ITT 
Population 
 
14.2.6.2.3 
Analysis of Change from Baseline in the 
Cystic Fibrosis Questionnaire-Revised (CFQ-
R) Teen/Adult Scaled Scores  at Weeks 4, 
12, and 20 
13 Years < Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.6.2.4 
Analysis of Change from Baseline in the 
Cystic Fibrosis Questionnaire-Revised (CFQ-
R) Teen/Adult Scaled Scores  at Weeks 4, 
12, and 20 
Subjects > 21 Years 
TT 
Population 
 
14.2.6.3.1 
Analysis of Change from Baseline in the 
Cystic Fibrosis Questionnaire-Revised (CFQ-
R) Parent Scaled Scores and Teen/Adult 
Scaled Scores at Weeks 4, 12, and 20 
Subjects ≤ 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 
14.2.6.3.2 
Analysis of Change from Baseline in the 
Cystic Fibrosis Questionnaire-Revised (CFQ-
R) Parent Scaled Scores at Weeks 4, 12, and 
20  
Subjects ≤ 13 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 
14.2.6.3.3 
Analysis of Change from Baseline in the 
Cystic Fibrosis Questionnaire-Revised (CFQ-
R) Teen/Adult Scaled Scores  at Weeks 4, 
12, and 20 
13 Years < Subjects ≤ 21 Years with no 
Trikafta use at Baseline or During Period 1 
ITT 
Population 
 
14.2.6.3.4 
Analysis of Change from Baseline in the 
Cystic Fibrosis Questionnaire-Revised (CFQ-
R) Teen/Adult Scaled Scores  at Weeks 4, 
12, and 20  
Subjects > 21 Years with no Trikafta use at 
Baseline or During Period 1 
TT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.6.4.1 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Parent 
Scaled Scores  by Period 
Subjects ≤ 13 Years 
ITT 
Population 
 
14.2.6.4.2 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores by Period 
13 Years < Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.6.4.3 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores by Period 
Subjects > 21 Years 
TT 
Population 
 
14.2.6.5.1 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Parent 
Scaled Scores  by Period and Trikafta use at 
Baseline or During Period 1 
Subjects ≤ 13 Years 
ITT 
Population 
 
14.2.6.5.2 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores by Period and Trikafta use at 
Baseline or During Period 1 
13 Years < Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.6.5.3 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores by Period and Trikafta use at 
Baseline or During Period 1 
Subjects > 21 Years 
TT 
Population 
 
14.2.6.6.1 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Parent 
Scaled Scores  by Period and Baseline FEV1 
Subjects ≤ 13 Years 
ITT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.6.6.2 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores by Period and Baseline FEV1 
13 Years < Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.6.6.3 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores by Period and Baseline FEV1 
Subjects > 21 Years 
TT 
Population 
 
14.2.6.7.1 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Parent 
Scaled Scores  by Period and Prior 
Exacerbations Treated with Antibiotics 
during the Previous 12 Months 
Subjects ≤ 13 Years 
ITT 
Population 
 
14.2.6.7.2 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores by Prior Exacerbations 
Treated with Antibiotics during the Previous 
12 Months 
13 Years < Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.6.7.3 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores by Period and Prior 
Exacerbations Treated with Antibiotics 
during the Previous 12 Months 
Subjects > 21 Years 
TT 
Population 
 
14.2.6.8.1 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Parent 
Scaled Scores  by Period and P. aeruginosa 
Treatment 
Subjects ≤ 13 Years 
ITT 
Population 
 


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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.6.8.2 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores by Period and P. aeruginosa 
Treatment 
13 Years < Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.6.8.3 
Summary of Actual and of Change from 
Baseline in the Cystic Fibrosis 
Questionnaire-Revised (CFQ-R) Teen/Adult 
Scaled Scores by Period and P. aeruginosa 
Treatment 
Subjects > 21 Years 
TT 
Population 
 
14.2.7.1.1 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) 
Scores at Weeks 4, 12, and 20 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.7.1.1.1 Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) 
Scores at Weeks 4, 12, and 20 using Strata 
as Reported in Database 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.7.1.2 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) 
Scores at Weeks 4, 12, and 20 
Subjects > 21 Years 
ITT 
Population 
 
14.2.7.1.3 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) 
Scores at Weeks 4, 12, and 20 
Subjects ≤ 21 Years 
Per-
Protocol 
Population 
 
14.2.7.1.4 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) 
Scores at Weeks 4, 12, and 20  
Subjects ≤ 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 
14.2.7.1.5 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) 
Scores at Weeks 4, 12, and 20  
Subjects > 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
 


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
Syneos Health #1006732 
 
This document is proprietary and confidential to Syneos Health. 
03.007A.03     
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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.7.1.6 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) 
Scores at Weeks 4, 12, and 20 by i.v. 
Vancomycin use during Period 1 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.7.1.7 
Analysis of Change from Baseline in Chronic 
Respiratory Symptom Score (CFRSD-CRISS) 
Scores at Weeks 4, 12, and 20 by i.v. 
Vancomycin use during Period 1 
Subjects> 21 Years 
ITT 
Population 
 
14.2.7.2.1 
Summary of Actual and Change from 
Baseline in Chronic Respiratory Symptom 
Score (CFRSD-CRISS) Scores by Period  
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.7.2.2 
Summary of Actual and Change from 
Baseline in Chronic Respiratory Symptom 
Score (CFRSD-CRISS) Scores by Period  
Subjects > 21 Years  
ITT 
Population 
 
14.2.7.3.1 
Summary of Actual and Change from 
Baseline in Chronic Respiratory Symptom 
Score (CFRSD-CRISS) Scores by Period and 
Trikafta use at Baseline or During Period 1 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.7.3.2 
Summary of Actual and Change from 
Baseline in Chronic Respiratory Symptom 
Score (CFRSD-CRISS) Scores by Period and 
Trikafta use at Baseline or During Period 1 
Subjects > 21 Years  
ITT 
Population 
 
14.2.7.4.1 
Summary of Actual and Change from 
Baseline in Chronic Respiratory Symptom 
Score (CFRSD-CRISS) Scores by Period and 
Baseline FEV1 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.7.4.2 
Summary of Actual and Change from 
Baseline in Chronic Respiratory Symptom 
Score (CFRSD-CRISS) Scores by Period and 
Baseline FEV1 
Subjects > 21 Years 
ITT 
Population 
 


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
Syneos Health #1006732 
 
This document is proprietary and confidential to Syneos Health. 
03.007A.03     
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Page 124 of 126 
Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.7.5.1 
Summary of Actual and Change from 
Baseline in Chronic Respiratory Symptom 
Score (CFRSD-CRISS) Scores by Period and 
Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.7.5.2 
Summary of Actual and Change from 
Baseline in Chronic Respiratory Symptom 
Score (CFRSD-CRISS) Scores by Period and 
Prior Exacerbations Treated with 
Antibiotics During the Previous 12 Months 
Subjects > 21 Years 
ITT 
Population 
 
14.2.7.6.1 
Summary of Actual and Change from 
Baseline in Chronic Respiratory Symptom 
Score (CFRSD-CRISS) Scores by Period and 
P. Aeruginosa Treatment 
Subjects ≤ 21 Years 
ITT 
Population 
 
14.2.7.6.2 
Summary of Actual and Change from 
Baseline in Chronic Respiratory Symptom 
Score (CFRSD-CRISS) Scores by Period and 
P. Aeruginosa Treatment 
Subjects > 21 Years 
ITT 
Population 
 
14.2.8.1.1 
Analysis of Area Under the FEV1–time 
Profile 
Subjects ≤ 21 Years 
ITT 
Population 
Updated 
Analysis 
14.2.8.1.1.1 Analysis of Area Under the FEV1–time 
Profile using Strata as Reported in Database 
Subjects ≤ 21 Years 
ITT 
Population 
Updated 
Analysis 
14.2.8.1.1.2 Analysis of Area Under the FEV1–time 
Profile 
Original Planned Analysis 
Subjects ≤ 21 Years 
ITT 
Population 
New 
(Original 
14.2.8.1.1) 
14.2.8.1.2 
Analysis of Area Under the FEV1–time 
Profile 
Subjects > 21 Years 
ITT 
Population 
Updated 
Analysis 
14.2.8.1.3 
Analysis of Area Under the FEV1–time 
Profile 
Subjects ≤ 21 Years 
Per-
Protocol 
Population 
Updated 
Analysis 


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
Syneos Health #1006732 
 
This document is proprietary and confidential to Syneos Health. 
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Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.8.1.4 
Analysis of Area Under the FEV1–time 
Profile  
Subjects ≤ 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
Updated 
Analysis 
14.2.8.1.5 
Analysis of Area Under the FEV1–time 
Profile  
Subjects > 21 Years with no Trikafta use at 
Baseline or During Period 1 
ITT 
Population 
Updated 
Analysis 
14.2.8.1.6 
Analysis of Area Under the FEV1–time 
Profile by i.v. Vancomycin use during Period 
1 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.8.1.7 
Analysis of Area Under the FEV1–time 
Profile by i.v. Vancomycin use during Period 
1 
Subjects > 21 Years 
ITT 
Population 
 
14.2.8.2.1 
Summary of Area Under the FEV1–time 
Profile by Period  
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.8.2.2 
Summary of Area Under the FEV1–time 
Profile by Period  
Subjects > 21 Years  
ITT 
Population 
 
14.2.8.3.1 
Summary of Area Under the FEV1–time 
Profile by Period and Trikafta use at 
Baseline or During Period 1 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.8.3.2 
Summary of Area Under the FEV1–time 
Profile by Period and Trikafta use at 
Baseline or During Period 1 
Subjects > 21 Years  
ITT 
Population 
 
14.2.8.4.1 
Summary of Area Under the FEV1–time 
Profile by Period and Baseline FEV1 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.8.4.2 
Summary of Area Under the FEV1–time 
Profile by Period and Baseline FEV1 
Subjects > 21 Years  
ITT 
Population 
 


Statistical Analysis Plan 
Savara Inc. Protocol SAV005-04 
Version 3.0 Amendment 2 
Syneos Health #1006732 
 
This document is proprietary and confidential to Syneos Health. 
03.007A.03     
  Syneos Health 
Page 126 of 126 
Table 
Number 
Table Title 
Population 
New or 
Updated 
Analysis 
14.2.8.5.1 
Summary of Area Under the FEV1–time 
Profile by Period and Prior Exacerbations 
Treated with Antibiotics During the 
Previous 12 Months 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.8.5.2 
Summary of Area Under the FEV1–time 
Profile by Period and Prior Exacerbations 
Treated with Antibiotics During the 
Previous 12 Months  
Subjects > 21 Years  
ITT 
Population 
 
14.2.8.6.1 
Summary of Area Under the FEV1–time 
Profile by Period and P. Aeruginosa 
Treatment 
Subjects ≤ 21 Years  
ITT 
Population 
 
14.2.8.6.2 
Summary of Area Under the FEV1–time 
Profile by Period and P. Aeruginosa 
Treatment 
Subjects > 21 Years  
ITT 
Population 
 
Note: New or Updated Analysis column indicates a table as either New (new table 
number and title) or Updated Analysis (Same table title, number and design, but a 
change in analysis due to the COVID-19 epidemic). If there is no change in a table or the 
presented analysis, this column is left blank.