A Randomised, Parallel Group 2:1 Comparison of the Efficacy and Safety of FP-1201-lyo (Interferon Beta-1a) and Placebo in the Prevention of Multi-Organ Failure on Patients Surviving Open Surgery for a Ruptured Abdominal Aortic Aneurysm
Phase: PHASE2
Conditions: Preventive Medicine, Multi Organ Failure
Sponsor: Faron Pharmaceuticals Ltd

A P h a s e II  D o u bl e- bli n d,  R a n d o mi s e d, P ar all el  Gr o u p 2: 1
C o m p ari s o n of t h e Effi c a c y a n d S af et y of F P- 1 2 0 1-l y o
( R e c o m bi n a nt  H u m a n I nt erf er o n b et a- 1 a) a n d Pl a c e b o i n
t h e Pr e v e nti o n of  M ulti- Or g a n F ail ur e o n P ati e nt s S ur vi vi n g
O p e n S ur g er y f or a  R u pt ur e d  A b d o mi n al  A orti c  A n e ur y s m
N C T 0 3 1 1 9 7 0 1
P r ot o c ol V er si o n: 0 5
Pr ot o c ol  D at e: 1 6 A pr 2 0 1 9

N C T 0 3 1 1 9 7 0 1

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
4 of 6 8  
1 6  A pr 2 0 1 9  
Decl ar ati o n of t he N ati o n al C o - or di n ati n g I n vesti g at or 
Title : A P h ase II D o u ble- bli n d, R a n d o mise d, P ar allel Gr o u p 2: 1 C o m p aris o n of 
t he  Effic ac y  a n d  S afet y  of  F P- 1 2 0 1-l y o  ( Rec o m bi n a nt  H u m a n  I nterfer o n  bet a-
1 a) a n d Pl ace b o i n t he Pre ve nti o n of M ulti- Or g a n F ail ure o n P atie nts S ur vi vi n g 
O pe n S ur ger y f or a R u pt ure d A b d o mi n al A ortic A ne ur ys m 
T his  st u dy  pr ot oc ol  w as  s u bjecte d  t o  critic al  revie w  a n d  h as  bee n  a p pr ove d  by  t he 
S p o ns or.  T he  i nf or m ati o n  it  c o nt ai ns  is  c o nsiste nt  wit h  t he  c urre nt  risk/ be nefit 
ev al u ati o n  of  t he  i nvesti g ati o n al  pr o d uct  as  well  as  wit h  t he  m or al,  et hic al  a n d 
scie ntific  pri nci ples  g over ni n g  cli nic al  rese arc h  as  set  o ut  i n  t he  Decl ar ati o n  of 
Helsi nki, as a me n de d i n 2 0 1 3, a n d t he I C H g ui deli nes o n G o o d Cli nic al Pr actice. 
 
N ati o n al C o - or di n ati n g I n vesti g at or 
 
 
 
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Si g nat ure 
Date  
 
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Na me ( bl oc k letters) 
 
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Title ( bl oc k letters) 
 
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I nstit uti o n ( bl oc k letters) 
 
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P h o ne n u m ber 
 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
5 of 6 8  
1 6  A pr 2 0 1 9  
Decl a r ati o n of t he I n vesti g at or 
Title : A P h ase II D o u ble- bli n d, R a n d o mise d, P ar allel Gr o u p 2: 1 C o m p aris o n of 
t he  Effic ac y  a n d  S afet y  of  F P- 1 2 0 1-l y o  ( Rec o m bi n a nt  H u m a n  I nterfer o n  bet a-
1 a) a n d Pl ace b o i n t he Pre ve nti o n of M ulti- Or g a n F ail ure o n P atie nts S ur vi vi n g 
O pe n S ur ger y f or a R u pt ure d A b d o mi n al A ortic A ne ur ys m 
All  d oc u me nt ati o n  f or  t his  st u dy  t h at  is  s u p plie d  t o me,   a n d  t h at  h as  n ot  bee n 
previ o usly  p u blis he d  will  be  ke pt  i n  t he  strictest  c o nfi de nce.  T his  d oc u me nt ati o n 
i ncl u des  t his  st u dy  pr ot oc ol,  I nvesti g at or’s  Br oc h ure,  electr o nic  C ase  Re p ort  F or m, 
a n d ot her scie ntific d at a. 
T he  st u dy  will  n ot  c o m me nce  wit h o ut  a  pri or  writte n  a p pr ov al  of  a  pr o perly 
c o nstit ute d  I n de pe n de nt  Et hics  C o m mittee  (I E C).  N o  s u bst a nti al  c h a n ges  will  be 
m a de t o t he st u dy pr ot oc ol wit h o ut a pri or writte n a p pr ov al of t he S p o ns or a n d t he 
I E C, exce pt w here necess ary t o eli mi n ate a n i m me di ate h az ar d t o t he p atie nts. 
I h ave re a d a n d u n derst o o d a n d a gree t o a bi de by all t he c o n diti o ns a n d i nstr ucti o ns 
c o nt ai ne d i n t his pr ot oc ol. 
 
Res p o nsi ble I n vesti g at or of t he l oc al st u d y ce ntre 
 
 
 
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Si g nat ure 
Date  
 
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Na me ( bl oc k letters) 
 
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Title ( bl oc k letters) 
 
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I nstit uti o n ( bl oc k letters) 
 
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P h o ne n u m ber 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
6 of 6 8  
1 6  A pr 2 0 1 9  
P R O T O C O L S Y N O P SI S 
Title  
A  P hase II  D o u ble- bli n d,  Ra n d o mise d,  Parallel  Gr o u p  2: 1 
C o m paris o n  of  t he  Efficac y  a n d  Safet y  of F P - 1 2 0 1-l y o 
( Rec o m bi na nt  H u ma n  I nterfer o n  beta- 1a)  a n d  Place b o  i n 
t he Pre ve nti o n of M ulti- Or ga n Fail ure o n Patie nts S ur vi vi n g 
O pe n S ur ger y f or a R u pt ure d A b d o mi nal A ortic A ne ur ys m  
S p o ns or St u d y N o.  
F P 1 C LI 0 0 6  
P h ase  
II 
S p o ns or  
Far o n P har mace uticals Lt d  
C o -or di n at i n g 
I n vesti g at ors 
 
 
St u d y Ce ntr e(s) 
A p pr o xi matel y  1 0- 1 8  i n vesti gati o nal  sites  l ocate d  i n 
Fi nla n d,  U K,  Lit h ua nia  a n d  Est o nia  a n d  p ossi bl y  i n  ot her 
E E A c o u ntries a n d i n U S A will partici pate i n t he st u d y. 
O bjecti ve s 
 
Pri m ar y O bjecti ve  
T o  e val uate  t he  efficac y  a n d  safet y  of  F P- 1 2 0 1-l y o  o ver 
place b o  o n all-ca use  m ortalit y  at  st u d y  da y 3 0;  D3 0 
( 3 0 da ys fr o m t he first d ose of t he st u d y me dicati o n). 
 
Sec o n d ar y O bjecti ves  
1.  T o  e val uate  t he  efficac y  of  F P- 1 2 0 1-l y o  treat me nt 
b y  assessi n g  s h ort  ter m  o utc o mes  ( D 3 0)  a n d  mi d-
ter m o utc o mes ( D 9 0 [ 3 m o nt hs]) 
2.  T o  e val uate  t he  safet y  a n d  t olera bilit y  of  F P- 1 2 0 1-
l y o treat me nt  
3.  T o  e val uate  t he  p har mac o d y na mics ( P D)  of  F P-
1 2 0 1-l y o 
4.  T o  e val uate  t he  Te ntati ve  Disease  S pecific  Mar ker 
C D 7 3 a n d P ote ntial I nfla m mat or y Mar kers ( PI M) 
5.  T o  e val uate  ne utralizi n g  a nti b o dies  a gai nst  I F N 
beta- 1a ( N A bs) 
 
Effic ac y  
Pri m ar y Effic ac y E n d p oi nt:  
•  A ll-ca use m ortalit y at D 3 0 
Sec o n d ar y Effic ac y E n d p oi nts: 
•  A ll-ca use m ortalit y at D 9 0 ( 3 m o nt hs)  
•  N u m ber of ve ntilat or free da ys ( V F Ds) at D 3 0 
•  N u m ber of da ys recei vi n g hae m o dial ysis at D 3 0 a n d 
D 9 0 
•  N u m ber  of  or ga n  fail ure  free  da ys  u p  t o  D 3 0  b y 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
7 of 6 8  
1 6  A pr 2 0 1 9  
mea ns of t he S O F A sc ore  
•  Pre vale nce  of  a b d o mi nal  c o m part me nt  s y n dr o me, 
i.e.  i ntra-a b d o mi nal  press ure  (I A P)  bet wee n  st u d y 
gr o u ps 
•  Ne utralizi n g a nti b o dies a gai nst I F N beta- 1a ( N A bs) 
i n w h ole bl o o d sa m ples u p t o D 3 0 
•  Disa bilit y  o n  D 9 0  meas ure d  b y  m o difie d  ra n ki n g 
scale ( m R S) 
 
  S afet y   
•  Cli nicall y  si g nifica nt  treat me nt  e mer ge nt  a d verse 
e ve nts ( T E A Es)  u p  t o  D 3 0  fr o m  vital  si g ns  data, 
la b orat or y  
data,  
p h ysical  
e xa mi nati o ns  
a n d 
s p o nta ne o us re p orti n g w he n c o nsci o us 
 
P h ar m ac oec o n o mics  
•  Le n gt h  of  I C U  sta y,  i n  ter ms  of  I C U  free  da ys  at 
D 3 0 
•  Le n gt h  of  h os pital  sta y,  i n  ter ms  of  h os pital  free 
da ys at D 9 0 
•  Le n gt h of sta y at a n ot her healt h care facilit y at D 9 0 
•  Le n gt h of hae m o dial ysis nee de d 
•  Ve ntilati o n free da ys at D 3 0 
 
P h ar m ac o d y n a mics  ( P D) 
 
 
•  M x A  ( pr otei n)  c o nce ntrati o n  i n  w h ole  bl o o d 
sa m ples fr o m baseli ne u p t o D 1 3 
 
Te nt ati ve Dise ase 
S pecific M ar ker                   
 
 
•  C D 7 3 c o nce ntrati o n/acti vit y i n ser u m sa m ples fr o m 
baseli ne u p t o D 1 3 
•  P ote ntial  I nfla m mat or y  Mar kers  (I L- 6  a n d  H G F)  i n 
ser u m sa m ples fr o m baseli ne u p t o D 1 3 
 
Desi g n  
 
 
 
 
 
 
M ultice ntre,  ra n d o mise d,  d o u ble- bli n de d,  P hase  II, 
parallel gr o u p c o m paris o n st u d y of t he efficac y a n d 
safet y  of  F P- 1 2 0 1-l y o  c o m pare d  t o  place b o  i n 
patie nts  s ur vi vi n g  e mer ge nc y  o pe n  s ur ger y  f or  a n 
i nfra-re nal r u pt ure d a b d o mi nal a ortic a ne ur ys m. 
Recei vi n g as p ost-s ur gical pre ve nti ve treat me nt 
eit her F P- 1 2 0 1-l y o or place b o.  B ot h treat me nt 
gr o u ps will recei ve sta n dar d s u p p orti ve care.   
 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
8 of 6 8  
1 6  A pr 2 0 1 9  
Tre at me nt  
 
 
 
 
 
 
 
 N u m ber of p atie nts  
 
1 0 µ g  F P- 1 2 0 1-l y o  or  place b o  will  be  a d mi nistere d 
dail y  e ver y  2 4  hrs  f or  6  da ys  ( D 0    D 5).  T he  first 
d ose  will  be  gi ve n  after  s uccessf ul  s ur ger y  at  t he 
p oi nt w he n t he patie nt arri ves t o t he I C U.  
N o  d ose  m o dificati o ns  or  s h ort  i nterr u pti o ns  of 
st u d y treat me nt are all o we d. 
Retreat me nt  wit h  a  sec o n d  c o urse  of  st u d y 
me dicati o n is n ot per mitte d.   
 
Wit h  a n  esti mate d  scree ni n g  fail ure  rate  of  a p pr o xi matel y 
1 5 %,  1 8 0 patie nts  dia g n ose d  wit h  a  r u pt ure d  a b d o mi nal 
a ortic  a ne ur ys m  re q uiri n g  a n d  eli gi ble  f or  i m me diate  o pe n 
a ortic re pair will be c o nse nte d a n d e ntere d i nt o t he st u d y i n 
or der  t o  ra n d o mise  a n d  i nitiate  treat me nt  of  1 5 2  patie nts. 
F or t he fi nal a nal ysis, a mi ni m u m of 1 2 9 e val ua ble patie nts 
will  be  re q uire d  (e xcl u di n g  earl y  deat hs).  T here  is  a 
p ossi bilit y  of  earl y  st o p pi n g  f or  efficac y  or  f utilit y  after at 
least 3 1 a n d 8 4 e val ua ble patie nts base d o n i nteri m a nal ysis. 
T he  sa m ple  size  calc ulati o ns  will  be  re-e val uate d  after  t he 
first i nteri m a nal ysis has bee n perf or me d.  
 
 
I ncl usi o n Criteri a: 
T o  be  eli gi ble  f or  i ncl usi o n  i nt o  t his  st u d y,  eac h  patie nt 
m ust  f ulfil  t he  f oll o wi n g  i ncl usi o n  criteria 
d uri n g 
scree ni n g  a n d  pri or  t o  t he  first  d ose  of  t he  st u d y 
me dic ati o n  bei n g  a d mi nistere d  o n  D 0  (criteri a  1  or  2 
a n d all 3, 4 a n d 5) : 
1.  Patie nts ( male or fe male) prese nti n g wit h a r u pt ure d 
a b d o mi nal  a ortic  a ne ur ys m  ( R A A A)  dia g n ose d  b y 
ultras o u n d or C T-sca n i n t he e mer ge nc y r o o m 
•  all  f or ms  of  i nfrare nal  R A A As  wit h  or  wit h o ut 
c oe xisti n g iliac a ne ur ys ms are i ncl u de d 
or 
2.  Patie nts ( male or fe male) prese nti n g wit h s y m pt o ms 
of  R A A A  k n o w n  t o  ha ve  a n  i nfrare nal  A A A  a n d 
pr ocee di n g  strai g ht  t o  o pe n  re pair  
wit h o ut 
ra di ol o gical  assess me nt  a n d  c o nfir me d  r u pt ure 
( retr o perit o neal hae mat o ma) i n o perati o n 
a n d 
3.  A ne ur ys ma  re pair  m ust  be  i nfra-re nal,  i.e.  t he 
pr o xi mal  a nast o m osis  m ust  be  bel o w  t he  re nal 
arteries  a n d  t he  re nal  arteri es m ust  sta y  i ntact. 
Te m p orar y a b o ve t he re nal cla m pi n g ca n be use d f or 
a ma xi m u m of 3 0 mi n utes (t otal cla m pi n g ti me) 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
9 of 6 8  
1 6  A pr 2 0 1 9  
a n d 
4.  Pa tie nts  or  t heir  ne xt  of  ki n  pr o vi di n g  i nf or me d 
c o nse nt ( writte n si g ne d or wit nesse d) 
 a n d 
5.  A ge of 1 8 years or hi g her 
 
E xcl usi o n Criteri a : 
 
 
T o  be  eli gi ble  f or  i ncl usi o n  i nt o  t his  st u d y,  eac h  patie nt 
m ust n ot meet a n y of t he f oll o wi n g e xcl usi o n criteria d uri n g 
scree ni n g  or  pri or  t o  t he  first  d ose  of  t he  st u d y  me dicati o n 
bei n g a d mi nistere d: 
1.  
M ori b u n d patie nt n ot eli gi ble f or treat me nt i n I C U 
or e x pecte d t o s ur vi ve s ur ger y 
2.  
Mar ke dl y  s h ort  life  e x pecta nc y,  e. g.  a d va nce d 
mali g na nt disease 
3.  
C urre nt  partici pati o n  i n  a n ot her  e x peri me ntal 
treat me nt pr ot oc ol  
4.  
Si g nifica nt  c o n gesti ve  heart  fail ure,  defi ne d  as 
Ne w Y or k Heart Ass ociati o n ( N Y H A) class I V 
5.  
C urre nt treat me nt wit h I F N al p ha or I F N beta 
6.  
Dial ysis t hera p y f or c hr o nic re nal fail ure 
7.  
Irre versi ble s h oc k fr o m hae m orr ha ge 
8.  
U nc o nsci o us ness w he n arri vi n g t o t he h os pital a n d 
d uri n g scree ni n g 
9.  
r E V A R first ( pri or atte m pt f or e n d o vasc ular a ortic 
re pair f or t he c urre nt r u pt ure) 
1 0.  
Dia g n ose d cirr h osis 
1 1.  
Pre g na nc y  a n d  w o me n  wit h  c hil d  beari n g 
p ote ntial wit h o ut a ne gati ve pre g na nc y test 
1 2.  
R u pt ure n ot c o nfir me d b y C T or i ntra- o perati vel y 
(i m pe n di n g r u pt ures are e xcl u de d) 
1 3.  
R A A A  re q uiri n g  re pair  of  t he  re nal  arteries  or 
pr o xi mal a orta 
•  t h orac oa b d o mi nal  
a ne ur ys ms  
re q uiri n g 
i m me diate re pair 
•  da ma ge d  re nal  arteries  d uri n g  e mer ge nc y 
cla m pi n g re q uiri n g re pair 
N O T E: 
•  te m p orar y  cla m pi n g  a b o ve  t he  re nal  arteries 
( ma x 3 0 mi n  t otal cla m pi n g ti me a b o ve t he re nal 
arteries) d oes n ot  lea d t o e xcl usi o n 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
1 0  of 6 8  
1 6  A pr 2 0 1 9  
•  li gati o n  of  t he  left  re nal  vei n d oes  n ot   lea d  t o 
e xcl usi o n 
 
St atistic al Met h o d : 
1 5 2  ra n d o mise d  a n d  treate d  patie nts  are  nee de d  t o  ac hie ve 
t he  sa m ple  size  of  1 2 9  e val ua ble  patie nts  f or  t he  pri mar y 
efficac y  e n d p oi nt.  T he  sa m ple  size  calc ulati o ns  will  be  re-
e val uate d after t he first i nteri m a nal yses. 
Sta n dar d  statistical  met h o ds  will  be  use d  i n  t he  pri mar y 
efficac y  o utc o me  a nal yses.  L o gistic  re gressi o n  m o del  will 
be  use d  f or  t he  a nal yses  of  o bser ve d  m ortalit y  rates i n  t he 
t w o  treat me nt  gr o u ps.  Stratificati o n  fact ors  use d  i n  t he 
ra n d o misati o n will be i ncl u de d i n t he m o del. 
Data  f or  t he  pri mar y  efficac y  e n d p oi nt  will  als o  be 
prese nte d  f or  ke y,  pre- defi ne d  s u b gr o u ps  of  patie nts. 
M ortalit y  at  D 3 0  will  be  ill ustrate d  als o  usi n g  s ur vi val 
f u ncti o n a n d Ka pla n- Meier c ur ves i ncl u di n g l o g-ra n k test as 
a n e x pl orat or y a nal ysis. 
 
A n al ysis Sets:  
 
T he  F ull  A nal ysis Set f or  efficac y  ( F A S- E)  will  c o nsist  of 
all  ra n d o mise d  patie nts  e xcl u di n g  earl y  deat hs  ( wit hi n  3 6 
h o urs fr o m treat me nt i nitiati o n) a n d will be t he a nal ysis set 
o n w hic h t he pri mar y efficac y a nal ysis will be base d. 
T he Per Pr ot oc ol Set ( P P S) will c o nsist of t h ose patie nts i n 
t he  F A S- E  e xcl u di n g  patie nts  wit h  maj or  pr ot oc ol 
vi olati o ns.  A  rele va nt  list  of  maj or  pr ot oc ol  vi olati o ns  will 
be detaile d i n t he S A P. T he precise defi niti o n of t he P P S at 
patie nt le vel will be i de ntifie d at t he bli n d re vie w. 
Statistical a nal yses f or t he pri mar y a n d sec o n dar y e n d p oi nts 
will be perf or me d o n b ot h t he F A S- E a n d P P S. 
T he F ull A nal ysis Set f or safet y ( F A S-S)  will c o nsist of all 
patie nts  w h o  recei ve  at  least  o ne  d ose  of  st u d y  me dicati o n 
a n d  will  be  t he  a nal ysis  set  o n  w hic h  all  safet y  a n d 
t olera bilit y  a nal yses  will  be  base d.  A  patie nt  recei vi n g  t he 
wr o n g  treat me nt  acc or di n g  t o  t he  ra n d o misati o n  will  be 
a nal yse d  f or  safet y  a n d  t olera bilit y  i n  t he  treat me nt  gr o u p 
c orres p o n di n g t o t he treat me nt recei ve d. 
 
I nteri m A n al yses:  
 
I nteri m a nal ysis will be perf or me d after t here are at least 3 1 
a n d 8 4 e val ua ble patie nts f or t he pri mar y efficac y e n d p oi nt 
a nal ysis. At t his p oi nt t he st u d y ca n be st o p pe d f or efficac y 
or  f utilit y  de pe n di n g  o n  t he  i nteri m  a nal ysis  res ults.  T he 
first i nteri m is br o u g ht f urt her u p as t he recr uit me nt rate has 
mar ke dl y  sta g nate d,  mai nl y  d ue  t o  c ha n ges  i n  treat me nt 
practices of R A A A. T he sa m ple size calc ulati o ns will be re-
e val uate d after t he first i nteri m  a nal ysis. 

Far o n P har mace uticals Lt d  
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Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
1 1  of 6 8  
1 6  A pr 2 0 1 9  
 
In de pe n de nt d at a 
m o nit ori n g c o m mittee 
(I D M C) 
I D M C c o nsist of ke y o pi ni o n lea ders i n scie ntific fiel d a n d 
is  res p o nsi ble  f or  o verl o o ki n g  t he  o verall  safet y  of  t he 
st u d y.  I D M C  is  o bli ge d  t o  disc o nti n ue  t he  st u d y,  if  t he 
be nefit ris k bala nce is ne gati ve.  
 

Far o n P har mace uticals Lt d  
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C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
1 4  of 6 8  
1 6  A pr 2 0 1 9  
T A B L E O F C O N T E N T S 
 
P R O T O C OL S Y N O P SI S  ........................................................................................................ 6 
LI S T O F S T U D Y P E R S O NN EL  .............................................................................................. 1 2  
LI S T O F A B B R E VI A TI O NS A N D D E FI NI TI O N S O F  T E R M S  .................................................... 1 7  
 
I N T R O D U C TI O N ........................................................................................................ 1 9  
 
D I S E AS E R E VI E W A N D R ATI O N AL E F O R T H E S T U D Y ........................................................... 1 9  
 
IN V E S TI G A TI O N AL M E DI C I N AL P R O D U C T ........................................................................ 2 0  
 
M E C H A NI S M OF A C TI O N  ............................................................................................ 2 0  
 
P R E CLI NI C AL A N D CLI NI C AL D A T A  ................................................................................. 2 1  
 
S T U D Y O BJ E C TI V E S  ................................................................................................... 2 2  
 
P RI M A R Y O BJ E C TI V E  .................................................................................................. 2 2  
 
S E C O N D A R Y O BJ E C TI V E S  ............................................................................................ 2 2  
 
O V E R ALL D E SI G N A N D P L A N O F T H E S T U D Y .............................................................. 2 3  
 
S U M M A R Y OF S T U D Y D E SI G N ...................................................................................... 2 3  
 
C RI T E RI A F O R T H E S T U D Y A S S E S S M E N T S  ........................................................................ 2 5  
 
Pri m ary Effic acy E n d p oi nt:  ................................................................................ 2 5  
 
S af ety  ................................................................................................................ 2 5  
 
P h ar m ac o ec o n o mics ass ess m e nts  .................................................................... 2 5  
 
Ex pl or at ory e n d p oi nts ass ess m e nts  .................................................................. 2 5  
 
JUS TI FI C A TI O N OF T H E S T U D Y D E SI G N ........................................................................... 2 6  
 
S T U D Y P O P UL A TI O N  ................................................................................................. 2 7  
 
IN CL USI O N C RI T E RI A  .................................................................................................. 2 7  
 
E X CL USI O N C RI T E RI A  ................................................................................................. 2 7  
 
C O NFI R M A TI O N OF P A TI E N T E LI GI BILI T Y ........................................................................ 2 8  
 
P A TI E N T W I T H D R A W AL A N D R E PL A C E M E N T  .................................................................. 2 8  
 
Disc o nti n u ati o n Crit eri a .................................................................................... 2 8  
 
R e pl ac e m e nt P olicy ........................................................................................... 3 0  
 
P L A N N E D S A M PL E S I Z E A N D N U M B E R OF S T U D Y C E N T R E S  ............................................... 3 0  
 
P A TI E N T R A N D O MI S A TI O N  ......................................................................................... 3 0  
 
R a n d o mis ati o n Sc h e m e ..................................................................................... 3 0  
 
R a n d o mis ati o n of P ati e nts t o Tr e at m e nt .......................................................... 3 0  
 
S T U D Y D R U G  ............................................................................................................ 3 1  
 
ID E N TI T Y  ................................................................................................................. 3 1  
 
A D MI NI S T R A TI O N  ..................................................................................................... 3 1  
 
P A C K A GI N G , LA B ELLI N G A N D S T O R A G E  ......................................................................... 3 2  
 
B LI N DI N G A N D B R E A KI N G T H E B LI N D ............................................................................ 3 2  
 
D R U G A C C O U N T A BILI T Y  ............................................................................................. 3 3  
 
C O M PLI A N C E  ........................................................................................................... 3 3  
 
P R E VI O US A N D C O N C O MI T A N T M E DI C A TI O NS  ............................................................... 3 3  
 
G UI D A N C E O N M E DI C A TI O NS T O B E A D MI NI S T E R E D /P A TI E N T M A N A G E M E N T F O R E X P E C T E D 
A D V E R S E E V E N T S  .................................................................................................................... 3 3  
 
V A RI A BL E S A N D M E T H O D S O F A S S E S S M E N T  ............................................................ 3 4  
 
E F FI C A C Y V A RI A BL E S  ................................................................................................. 3 4  
 
M E T H O DS A N D T I MI N G F O R A S S E S SI N G, R E C O R DI N G A N D A N AL Y SI N G E F FI C A C Y P A R A M E T E R S
 
3 4  
 
M ort ality ass ess m e nts  ...................................................................................... 3 4  

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Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
1 5  of 6 8  
1 6  A pr 2 0 1 9  
 
Dis a bility ass ess m e nt ........................................................................................ 3 4  
 
V e ntil at or fr e e d ays  ( V F Ds) ............................................................................... 3 4  
 
I C U fr e e d ays ..................................................................................................... 3 5  
 
Or g a n f ail ur e fr e e d ays  ..................................................................................... 3 5  
 
D ays i n h os pit al a n d/ or ot h er h e alt h c ar e u nit ................................................. 3 6  
 
D ays o n h a e m o di alysis ...................................................................................... 3 7  
 
Pr ev al e nc e of c o m p art m e nt sy n dr o m e as m e as ur e d by i ntr a-a b d o mi n al 
pr ess ur e (I A P)  .................................................................................................................. 3 7  
 
S AF E T Y V A RI A BL E S  .................................................................................................... 3 7  
 
A dv ers e Ev e nts  .................................................................................................. 3 7  
 
L a b or at ory V ari a bl es ........................................................................................ 4 1  
 
Vit al Si g ns  ......................................................................................................... 4 3  
 
P hysic al ex a mi n ati o n  ........................................................................................ 4 3  
 
B AS ELI N E C H A R A C T E RI S T I C S A N D DI S P O SI TI O N ................................................................ 4 3  
 
P H A R M A C O E C O N O MI C E V AL U A TI O N  ............................................................................ 4 3  
 
E X PL O R A T O R Y V A RI A BL E S  ........................................................................................... 4 4  
 
M et h o ds a n d Ti mi n g f or Ass essi n g, R ec or di n g a n d A n alysi n g P h ar m ac o dy n a mic 
P ar a m et ers  ...................................................................................................................... 4 4  
 
S T U D Y C O N D U C T  ...................................................................................................... 4 5  
 
S T U D Y P R O C E D U R E S F L O W C H A R T S  ............................................................................. 4 5  
 
A S S E S S M E N T OF D I S C O N TI N U E D P A TI E N T S  .................................................................... 4 8  
 
S E Q U E N TI AL O R G A N F AIL U R E A S S E S S M E N T ( S O F A) ....................................................... 5 0  
 
P R O C E D U R E S B Y V I SI T ................................................................................................ 5 1  
 
Pr e -scr e e ni n g Ev al u ati o n a n d scr e e ni n g l o g ..................................................... 5 1  
 
Scr e e ni n g Ass ess m e nts a n d Pr e -d os e Pr oc e d ur es  ............................................ 5 1  
 
T R E A T M E N T  P E RI O D  ( D 0 T O D 5)  A N D S H O R T  T E R M  F OLL O W-U P P E RI O D ( D 6 T O D 3 0):  
S T U D Y  M E DI C A TI O N  A D MI NI S T R A TI O N,  P A TI E N T  C A R E,  A N D  A S S E S S M E N T S  .................... 5 3  
 
Sc h e d ul e of ass ess m e nts f or D 0 t o D 5  .............................................................. 5 3  
 
Sc h e d ul e of ass ess m e nts f or t h e s h ort t er m f oll o w -u p p eri o d ( D 6 t o D 3 0)  ..... 5 4  
 
D I S C H A R G E .............................................................................................................. 5 6  
 
Disc h ar g e pri or t o D 3 0  ...................................................................................... 5 6  
 
F I N AL F OLL O W -U P  A T D 9 0  ( 3 M O N T H S ) .................................................................... 5 7  
 
S T A TI S TI C AL M E T H O D S  ............................................................................................. 5 8  
 
P O P UL A TI O NS F O R A N AL Y SI S ....................................................................................... 5 8  
 
S A M PL E SI Z E E S TI M A TI O N  ........................................................................................... 5 8  
 
B A S ELI N E  C H A R A C T E RI S TI C S  A N D  DI S P O SI TI O N  ................................................... 5 8  
 
E V AL U A TI O N OF S AF E T Y  ............................................................................................. 5 9  
 
E V AL U A TI O N OF E F FI C A C Y ........................................................................................... 5 9  
 
Ev al u ati o n of pri m ary effic acy e n d p oi nt  ........................................................... 5 9  
 
Ev al u ati o n of s ec o n d ary effic acy e n d p oi nts  ...................................................... 6 0  
 
I N T E RI M A N AL Y SI S  ................................................................................................ 6 1  
 
E T HI C AL, L E G AL A N D A D MI NI S T R A TI V E A S P E C T S ...................................................... 6 2  
 
D A T A Q U ALI T Y A S S U R A N C E ........................................................................................ 6 2  
 
D at a b as e M a n a g e m e nt a n d Q u ality C o ntr ol .................................................... 6 2  
 
C AS E R E P O R T F O R MS A N D S O U R C E D O C U M E N T A TI O N  .................................................... 6 2  
 
D at a C oll ecti o n  .................................................................................................. 6 2  
 
A C C E S S T O S O U R C E D A T A  .......................................................................................... 6 3  
 
A R C HI VI N G S T U D Y R E C O R D S  ....................................................................................... 6 3  
 
G O O D C LI NI C AL P R A C TI C E  .......................................................................................... 6 3  
 
INF O R M E D C O NS E N T  ................................................................................................. 6 3  

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
1 6  of 6 8  
1 6  A pr 2 0 1 9  
9. 6. 1.  
C o ns e nt Pr oc e d ur e  ........................................................................................... 6 4  
9. 7.  
P R O T O C OL A P P R O V AL A N D A M E N D M E N T  ..................................................................... 6 5  
9. 8.  
IN D E P E N D E N T D A T A M O NI T O RI N G C O M MI T T E E  ............................................................. 6 5  
9. 9.  
P R E M A T U R E T E R MI N A TI O N OF T H E S T U D Y  .................................................................... 6 5  
9. 1 0.  
C O NFI D E N TI ALI T Y  ...................................................................................................... 6 5  
9. 1 1.  
O T H E R E T HI C AL A N D R E G UL A T O R Y IS S U E S ..................................................................... 6 6  
9. 1 2.  
P U BLI C A TI O N P OLI C Y  ................................................................................................. 6 6  
1 0.  
R E F E R E N C E LI S T  ..................................................................................................... 6 7  
 
 
 
T a bles 
Ta ble 1:  T he S O F A sc ore ................................................................................................ 3 6  
Ta ble 2:  La b orat or y Varia bles ........................................................................................ 4 2  
Ta ble 3:  T otal V ol u me of Bl o o d re q uire d f or Bi oc he mistr y/ Hae mat ol o g y 
Sa m ples ............................................................................................................. 4 2  
Ta ble 4  T otal V ol u me of Bl o o d re q uire d f or M x A, C D 7 3 a n d PI Ms ............................ 4 4  
Ta ble 5:  Fl o w C hart f or Baseli ne a n d Treat me nt Peri o ds ............................................... 4 5  
Ta ble 6:  Fl o w C hart f or t he S h ort Ter m a n d Mi d Ter m F oll o w- u p Peri o ds ................... 4 7  
Ta ble 7:  Fl o w C hart f or Disc har ge Pri or t o D 3 0 a n d After D 3 0 .................................... 4 9  
Ta ble 8:  Sc he d ules f or S O F As ........................................................................................ 5 0  
Ta ble 9:  M o difie d Ra n ki n g Scale ( m R S) ........................................................................ 5 0  
 
Fi g ures 
Fi g ure 1:  Fl o w Dia gra m of St u d y Desi g n ........................................................................ 2 4  
 
 

Far o n P har mace uticals Lt d  
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C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
1 7  of 6 8  
1 6  A pr 2 0 1 9  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S 
        
 
 
 
 
A E  
A d verse E ve nt 
A L A T  
Ala ni ne Tra nsa mi nase ( S G P T)  
A LI  
Ac ute L u n g I nj ur y  
A R D S 
Ac ute Res pirat or y Distress S y n dr o me 
A S A T  
As partate Tra nsa mi nase ( S G O T)  
BI P A P 
Bile vel P ositi ve Air wa y Press ure  
B P  
Bl o o d Press ure  
CI 
C o nfi de nce I nter val 
C P A P  
C o nti n u o us P ositi ve Air wa y Press ure  
C R A 
Cli nical Researc h Ass ociate 
e C R F 
Electr o nic Case Re p ort F or m  
C R O 
C o ntract Researc h Or ga nisati o n 
C T 
C o m p uterise d T o m o gra p h y 
D 
Da y (as i n treat me nt da y/ p ost o perati ve da y) 
dl  
De cilitre 
E R  
E mer ge nc y r o o m 
F A S  
F ull A nal ysis Set  
Fi O 2  
Fracti o n of I ns pire d O x y ge n 
G C S  
Glas g o w C o ma Scale  
H R  
Heart Rate 
hr  
H o ur  
I A P 
I ntra-a b d o mi nal press ure 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I C U 
I nte nsi ve Care U nit 
I D M C 
I n de pe n de nt Data M o nit ori n g C o m mittee 
I E C 
I n de pe n de nt Et hics C o m mittee 
I F N 
I nterfer o n 
I W R S 
I nteracti ve We b Res p o nse S yste m  
k g 
Kil o gra m 
l 
Litre  
M A P  
Mea n Air wa y Press ure 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
mi n  
Mi n utes 
ml  
Millilitre  
m m  
Milli metre 
m m H g  
Milli metres of merc ur y  
m ol 
M ole 
M x A  
M y x o vir us Resista nt Pr otei n A  
N A bs 
N Y H A  
Ne utralizi n g a nti b o dies 
Ne w Y or k Heart Ass ociati o n  
O R  
O perati o n R o o m 
P 
P ulse 
Pa O 2 
Partial Press ure of O x y ge n 
P D  
P har mac o d y na mic  
PI C D 
Patie nt I nf or me d C o nse nt D oc u me nt 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
1 8  of 6 8  
1 6  A pr 2 0 1 9  
P P S  
Per Pr ot oc ol Set  
P S  
Press ure S u p p ort  
R A A A  
R u pt ure d a b d o mi nal a ortic a ne ur ys m  
r E V A R 
R u pt ure d E n d o vasc ular A ortic Re pair 
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical A nal ysis Pla n 
S D  
Sta n dar d De viati o n  
SI R S 
S O F A  
S yste mic I nfla m mat or y Res p o nse S y n dr o me 
Se q ue ntial Or ga n Fail ure Assess me nt 
S U S A R  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n  
T E A E  
Treat me nt E mer ge nt A d verse E ve nt 
U A B  
U nassiste d Breat hi n g  
V F D  
Ve ntilat or Free Da ys 
W FI  
Water f or I njecti o n  
 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
1 9  of 6 8  
1 6  A pr 2 0 1 9  
 
I N TR O D U C TI O N 
T his is a P hase II cli nical st u d y t o i n vesti gate t he efficac y a n d safet y of F P- 1 2 0 1-l y o 
( Rec o m bi na nt H u ma n I nterfer o n [I F N] beta- 1a) i n patie nts s ur vi vi n g e mer ge nc y o pe n 
s ur ger y  f or  a n  i nfrare nal  r u pt ure d  a b d o mi nal  a ortic  a ne ur ys m.  F P- 1 2 0 1-l y o  is  a 
l y o p hilise d p o w der f or m of Rec o m bi na nt H u ma n I F N beta- 1a rec o nstit ute d i n water 
f or i njecti o n a n d is a d mi nistere d i ntra ve n o usl y as a b ol us i njecti o n f or 6 c o nsec uti ve 
da ys.   
 
Dise ase re vie w a n d r ati o n ale f or t he st u d y 
R u pt ure d  a b d o mi nal  a ortic  a ne ur ys m  ( R A A A)  is  a  s ur gical  e mer ge nc y  wit h  a n 
o verall m ortalit y of 7 0   8 0 % ( B o w n et al. 2 0 0 2). It re q uires i m me diate s ur ger y a n d 
a ortic  re pair.  A p pr o xi matel y  half  of  R A A A  patie nts  d o  n ot  reac h  t he  h os pital  a n d 
des pite i m me diate s ur ger y a n d i nte nsi ve care treat me nt a n ot her half of t he patie nts die 
i n  h os pital  wit hi n  3 0  da ys  p ost- o perati vel y  m ostl y  d ue  t o  m ulti- or ga n  fail ure. 
S ur vi vi n g R A A A patie nts ha ve a l o n g-life e x pecta nc y c o m para ble t o t hat of t heir a ge 
gr o u p ( Alric et al. 2 0 0 3, K or h o ne n et al. 2 0 0 3 a n d Bia ncari et al. 2 0 1 1). T he ca use of 
hi g h  p ost- o perati ve  m ortalit y  is  i n  part  d ue  t o  pr ol o n ge d  h y p ote nsi o n  fr o m  t he 
r u pt ure d  a orta  a n d  t he  after mat h  of  rest ori n g  bl o o d  fl o w;  re perf usi o n,  vasc ular 
lea ka ge  a n d  fail ure  of  vital  or ga ns.  Dia g n ose d  pri mar y  ca uses  of  p ost- o perati ve 
m ortalit y  are  ac ute  re nal  fail ure,  i ntesti nal  i nfarcti o n,  m y ocar dial  i nfarcti o n, 
res pirat or y i ns ufficie nc y a n d m ulti- or ga n fail ure ( B o w n et al. 2 0 0 4). 
Des pite  se veral  deca des  of  R A A A  s ur ger y  a n d  a d va nce me nts  i n  m o der n  me dici ne 
s ur prisi n gl y little has bee n ac hie ve d i n re d uci n g p ost- o perati ve m ortalit y ( B o w n et al. 
2 0 0 1 a n d Vä n ni et al. 2 0 1 6). A maj or a d va nce me nt be nefiti n g t he patie nts has bee n 
t he mi ni misati o n of t he ti me of h y p ote nsi o n, i.e. t he ti me fr o m r u pt ure t o cla m pi n g of 
t he a orta. F or se veral deca des i ntra- o perati ve m ortalit y has re mai ne d rat her s mall a n d 
c o nsta nt,  at  ar o u n d  3, 5  %.  P ost- o perati ve  m ortalit y  has  s h o w n  a  sli g ht  decli ne  o ver 
t he deca des b ut still re mai ns hi g h at ar o u n d 2 5   5 0 % de pe n di n g o n patie nt c o h orts. 
Rece ntl y  ver y  si g nifica nt  p u blicati o ns  ha ve  bee n  ma de  o n  t he  m ortalit y  of  R A A A, 
beca use e n d o vasc ular a ortic re pair ( E V A R) has bee n s u g geste d a pr o misi n g treat me nt 
wit h o ut  maj or  s ur gical  tra u ma  a n d  l o wer  m ortalit y.    O pe n  a n d  e n d o vasc ular  a ortic 
re pair f or a r u pt ure (r E V A R) ha ve bee n st u die d a gai nst eac h ot her i n b ot h pr os pecti ve 
ra n d o mize d setti n gs a n d re gistr y base d st u dies, b ut n o clear si g nifica nt differe nce has 
bee n  see n  i n  m ortalit y  rates  (I M P R O V E  trialists  2 0 1 4  a n d  Kart hi kesali n ga m et  al. 
2 0 1 4).  T h us,  we  ca n  n o w  state  t hat  d ue  t o  t he  o verall  hae m orr h a gic  s h oc k  a n d 
isc he mia-re perf usi o n  i nj ur y  lea di n g  t o  a  s yste mic  i nfla m mat or y  res p o nse  s y n dr o me 
( SI R S)  a n d  m ulti- or ga n  fail ure  ( M O F)  t he  m ortalit y  of  R A A A  is  ver y  precisel y 
ar o u n d 3 0- 3 5 %, w hic h als o a p plies t o Fi nla n d ( Ka nt o ne n et al. 1 9 9 9, Bia ncari et al. 
2 0 1 1 a n d Vä n ni et al. 2 0 1 6). 
E ve n  i n  electi ve  n o n-e mer ge nc y  A A A  re pair,  patie nts  e x perie nce  a  SI R S  d ue  t o 
cla m pi n g  a n d  u ncla m pi n g  of  t he  a orta  ( B o w n  et  al.  2 0 0 1).  C o m pare d  t o  patie nts 
u n der g oi n g  e n d o vasc ular  re pair  f or  a  r u pt ure d  a ne ur ys m  patie nts  u n der g oi n g  o pe n 
re pair are c o nsi dere d t o s uffer fr o m a t w o-f ol d SI R S strai n d ue t o t he i nitial r u pt ure 
a n d t he n t he o pe n s ur ger y i n v ol vi n g cla m pi n g a n d u n-cla m pi n g of t he a orta ( Ma kar et 
al.  2 0 1 3).  I n  a d diti o n,  preli mi nar y  h u ma n  data  has  s h o w n  t hat  cr oss-cla m pi n g  t he 
i nfra-re nal a orta is ass ociate d wit h decrease d C D 7 3 acti vit y i n p ost- o perati ve ser u m 
sa m ples, w hic h i m plies t hat h y p o xia a n d C D 7 3 me diate d c o m pe nsat or y mec ha nis ms 
are  i m paire d  or  a da pt  t o o  sl o wl y  t o  t he  isc he mic  i ns ult  (Jal ka ne n  et  al.  2 0 1 6).  T his 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
2 0  of 6 8  
1 6  A pr 2 0 1 9  
i m plies t hat a n y dr u g s u bsta nce t hat c o ul d e n ha nce t he nat ural res p o nse t o h y p o xia b y 
i ncreasi n g C D 7 3 acti vit y me diate d a de n osi ne pr o d ucti o n, c o ul d be be neficial a gai nst 
h y p o xia-i n d uce d i nfla m mati o n a n d i ncrease d ca pillar y lea ka ge ( Eltzs c hi g et al. 2 0 1 2).  
It  has  bee n  well  esta blis he d  t hat  C D 7 3  e x pressi o n  a n d  it’s  ect o- 5’- n ucle oti dase 
acti vit y  ca n  be  i n d uce d  b y  I F N  beta  i n  c ult ure d  e n d ot helial  cells  wit h  a  c o nse q ue nt 
decrease i n vasc ular per mea bilit y ( Nie melä et al. 2 0 0 4). I F N beta- 1a has alrea d y bee n 
de m o nstrate d  as  safe  a n d  effecti ve  i n  t he  treat me nt  of  A R D S  patie nts  i n  t he 
F P C LI 0 0 1  st u d y,  wit h  a  si milar  u n derl yi n g  pat h ol o gical  m olec ular  mec ha nis m 
( Belli n ga n et al. 2 0 1 4). T h us, F P - 1 2 0 1-l y o offers a pr o misi n g treat me nt f or C D 7 3 a n d 
a de n osi ne  re g ulate d  p ost-isc he mic  i nj ur y  n ot  i n  o ne  b ut  se veral  or ga ns  u n der  ris k 
d uri n g o perati ve treat me nt of R A A A. 
 
I n vesti g ati o n al me dici n al pr o d uct 
Rec o m bi na nt H u ma n I F N beta- 1a is a n a p pr o ve d treat me nt f or patie nts wit h rela psi n g 
re mitti n g  m ulti ple  scler osis  a n d  t he  safet y  pr ofile  i n  s uc h  patie nts  is  well 
c haracterise d. M ore rece ntl y Rec o m bi na nt H u ma n I F N beta- 1a was assesse d f or t he 
treat me nt of ac ute l u n g i nj ur y ( A LI) a n d ac ute res pirat or y distress s y n dr o me ( A R D S) 
i n a p hase I/II st u d y ( F P C LI 0 0 1). Acc or di n g t o t he F P C LI 0 0 1 st u d y A R D S patie nts 
recei vi n g I F N beta- 1a be nefite d s u bsta ntiall y ( Belli n ga n et al. 2 0 1 4). Base d o n d ose 
fi n di n gs, 1 0 µ g  i. v. dail y d ose of I F N beta- 1a f or 6 c o nsec uti ve da ys was f o u n d t o be 
t he  o pti mal  t olerate d  d ose  wit h  a  g o o d  safet y  pr ofile  i n  t his  se verel y  ill  patie nt 
p o p ulati o n of A LI/ A R D S. 
F P - 1 2 0 1-l y o is a  l y o p hilise d  p o w der  f or m  of  Rec o m bi na nt  H u ma n  I F N  beta- 1a 
rec o nstit ute d  i n  water.  A d diti o nall y, F P - 1 2 0 1-l y o  has  bee n  i n vesti gate d  i n  Ja pa nese 
m o derate/se vere  A R D S  patie nts  wit h  c o m para ble  res ults  t o  F P C LI 0 0 1  st u d y  (fi nal 
st u d y re p ort pe n di n g).  
Base d o n t he p hase I/II st u d y ( F P C LI 0 0 1) d ose fi n di n g, it is e x pecte d t hat t he 1 0 µ g 
i. v. dail y d ose of F P- 1 2 0 1-l y o f or 6 c o nsec uti ve da ys w o ul d be o pti mal als o i n R A A A 
patie nts,  t he  sa me  d ose  as  i n  u n der g oi n g  p hase  III  trial  i n  m o derate/se vere  A R D S 
(I N T E R E S T trial). 
 
Mec h a nis m of Acti o n 
C D 7 3  is  a n  ect o- 5'- n ucle oti dase  e nz y me  e x presse d  o n  vasc ular  e n d ot heli u m, 
e pit helial  cells  a n d  o n  a  s u bset  of  le u k oc ytes  ( Zi m mer ma n n  et  al.  1 9 9 2).  T hr o u g h 
de p h os p h or ylati o n of a de n osi ne m o n o p h os p hate ( A M P), it yiel ds a de n osi ne, a p ote nt 
a nti-i nfla m mat or y m olec ule, w hic h pre ve nts vasc ular lea ka ge a n d i n hi bits le u k oc yte 
recr uit me nt  i nt o  sites  of  i nfla m mati o n  ( C ol ga n  et  al.  2 0 0 6).  S uc h  e n d o ge n o us 
pr otecti ve  mec ha nis ms  are  e n ha nce d  i n  t he  prese nce  of  h y p o xia  ( T h o m ps o n  et  al. 
2 0 0 4).  C D 7 3  e x pressi o n  o n  i m m u ne  a n d  vasc ular  cells  a n d  e xtracell ular  a de n osi ne 
pr o d ucti o n  ha ve  bee n  li n ke d  t o  t he  alle viati o n  of  isc he mia-re perf usi o n  i nj ur y  of  t he 
m y ocar di u m, i ntesti ne a n d ki d ne ys i n precli nical setti n gs. 
Precli nical  st u dies  ha ve  s h o w n  t hat  C D 7 3  e x pressi o n  is  u p-re g ulate d  i n  t he 
e n d ot heli u m b y I F N beta- 1a treat me nt i n a ti me a n d d ose de pe n de nt fas hi o n ( Nie melä 
et al. 2 0 0 4). Als o, i n a m o use m o del of M O F , I F N beta was s h o w n t o be of be nefit i n 
pr otecti n g  t he  al ve olar  str uct ure  fr o m  da ma ge  w he n  c o m pare d  t o  ve hicle  treate d 
c o ntr ols ( Kiss et al. 2 0 0 7). I n a d diti o n, I F N beta treat me nt has bee n s h o w n t o pre ve nt 
vasc ular lea ka ge i n A LI a ni mal m o dels. E n ha nce d a de n osi ne pr o d ucti o n als o i n hi bits 
le u k oc yte  i nfiltrati o n,  t h us  re d uci n g  t he  escalati o n  of  i nfla m mati o n  a n d  re perf usi o n 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
2 1  of 6 8  
1 6  A pr 2 0 1 9  
i nj ur y ( K oszal ka et al. 2 0 0 4, Le n n o n et al. 1 9 9 8 a n d V ol mer et al. 2 0 0 6). I n a rece nt 
st u d y, I F N beta- 1a t hera p y was s h o w n t o re d uce m ortalit y i n patie nts wit h A R D S b y 
o ver  8 0  %  ( Belli n ga n  et  al.  2 0 1 4).  Pre-cli nical  data  s u g gests  t hat  acc or di n g  t he 
mec ha nis m of acti o n, F P - 1 2 0 1-l y o c o ul d als o be pr otecti ve i n t he re perf usi o n i nj ur y 
of t he m y ocar di u m ( Ec kle et al. 2 0 0 7), i ntesti ne ( Hart et al. 2 0 1 1) a n d ki d ne ys ( Gre nz 
et al. 2 0 0 8) a n d a gai nst SI R S i n d uce d b y h y p o xia ( Eltzsc hi g et al. 2 0 1 2). 
 
Precli nic al a n d cli nic al d at a 
F ull  details  of  precli nical  a n d  cli nical  i nf or mati o n  of F P - 1 2 0 1-l y o  are  f o u n d  i n  t he 
I n vesti gat or’s Br oc h ure. 
 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
2 2  of 6 8  
1 6  A pr 2 0 1 9  
 
S T U D Y O B J E C TI V E S 
 
Pri m ar y O bjecti ve 
T o e val uate t he safet y a n d t he efficac y of F P- 1 2 0 1-l y o o ver place b o o n re d uci n g all-
ca use  m ortalit y  at  st u d y  da y  3 0 ;  D3 0  ( 3 0  da ys  fr o m  t he  first  d ose  of  st u d y 
me dicati o n). 
 
Sec o n d ar y O bjecti ves 
1.  T o  e val uate  t he  efficac y  of  F P- 1 2 0 1-l y o  treat me nt  b y  assessi n g  s h ort  ter m 
o utc o mes ( D 3 0) a n d mi d-ter m o utc o mes D 9 0 ( 3 m o nt hs) 
2.  T o e val uate t he safet y a n d t olera bilit y of F P- 1 2 0 1-l y o treat me nt  
3.  T o e val uate t he p har mac o d y na mics ( P D) of F P- 1 2 0 1-l y o 
4.  T o  e val uate  t he  Te ntati ve  Disease  S pecific  Mar ker  C D 7 3  a n d  P ote ntial 
I nfla m mat or y Mar kers I L- 6 a n d H G F 
5.  T o e val uate ne utralizi n g a nti b o dies a gai nst I F N beta- 1a ( N A bs) 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
2 3  of 6 8  
1 6  A pr 2 0 1 9  
 
O V E R A L L D E SI G N A N D P L A N O F T H E S T U D Y 
 
S u m m ar y of St u d y Desi g n 
T his is a m ultice ntre, ra n d o mise d, d o u ble- bli n d, P hase II, parallel gr o u p c o m paris o n 
st u d y  of  t he  efficac y  a n d  safet y  of  F P- 1 2 0 1-l y o  c o m pare d  t o  place b o  i n  patie nts 
s ur vi vi n g  e mer ge nc y  o pe n  s ur ger y  f or  a n  i nfra-re nal  r u pt ure d  a b d o mi nal  a ortic 
a ne ur ys m.  B ot h treat me nt gr o u ps will recei ve sta n dar d s u p p orti ve care.   
Wit h  a n  esti mate d  scree ni n g  fail ure  rate  of  a p pr o xi matel y  1 5 %,  ma xi m u m  of 
1 8 0 patie nts will be c o nse nte d a n d e ntere d i nt o t he st u d y i n or der t o ra n d o mise a n d 
i nitiate  treat me nt  of  1 5 2 patie nts.  T he  sa m ple  size  calc ulati o ns  will  be  re-e val uate d 
after t he first i nteri m a nal ys is has bee n perf or me d.  
    
T he  st u d y  desi g n  i nc or p orates  a n  I n de pe n de nt  Data  M o nit ori n g  C o m mittee (I D M C) 
t hat  will  re vie w  safet y  data  retrie ve d  f or  i nteri m  a nal ysis  (i.e.  A d verse  E ve nts  [ A E] 
a n d Seri o us A d verse E ve nts [ S A E]). Details of t he I D M C are gi ve n i n Secti o n 9. 8.   
Patie nts will recei ve 1 0 µ g F P- 1 2 0 1-l y o or place b o i ntra ve n o usl y as a b ol us i njecti o n 
o nce e ver y 2 4 h o urs.  T he ma xi m u m d urati o n of treat me nt will be 6 da ys. Treat me nt 
ma y  be  disc o nti n ue d  bef ore  6  da ys  if  t he  patie nt’s  c o n diti o n  i m pr o ves  be y o n d  t he 
nee d  f or  I C U  treat me nt  a n d  if,  i n  t he  o pi ni o n  of  t he  I n vesti gat or,  t he  patie nt  w o ul d 
li kel y n ot be nefit fr o m c o nti n uati o n of treat me nt.   
A sc he d ule f or t he tests a n d assess me nts t o be c o n d ucte d d uri n g t his st u d y is f o u n d i n 
t he Ta bles 5- 8. 
T he st u d y o bjecti ves a n d o utc o me meas ures t o be use d i n t his st u d y are descri be d i n 
Secti o ns 2 a n d 6.   
T he st u d y desi g n is s u m marise d bel o w i n Fi g ure 1.   
 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
2 5  of 6 8  
1 6  A pr 2 0 1 9  
 
Criteri a f or t he St u d y assess me nts 
 Pri m ary Effic acy E n d p oi nt: 
•  A ll-ca use m ortalit y at D 3 0 
 
   Sec o n d ar y Effic ac y E n d p oi nts: 
•  A ll-ca use m ortalit y at D 9 0 ( 3 m o nt hs)  
•  N u m ber of ve ntilat or free da ys ( V F Ds) at D 3 0 
•  N u m ber of da ys recei vi n g he m o dial ysis at D 3 0 a n d D 9 0 
•  N u m ber of or ga n fail ure free da ys u p t o D 3 0 b y mea ns of t he S O F A sc ore  
•  Pre vale nce  of  a b d o mi nal  c o m part me nt  s y n dr o me,  i.e.  i ntra-a b d o mi nal 
press ure (I A P) bet wee n st u d y gr o u ps 
•  Ne utralizi n g a nti b o dies a gai nst I F N beta- 1a ( N A bs) i n w h ole bl o o d sa m ples 
u p t o D 3 0 
•  Disa bilit y at D 9 0 ( 3 m o nt hs) b y m o difie d ra n ki n g scale. 
 
 S afety  
•  Cli nicall y si g nifica nt treat me nt e mer ge nt a d verse e ve nts ( T E A Es) u p t o D 3 0 
fr o m  vital  si g ns  data,  la b orat or y  data,  p h ysical  e xa mi nati o ns  a n d 
s p o nta ne o us re p orti n g w he n c o nsci o us 
 
 P h ar m ac oe c on o mics assess me nts  
•  Le n gt h of I C U sta y, i n ter ms of I C U free da ys at D 3 0 
•  Le n gt h of h os pital sta y, i n ter ms of h os pital free da ys at D 9 0 
•  Le n gt h of sta y at a n ot her healt h care facilit y at D 9 0 
•  Le n gt h of he m o dial ysis nee de d 
•  Ve ntilati o n free da ys at D 3 0 
 
 E x pl or at ory e n d p oi nts assess me nts  
P h ar m ac o d y n a mics ( P D):   
•  M x A  ( pr otei n)  c o nce ntrati o n  i n  w h ole  bl o o d  sa m ples  fr o m  baseli ne  u p  t o 
D 1 3. 
 
Te nt ati ve Dise ase S pecific M ar ker: 
•  C D 7 3 c o nce ntrati o n/acti vit y i n ser u m sa m ples fr o m baseli ne u p t o D 1 3 
•  P ote ntial  I nfla m mat or y  Mar kers  I L- 6  a n d  H G F  i n  ser u m  sa m ples  fr o m 
baseli ne u p t o D 1 3 
 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
2 6  of 6 8  
1 6  A pr 2 0 1 9  
 
 
 
J ustific ati o n of t he St u d y Desi g n 
T his  is  a  P hase II  st u d y  t o  e val uate  t he  efficac y  a n d  safet y  of  F P- 1 2 0 1-l y o  i n  t he 
treat me nt  of  patie nts  s ur vi vi n g  o pe n  s ur ger y  f or  R A A A.  T he  st u d y  is  desi g ne d  as  a 
ra n d o mise d,  d o u ble- bli n d,  place b o-c o ntr olle d,  parallel  gr o u p,  m ulti-ce ntre  cli nical 
st u d y.  
D ue  t o  t he  ra n d o misati o n  pr oce d ure  a n d  t he  d o u ble- bli n d  nat ure  of  t his  st u d y  t he 
p ote ntial bias of t he st u d y res u lts is mi ni mise d.  
If  t here  is  a n y  d o u bt  re gar di n g  t he  i nte grit y  of  t he  d o u ble- bli n d  desi g n,  a p pr o priate 
meas ures will be ta ke n (refer t o Secti o n 5. 4). 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
2 7  of 6 8  
1 6  A pr 2 0 1 9  
 
S T U D Y P O P U L A TI O N 
T he  st u d y  p o p ulati o n  will  c o nsist  of  patie nts  u n der g oi n g  e mer ge nc y  s ur ger y  f or  a 
r u pt ure d a b d o mi nal a ortic a ne ur ys m. Patie nts m ust meet all t he i ncl usi o n criteria a n d 
n o ne of t he e xcl usi o n criteria t o be e nr olle d i n t he st u d y. T he i ncl usi o n a n d e xcl usi o n 
criteria  a p pl y  d uri n g scree ni n g a n d  pri or  t o  a d mi nistrati o n  of  t he  first  d ose  of  st u d y 
dr u g o n D 0. 
 
I ncl usi o n Criteri a 
T o  be  eli gi ble  f or  i ncl usi o n  i nt o  t his  st u d y,  eac h  patie nt  m ust  f ulfil  t he  f oll o wi n g 
i ncl usi o n criteria (alter nati vel y 1 or 2 a n d all 3, 4 a n d 5) d uri n g scree ni n g a n d pri or t o 
ra n d o misati o n a n d t he first d ose of st u d y me dicati o n bei n g a d mi nistere d o n D 0:  
1.  Patie nts ( male or fe male) prese nti n g wit h a R A A A dia g n ose d b y ultras o u n d or 
C T-sca n i n t he e mer ge nc y r o o m 
•  all f or ms of i nfrare nal R A A As wit h or wit h o ut c oe xisti n g iliac a ne ur ys ms 
are i ncl u de d 
or 
2.  Patie nts ( male or fe male) prese nti n g wit h s y m pt o ms of R A A A k n o w n t o ha ve 
a n i nfrare nal A A A a n d pr ocee di n g strai g ht t o o pe n re pair wit h o ut ra di ol o gical 
assess me nt  a n d  r u pt ure  c o nfir me d  (retr o perit o neal  hae mat o ma)  i ntra-
o perati vel y 
a n d 
3.  A ne ur ys ma re pair m ust be i nfra-re nal, i.e. t he pr o xi mal a nast o m osis m ust be 
bel o w  t he  re nal  arteries  a n d  t he  re nal  arteries  m ust  sta y  i ntact.  Te m p orar y 
a b o ve  t he  re nal  cla m pi n g  ca n  be  use d  f or  a  ma xi m u m  of  3 0 mi n utes  (t otal 
cla m pi n g ti me) 
a n d 
4.  Patie nts pr o vi di n g i nf or me d c o nse nt ( writte n si g ne d or wit nesse d) 
Or t heir ne xt of ki n pr o vi di n g writte n i nf or me d c o nse nt 
5.  A ge o ver 1 8 years 
 
E xcl usi o n Criteri a 
T o  be  eli gi ble  f or  i ncl usi o n  i nt o  t his  st u d y,  eac h  patie nt  m ust  n ot  meet  a n y  of  t he 
f oll o wi n g  e xcl usi o n  criteria d uri n g  scree ni n g  or  pri or  t o  r a n d o mis ati o n  a n d  t he 
first d ose of st u d y me dic ati o n bei n g a d mi nistere d: 
1.  M ori b u n d  patie nt  n ot  eli gi ble  f or  treat me nt  i n  I C U  or  e x pecte d  t o  s ur vi ve 
s ur ger y 
2.  Mar ke dl y s h ort life e x pecta nc y, e. g. a d va nce d mali g na nt disease 
3.  C urre nt partici pati o n i n a n ot her e x peri me ntal treat me nt pr ot oc ol  
4.  Si g nifica nt  c o n gesti ve  heart  fail ure,  defi ne d  as  Ne w  Y or k  Heart 
Ass ociati o n ( N Y H A) class I V 
5.  C urre nt treat me nt wit h I F N al p ha or I F N beta 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
2 8  of 6 8  
1 6  A pr 2 0 1 9  
6.  Dial ysis t hera p y f or c hr o nic re nal fail ure 
7.  Irre versi ble s h oc k fr o m hae m orr ha ge 
8.  U nc o nsci o us ness w he n arri vi n g t o t he h os pital a n d d uri n g scree ni n g 
9.  r E V A R first ( pri or atte m pt f or e n d o vasc ular a ortic re pair f or c urre nt r u pt ure, 
pri or electi ve E V A R a p plica ble) 
1 0.  Earlier dia g n ose d cirr h osis i n me dical rec or ds 
1 1.  Pre g na nc y  a n d  w o me n  wit h  c hil d  beari n g  p ote ntial  wit h o ut  ne gati ve  bl o o d 
pre g na nc y test 
1 2.  R u pt ure  n ot  c o nfir me d  b y  C T  or  i ntra- o perati vel y  (i m pe n di n g  r u pt ures  are 
e xcl u de d) 
1 3.  R A A A re q uiri n g re pair of t he re nal arteries or t he pr o xi mal a orta 
•  t h orac oa b d o mi nal a ne ur ys ms re q uiri n g i m me diate re pair 
•  da ma ge d re nal arteries d uri n g e mer ge nc y cla m pi n g re q uiri n g re pair 
N O T E: 
•  te m p orar y  cla m pi n g a b o ve  t he  re nal  arteries  ( ma x  3 0 mi n   t otal  cla m pi n g 
ti me a b o ve t he re nal arteries) d oes n ot  lea d t o e xcl usi o n 
•  li gati o n of t he left re nal vei n d oes n ot  lea d t o e xcl usi o n 
 
C o nfir m ati o n of P atie nt Eli gi bilit y 
T o e ns ure a p pr o priate e nr ol me nt i nt o t he st u d y t here will be a f or mal c o nfir mati o n of 
eli gi bilit y pr ocess utilisi n g t he f oll o wi n g pr oce d ure: 
T here  will  be  a n  electr o nic  Case  Re p ort  F or m  (e C R F)  c hec klist  of  i ncl usi o n  a n d 
e xcl usi o n  criteria;  all  ite ms  will  nee d  t o  be  tic ke d  c orrectl y.  T he  Cli nical  Data 
Ma na ge me nt S yste m ( C D M S) will n ot all o w a patie nt t o pr o gress t o ra n d o misati o n if 
t hese  ha ve  bee n  c o m plete d  i nc orrectl y.  T he  vasc ular  s ur ge o n  will  perf or m  t his 
pr oce d ure a n d ra n d o mizati o n i m me diatel y after t he o perati o n. If t he tic ks c orres p o n d 
t o t he i ncl usi o n criteria, t he C D M S will ma ke t he patie nt a vaila ble t o be ra n d o mise d. 
If t he tic ks are a gai nst i ncl usi o n, t he patie nt ca n n ot be ra n d o mise d a n d t he reas o n f or 
t his will be n ote d i n t he e C R F, a n d t he patie nt will be re gar de d as a scree ni n g fail ure. 
Wit h t his met h o d, o nl y t h ose patie nts w h ose data are rec or de d as meeti n g eli gi bilit y 
criteria ca n be ra n d o mise d.  
 
P atie nt Wit h dr a w al a n d Re pl ace me nt 
 Disc o nti n u ati o n Criteri a 
Patie nts  ma y  disc o nti n ue  fr o m  t he  e ntire  st u d y,  i ncl u di n g  f oll o w- u p,  at  a n y  ti me 
wit h o ut  a n y  reas o n  a n d  wit h o ut  prej u dice  t o  t heir  f ut ure  me dical  care;  t he y  are  n ot 
o bli ge d t o state t heir reas o ns f or wit h dra wi n g.  
A d diti o nall y, t he I n vesti gat or ma y disc o nti n ue a patie nt at a n y ti me if it is c o nsi dere d 
t o be i n t he best i nterest of t he patie nt.  Disc o nti n uati o n of st u d y me dicati o n b y t he 
I n vesti gat or  d ue  t o  i m pr o ve me nt  of  a  patie nt’s  c o n diti o n d oes  n ot   c o nstit ute  a 
wit h dra wal as t he patie nt will c o nti n ue wit h t he st u d y assess me nts.    
A patie nt m a y be disc o nti n ue d  fr o m t he st u d y f or e xa m ple of t he f oll o wi n g reas o ns: 

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•  Pr ot oc ol vi olati o ns i ncl u di n g n o n-c o m plia nce wit h st u d y pr oce d ures or patie nt l ost 
t o f oll o w- u p 
•  S A Es  
•  A d mi nistrati ve reas o ns 
•  Patie nt re q uest 
•  S p o ns or re q uest 
•  I n vesti gat or re q uest 
•  A ut h orit y re q uest 
I n t he case of a disc o nti n uati o n, t he I n vesti gat or m ust e ns ure t hat t he stat us pa ge i n 
t he e C R F f or t he e n d of t he st u d y  is c o m plete d. 
Patie nts ma y be re q uire d t o disc o nti n ue fr o m st u d y dr u g after disc ussi o n wit h t he 
S p o ns or a n d/ or I n vesti gat or f or t he f oll o wi n g reas o ns: 
•  A Es  
•  At t he discreti o n of t he I n vesti gat or or if it is c o nsi dere d t o be i n t he patie nt’s best 
i nterest 
If  t he  a d mi nistrati o n  of  st u d y  me dicati o n  is  pre mat urel y  disc o nti n ue d,  t he  pri mar y 
reas o n  f or  disc o nti n uati o n  m ust  be  rec or de d  i n  t he  a p pr o priate  secti o n  of  t he  e C R F 
a n d  all  eff orts  ma de  t o  c o m plete  t he  o bser vati o ns  o n  t hat  st u d y  treat me nt  da y  as 
t h or o u g hl y as p ossi ble.  
A  c o m plete  fi nal  e val uati o n  f oll o wi n g  t he  patie nt’s  disc o nti n uati o n  s h o ul d  be  ma de 
o n  t he  da y  of  t he  disc o nti n uati o n/ disc har ge,  as  descri be d  i n  Secti o n  7. 2.  a n d  a n y 
o n g oi n g  A Es  s h o ul d  be  f oll o we d  u p  t o  res ol uti o n  or  st u d y  D 3 0,  w hic he ver  occ urs 
first.   
T he  st u d y  will  be  ter mi nate d  if,  i n  t he  o pi ni o n  of  t he  S p o ns or,  si g nifica nt  safet y 
c o ncer ns arise d uri n g t he c o n d uct of t he st u d y.   
Patie nts w h o disc o nti n ue st u d y dr u g ma y c o nti n ue i n t he st u d y. T he I n vesti gat or m ust 
e ns ure t hat t he stat us pa ge i n t he e C R F f or t he e n d of st u d y is c o m plete d. 
I n all cases, t he reas o n(s) f or disc o nti n uati o n, i ncl u di n g t he pri mar y reas o n, m ust be 
rec or de d  i n  t he  e C R F.  If  a  patie nt  pre mat urel y  disc o nti n ue  fr o m  t he  st u d y  dr u g  f or 
a n y  reas o n,  t he  I n vesti gat or  m ust  ma ke  e ver y  eff ort  t o  perf or m  t he  e val uati o ns 
descri be d  f or  t he  f oll o w- u p  visits.  A n y  o n- g oi n g  A Es  s h o ul d  be  f oll o we d  u p  t o 
res ol uti o n or D 3 0 w hic he ver is t he s o o ner. See als o Secti o n 7. 6. 1. A p er missi o n will 
be s o u g ht t o access t he patie nt’s me dical rec or ds f or data rele va nt t o t he st u d y (e. g., 
m ortalit y, V F Ds, etc.) t o c o m plete t he D 3 0 a n d D 9 0 f oll o w u p. See als o secti o n 9. 6. 2. 
Patie nts w h o wit h dra w c o nse nt f or t heir data t o be a nal yse d will be i de ntifie d i n t he 
C D M S. A n y data c ollecte d will n ot be delete d, b ut will n ot be use d i n a n y s u bse q ue nt 
o ut p uts. 
Patie nts t hat ha ve recei ve d at least o ne d ose of t he st u d y dr u g a n d disc o nti n ue d will 
n ot be re place d. 
T he  st u d y  will  be  ter mi nate d  if,  i n  t he  o pi ni o n  of  t he  I D M C  or  t he  S p o ns or, 
si g nifica nt safet y c o ncer ns arise d uri n g t he c o n d uct of t he st u d y. 
4. 4. 1. 1  N o n- atte n d a nce of F oll o w- u p Assess me nts 
Atte m pts  s h o ul d  be  ma de  t o  c o ntact  patie nts  disc har ge d  fr o m  h os pital  w h o  d o  n ot 
atte n d t heir st u d y f oll o w- u p assess me nts t o e ns ure t heir well - bei n g. I n s uc h cases, t he 

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patie nt will be c o ntacte d at least t wice b y tele p h o ne a n d o nce b y letter t o re q uest t hat 
t he y atte n d t he sc he d ule d f oll o w- u p assess me nt. If patie nts d o n ot res p o n d t he y will 
be c o nsi dere d as l ost t o f oll o w u p at t hat ti me p oi nt. If a patie nt is l ost t o f oll o w- u p, 
w here ver p ossi ble m ortalit y data will be s o u g ht at all re mai ni n g m ortalit y ti me p oi nts 
fr o m alter nati ve s o urces s uc h as t he patie nt’s l ocal p h ysicia n. 
 Re pl ace me nt P olicy 
All  patie nts  w h o  bec o me  i neli gi ble  after  c o nse nti n g  b ut  bef ore  ra n d o misati o n  are 
re place d  a n d  dee me d  as  scree ni n g  fail ures.  A  scree ni n g  fail ure  is  defi ne d  as  a n y 
patie nt  w h o  d oes  n ot  c o m pl y  wit h  t he  i ncl usi o n  a n d  e xcl usi o n  criteria  d uri n g 
scree ni n g or  pri or t o ra n d o misati o n a n d recei vi n g t he first d ose of st u d y me dicati o n. 
Patie nts w h o c o m plete scree ni n g a n d are ra n d o mise d a n d recei ve at least 1 d ose of t he 
st u d y me dicati o n will n ot be re place d e ve n if later wit h dra w n or l ost t o f oll o w u p.   
 
Pl a n ne d S a m ple Size a n d N u m ber of St u d y Ce ntres 
It is pla n ne d t o ra n d o mise 1 5 2 patie nts at 1 0- 1 8 h os pital st u d y ce ntres i n Fi nla n d, i n 
U K, i n Lit h ua nia a n d i n Est o nia a n d p ossi bl y i n ot her c o u ntries i n E E A a n d i n U S A  
f or  t his  st u d y.  P ossi ble  a d diti o nal  selecti o n  will  be  deci de d  later,  as  re q uire d. See 
Secti o n 8. 2. f or a disc ussi o n of sa m ple size. 
 
P atie nt R a n d o mis ati o n 
 R a n d o mis ati o n Sc he me 
Patie nts  are  ra n d o ml y  assi g ne d  t o  treat me nt  wit h F P - 1 2 0 1-l y o  or  place b o  i n  t he 
ra n d o misati o n rati o of 2: 1 (acti ve: place b o) f or treat me nt gr o u ps, stratifie d b y se x a n d 
a ge. 
T he  treat me nt  assi g ne d  t o  eac h  patie nt  is  deter mi ne d  acc or di n g  t o  a  c o m p uter- 
ge nerate d ra n d o misati o n list wit hi n e C R F . 
 R a n d o mis ati o n of P atie nts t o Tre at me nt 
Ra n d o misati o n  of  patie nts  t o  treat me nt  will  occ ur  i m me diatel y  after  c o m pleti o n  of 
s ur ger y  a n d  after  all  scree ni n g  pr oce d ures  ha ve  bee n  perf or me d  a n d  eli gi bilit y  f or 
i ncl usi o n  i n t he  st u d y  has  bee n  c o nfir me d.  Eac h  ra n d o mise d  patie nt  will  recei ve  a 
u ni q ue  ra n d o misati o n  n u m ber.  Ra n d o mise d  patie nts  w h o  ter mi nate  t heir  st u d y 
partici pati o n f or a n y reas o n, re gar dless of w het her st u d y dr u g was ta ke n or n ot, will 
retai n t heir ra n d o misati o n n u m ber. 
T he I n vesti gat or will use I W R S f or ra n d o misati o n of patie nts. Details ca n be f o u n d i n 
t he st u d y file. 

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1 6  A pr 2 0 1 9  
 
S T U D Y D R U G 
 
I de ntit y 
Re ntsc hler Bi o p har ma  
S E,  
La u p hei m,  
Ger ma n y  
ma n ufact ures  l y o p hilise d 
F P - 1 2 0 1-l y o  (rec o m bi na nt  h u ma n  I F N  beta- 1a)  a n d  t he  matc he d  place b o.  B ot h 
F P - 1 2 0 1-l y o  a n d  place b o  p o w ders  are  free  of  a ni mal  ser u m  a n d  h u ma n  ser u m 
al b u mi n.  Vetter  P har ma  I nter nati o nal  Ser vices,  Ra ve ns b ur g,  Ger ma n y  ma n ufact ures 
pre-fille d water f or i njecti o n ( W FI) dil ue nt s yri n ges.  
A Mi xJect Ò  tra nsfer de vice will be use d i n t his st u d y. T his Mi xJectÒ  tra nsfer de vice is 
a  si n gle  u nit  f or  rec o nstit uti n g  a  p o w der e d  dr u g  wit h  a  dil ue nt  pre-fille d  s yri n ge. 
U p o n  rec o nstit uti o n,  t he  dr u g  is  a vaila ble  f or  i m me diate  i njecti o n.  T he  Mi xJect Ò  
tra nsfer de vice e na bles t he safe, ra pi d a n d eas y pre parati o n of l y o p hilise d dr u gs. T he 
Mi xJect
Ò   tra nsfer  de vice  is  ma n ufact ure d  b y  West  P har mace utical  Ser vices  G m b H, 
Ger ma n y/ Ra’a na na, Israel. T he de vice carries t he C E mar k a n d has 5 1 0( k) a p pr o v al 
b y t he U nite d States F o o d a n d Dr u g A d mi nistrati o n. 
P CI, U K , is res p o nsi ble f or t he pac ka gi n g of F P - 1 2 0 1-l y o a n d matc he d place b o i n a 
cart o n b o x. T he pre-fille d W FI dil ue nt s yri n ge, t he Mi xJect Ò  tra nsfer de vice a n d t he 
rec o nstit uti o n  i nstr ucti o ns  are  pac ka ge d  i n  t he  access orial  cart o n  kit.  P CI,  U K  or 
Irela n d,   is  res p o nsi ble  f or  distri b uti n g  t he  i n vesti gati o nal  me dici nal  pr o d uct  t o  t he 
st u d y sites. 
 
A d mi nistr ati o n 
F P - 1 2 0 1-l y o  1 0 µ g   ( or  place b o)  will  be  dil ute d  i n W FI   near  t he  patie nt/i n  t he  I C U. 
O nce pre pare d, t he d ose m ust be a d mi nistere d t o t he patie nt i m me diatel y. T he dil ute d 
F P - 1 2 0 1-l y o or place b o will be a d mi nistere d as a n i ntra ve n o us b ol us i njecti o n via a 
ce ntral or peri p heral li ne. T he i njecti o n will be f oll o we d wit h a 5 m L fl us h of sterile 
sali ne ( n ot pr o vi de d). 
St u d y  dr u g  i njecti o ns  will  be  gi ve n  o nce  dail y  f or  6 da ys.  T he  i njecti o n  s h o ul d  be 
gi ve n at t he sa me ti me eac h da y ± 1 h o ur pr o vi di n g t he patie nt’s c o n diti o n all o ws t his. 
If f or a n y reas o n t his is n ot p ossi ble, t he treat me nt wi n d o w ma y be e xte n de d b y u p t o 
4  h o urs  i.e.  ± 2 h o urs.  T he  reas o n  f or  t he  dela y  m ust  be  e ntere d  i n  t he  e C R F. 
S u bse q ue nt  d oses  s h o ul d  n ot  be  dela ye d  a n d  s h o ul d  re vert  t o  t he  ori gi nal  ti me 
sc he d ule  (e. g.,  if  t he  D 1  d ose  was  at  1 3: 0 0,  t he  D 2  d ose  was  dela ye d  a n d  gi ve n  at 
1 5: 0 0, t he D 3 d ose s h o ul d be gi ve n at 1 3: 0 0 ± 1 h o ur). 
N o  d ose  m o dificati o ns  or  te m p orar y  cessati o ns  of  st u d y  dr u g  a d mi nistrati o n  are 
all o we d. If a dela y be y o n d t he 4- h o ur wi n d o w descri be d a b o ve is re q uire d, t he patie nt 
m ust  be  wit h dra w n  fr o m  st u d y  dr u g  b ut all data  m ust  c o nti n ue  t o  be  c ollecte d  per 
pr ot oc ol. A d mi nistrati o n of a sec o n d c o urse of st u d y dr u g is n ot per mitte d. 
T he first d ose of st u d y me dicati o n is a d mi nistere d w he n t he patie nt has arri ve d at t he 
I C U  after  s uccessf ul  i nfra-re nal  a ortic  re pair  wit h  i ntact  re nal  arteries  gi ve n  t he 
patie nt is via ble. A pri or te m p orar y pr o xi mal a ortic cla m p (t otal ma x i m u m cla m pi n g 
ti me of 3 0 mi n) ma y be use d t o asses a n d c o ntr ol t he o perati ve sit uati o n. S ur gical re-
i n ve nti o ns  (e. g.  blee di n g,  l o wer  li m b  e m b olia,  i ntra-a b d o mi nal  press ure  a n d  o pe n 
a b d o me n, b o wel resecti o n) d o n ot lea d t o e xcl usi o n if t he st u d y dr u g is a d mi nistere d 
as sc he d ule d a n d t he re-i nter ve nti o ns d o n ot vi olate t he i ncl usi o n criteria, i.e. re- d oi n g 
t he u p per a nast o m osis t o t he re nal arteries or a b o ve. 
 

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P ac k a gi n g, L a belli n g a n d St or a ge 
St u d y  dr u g,  i.e. F P - 1 2 0 1-l y o  or  matc he d  place b o, is  pac ka ge d  i n  a  cart o n.  T he  pre-
fille d  W FI  dil ue nt  s yri n ge  a n d  t he  Mi xJectÒ   tra nsfer  de vice  are  pac ka ge d  i n  a n 
access orial cart o n kit. 
Si x i n vesti gati o nal me dici nal pr o d ucts a n d si x access orial cart o n kits are reser ve d f or 
eac h patie nt t o c o ver t he 6- da y treat me nt peri o d. 
La belli n g will be pre pare d b y P CI t o meet t he l ocal re g ulat or y re q uire me nts. 
All  st u d y  dr u g  s u p plies  m ust  be  st ore d  i n  acc or da nce  wit h  t he  ma n ufact urer’s 
i nstr ucti o ns,  i.e., F P - 1 2 0 1-l y o/ place b o is  t o  be  st ore d  at  2 8° C  a n d  t he  access orial 
cart o n kits are t o be st ore d at r o o m te m perat ure. U ntil dis pe nse d t o t he patie nts, t he 
st u d y dr u g will be st ore d i n a sec urel y l oc ke d area, accessi ble t o a ut h orise d pers o n nel 
o nl y. 
T he  i n vesti gati o nal  me dici nal  pr o d uct  a n d  t he  access orial  cart o n  kits  are  dis pe nse d 
o nl y  b y  t he  I n vesti gat or  or  b y  a  me m ber  of  staff  s pecificall y  a ut h orise d  b y  t he 
I n vesti gat or, or b y a p har macist, as a p pr o priate. 
 
Bli n di n g a n d Bre a ki n g t he Bli n d 
T he  st u d y  will  be  perf or me d  i n  a  d o u ble- bli n d  ma n ner.  All  st u d y  dr u gs  will  be 
s u p plie d  i n  i de ntical  vials  a n d  will  be  si milar  i n  c ol o ur  a n d  a p peara nce,  t here b y 
e na bli n g d o u ble- bli n d c o n diti o ns. 
T he  treati n g  p h ysicia n  (i n vesti gat or)  is  res p o nsi ble  f or  t he  me dical  care  of  t he  trial 
patie nt a n d t he st u d y set u p all o ws t he i n vesti gat or t o ra pi d l y brea k t he treat me nt c o de 
i n case of a n e mer ge nc y. 
T he st u d y bli n d s h o ul d o nl y be br o ke n i n a me dical e mer ge nc y ( w here k n o wle d ge of 
t he  st u d y  dr u g  recei ve d  w o ul d  affect  t he  treat me nt  of  t he  e mer ge nc y)  or as  a 
re g ulat or y  re q uire me nt  (e. g.,  f or  S A Es  or  deat h).  N ote  t hat  t here  is  n o  s pecific 
a nti d ote or met h o d of re m o vi n g t he st u d y dr u g fr o m t he b o d y (s uc h as dial ysis) a n d 
t he best a vaila ble care f or t he patie nt s h o ul d be c o nti n ue d.  
If  t he  bli n d  is  br o ke n,  t he  date,  ti me  a n d  reas o n  m ust  be  rec or de d  i n  t he  patie nt’s 
e C R F  a n d  a n y  ass ociate d  A E  re p ort.  It  is  t he  res p o nsi bilit y  of  t he  i n vesti gat or  t o 
pr o m ptl y d oc u me nt a n d e x plai n a n y u n bli n di n g t o t he s p o ns or/ C R O. 
Detaile d i nstr ucti o ns f or t he use of t he I W R S i n or der t o brea k t he st u d y bli n d f or a 
patie nt are pr o vi de d i n a se parate d oc u me nt t hat will be file d i n t he Site File a n d Trial 
Master File. As well as t he I W R S, a bac k u p s yste m e na bli n g u n bli n di n g of treat me nt 
is pr o vi de d t o t he sites. 
After a patie nt has bee n u n bli n de d data c ollecti o n s h o ul d c o nti n ue as per pr ot oc ol.  
S us pecte d  u ne x pecte d  seri o us  a d verse  reacti o ns  ( S U S A Rs),  w hic h  are  s u bject  t o 
e x pe dite d  re p orti n g,  s h o ul d  be  u n bli n de d  bef ore  s u b missi o n  t o  t he  re g ulat or y 
a ut h orities a n d I n de pe n de nt Et hics C o m mittees (I E Cs). 
T he  o verall  ra n d o misati o n  c o de  will  be  br o ke n  o nl y  f or  re p orti n g  p ur p oses  (f or 
i nteri m  a n d  fi nal  a nal yses).  T his  will  occ ur  o nce  all  D 9 0  cli nical  data  ha ve  bee n 
e ntere d i nt o t he data base a n d all data q ueries ha ve bee n res ol ve d, a n d t he assi g n me nt 
of patie nts t o t he a nal ysis sets has bee n c o m plete d. T he ra n d o misati o n c o de will be 
o pe ne d  f or  t he  i nteri m  a nal ysis,  w hic h  is  perf or me d  w he n  at  least  3 1  patie nts  ha ve 
bee n e nr olle d a nd t he D 3 0 cli nical data is a vaila ble.   

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Dr u g Acc o u nt a bilit y 
T he  I n vesti gat or  is  res p o nsi ble  f or  mai ntai ni n g  acc urate  st u d y  dr u g  acc o u nta bilit y 
rec or ds t hr o u g h o ut t he st u d y. 
Eac h dis pe nsi n g of st u d y dr u g will be d oc u me nte d i n t he e C R F. 
T he I n vesti gat or is res p o nsi ble f or e ns uri n g all u n use d me dicati o n is destr o ye d at t he 
i n vesti gati o nal site f oll o wi n g t he a p pr o priate dr u g acc o u nta bilit y pr oce d ures. 
 
C o m pli a nce 
T he st u d y dr u g is a d mi nistere d i ntra ve n o usl y at t he st u d y site, s o it is n ot necessar y t o 
m o nit or patie nt c o m plia nce wit h t he st u d y dr u g re gi me n. 
 
Pre vi o us a n d C o nc o mit a nt Me dic ati o ns 
C o nc o mita nt  me dicati o n  or  t hera p y  w hic h  is  c o nsi dere d  necessar y  f or  t he  patie nt's 
welfare a n d w hic h will n ot i nterfere wit h t he st u d y me dicati o n, ma y be gi ve n at t he 
discreti o n of t he I n vesti gat or.  T here are n o pr o hi bite d me dicati o ns i n t his st u d y. 
C o nc o mita nt  me dicati o ns  a n d  t hera pies  will  be  rec or de d  fr o m  scree ni n g  t o  D 3 0. 
A d mi nistrati o n  of  all  c o nc o mita nt  dr u gs  a n d  t hera pies  m ust  be  re p orte d  i n  t he 
a p pr o priate secti o n of t he e C R F al o n g wit h t he mi ni m u m a n d ma xi m u m d ose le vels 
a d mi nistere d (if a p plica ble).  Rec or di n g of dates of a d mi nistrati o n/t hera p y f or c hr o nic 
treat me nt  a n d  act ual  dates  of  a d mi nistrati o n  of  all  ac ute  c o nc o mita nt  me dicati o n  is 
re q uire d. 
A d diti o nall y,  secti o n 5. 8  pr o vi des  g ui deli nes  f or  c o nc o mita nt  me dicati o ns  t o  be 
a d mi nistere d f or certai n me dicall y-e x pecte d A Es f or t his partic ular st u d y p o p ulati o n. 
If a patie nt is disc har ge d fr o m t he h os pital pri or t o D 3 0, t he patie nt m ust be i nstr ucte d 
t hat t he I n vesti gat or s h o ul d be i nf or me d a b o ut a d diti o nal me dicati o n u p t o D 3 0.   
Patie nts i n t his st u d y will be ma na ge d wit h s u p p orti ve care meas ures acc or di n g t o t he 
best cli nical practice esta blis he d l ocall y i n eac h I C U.  
 
G ui d a nce o n me dic ati o ns t o be a d mi nistere d/ p atie nt m a n a ge me nt f or 
e x pecte d A d verse E ve nts 
Rec o m bi na nt H u ma n I F N beta- 1a has bee n wi del y use d i n ma n f or t he treat me nt of 
m ulti ple scler osis a n d is c o nsi dere d safe. S o me a d ver se effects are a ntici pate d. M ost 
c o m m o n  are  c ha n ges  i n  bl o o d  bi oc he mistr y  of  li ver  f u ncti o n,  i.e.  A L A T,  A S A T, 
A F O S.  A  sli g ht  ele vati o n  i n  li ver  e nz y mes  is  ofte n  see n,  a n d  nee ds  t o  be  f oll o we d. 
T hese  c ha n ges  us uall y  s u bsi de  after  cessati o n  of  treat me nt.  M ost  c o m m o n  se vere 
a d verse effects are fe ver, tac h ycar dia a n d ri g or, si nce t he dr u g s u bsta nce is t o s o me 
e xte nt  p yr o ge nic  b y  nat ure.  T hese  a d verse  effects  m ostl y  occ ur  s h ortl y  after 
a d mi nistrati o n a n d cease after treat me nt. T hese a d verse effects ma y be ma na ge d wit h 
ot her wise  s uita ble  me dicati o n  de pe n di n g  o n  t he  s y m pt o m:  paraceta m ol  or  ot her 
a nti p yretics f or fe ver, beta bl oc kers f or tac h ycar dia, be nz o diaze pi nes f or ri g or or e ve n 
pr o p of ol se dati o n i n t he I C U setti n g. 
Fe w  a d verse  effects  are  e x pecte d  after  t he  treat me nt  peri o d  si nce,  as  s h o w n  i n  t he 
F P C LI 0 0 1  st u d y,  F P- 1 2 0 1  acti vit y  decreases  si g nifica ntl y  wit hi n  fe w  da ys  after 
a d mi nistrati o n, acc or di n g t o M x A meas ure me nts. T h us, t he I M P will be was he d o ut 
bef ore disc har ge fr o m t he h os pital. F or m ore i nf or mati o n o n t he a ntici pate d effects of 
t he F P- 1 2 0 1-l y o treat me nt see t he I n vesti g at ors’ Br oc h ure. 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
3 4  of 6 8  
1 6  A pr 2 0 1 9  
 
V A RI A B L E S A N D M E T H O D S O F A S S E S S M E N T 
T he ti mi n g of t he assess me nts of t he varia bles is s h o w n i n t he Sc he d ule of Pr oce d ures 
( Ta bles 5, 6 a n d 7). 
 
Effic ac y V ari a bles 
T he f oll o wi n g efficac y varia bles will be assesse d: 
•  M ortalit y assess me nts 
•  Ve ntilat or free da ys ( V F Ds) 
•  I C U free da ys 
•  Or ga n fail ure free da ys 
•  Da ys i n h os pital a n d/ or ot her healt h care facilit y 
•  Da ys o n hae m o dial ysis 
•  Pre vale nce  of  a b d o mi nal  c o m part me nt  s y n dr o me  as  meas ure d  b y  i ntra-
a b d o mi nal press ure (I A P) 
 
Met h o ds a n d Ti mi n g f or Assessi n g, Rec or di n g a n d A n al ysi n g Effic ac y 
P ar a meters  
 
M ort ality assess me nts 
T he f oll o wi n g m ortalit y assess me nts are t o be c o n d ucte d:  
•  A ll-ca use m ortalit y at D 3 0 a n d D 9 0 ( 3 m o nt hs)   
•  Ka pla n- Meier s ur vi val c ur ve t o D 9 0   
M ortalit y is t o be ca pt ure d b y assessi n g w het her t he patie nt is ali ve or dea d a n d b y 
rec or di n g t he date of deat h a n d reas o n/ dia g n osis lea di n g t o deat h w he n a vaila ble. 
 
Dis a bility assess me nt 
M o difie d ra n ki n g scale ( m R S) at D 0 a n d D 9 0 will be use d t o e val uate st u d y s u bject 
disa bilit y. Si n gle m R S val ue is a p plie d f or e ver y patie nt base d o n patie nt or care gi ver 
i nter vie w ( Ta ble 9). Pre- o perati o n D 0 m R S val ue is c ollecte d f or refere nce ( p ossi ble 
t o c ollect als o retr os pecti vel y b y i nter vie w). 
 
Ve ntil at or free d ays ( V F Ds) 
T he n u m ber of V F Ds at D 3 0 will be assesse d. 
Defi niti o n of V F D s t o D 3 0:  
V F Ds  t o  D 3 0  is  defi ne d  as  t he  n u m ber  of  cale n dar  da ys  after  i nitiati n g  u nassiste d 
breat hi n g ( U A B) t o D 3 0 fr o m first treat me nt, ass u mi n g a patie nt s ur vi ves at least 4 8 
c o nsec uti ve h o urs after i nitiati n g U A B.   
F or  e xa m ple:  If  a  patie nt  i nitiates  U A B  o n  D 1 6  a n d  s ur vi ves  t o  D 3 0,  t hat  patie nt 
w o ul d be assi g ne d a V F D val ue of 1 4. If a patie nt i nitiates U A B o n D 1 6 b ut dies o n 
D 2 5 he/s he w o ul d be assi g ne d a V F D val ue of 9.  If a patie nt s ur vi ves f or m ore t ha n 
4 8 h o urs  after  i nitiati n g  U A B  b ut  t he n  re q uires  assiste d  breat hi n g  (f or  a n y  reas o n) 
bef ore D 3 0 t he n t he V F D val ue w o ul d be t he t otal n u m ber of U A B da ys bef ore D 3 0 
u nless  a  peri o d  of  assiste d  breat hi n g  was  less  t ha n  2 4  h o urs  a n d  t he  p ur p ose  of 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
3 5  of 6 8  
1 6  A pr 2 0 1 9  
assiste d breat hi n g was a s ur gical pr oce d ure.  Patie nts w h o die wit h o ut i nitiati n g U A B 
will  be  assi g ne d  a  V F D  val ue  of  zer o.   All  p atie nts,  w het her  still  o n  or  alrea d y  off 
p ositi ve  press ure  ve ntilati o n,  w h o  are  tra nsferre d  t o  a n ot her  h os pital  or  healt hcare 
facilit y pri or t o D 3 0, will be f oll o we d u p t o assess t he V F D o utc o me at D 3 0.   
Patie nts tra nsferre d t o ot her healt h care facilities or t o a n ot her h os pital pri or t o D 3 0 
w hile  still  recei vi n g  assiste d  breat hi n g/ wit h o ut  assiste d  breat hi n g  will  be  f oll o we d 
u ntil D 3 0 t o assess t his efficac y meas ure. U nassiste d breat hi n g ( U A B) is defi ne d as 
a n y of t he f oll o wi n g:  
•  s p o nta ne o us breat hi n g wit h face mas k 
•  nasal pr o n g o x y ge n or r o o m air  
•  t-t u be breat hi n g 
•  trac he ost o m y mas k breat hi n g 
•  C P A P < 5 wit h o ut press ure s u p p ort ( P S) or I M V assista nce 
•  use of C P A P or BI P A P s olel y f or slee p a p n oea ma na ge me nt 
 
I C U free d ays 
T he n u m ber of I C U free da ys will be assesse d at D 3 0. 
Defi niti o n of I C U free d ays:  
I C U free da ys are defi ne d as t he n u m ber of da ys fr o m t he ti me of I C U disc har ge t o 
D 3 0  after  t he  first  d ose  of  st u d y  me dicati o n,  ass u mi n g  s ur vi val  f or  at  least  t w o 
c o nsec uti ve  cale n dar  da ys  after  I C U  disc har ge  a n d  c o nti n ue d  sta y  o utsi de  t he  I C U 
setti n g t o D 3 0.  If a patie nt ret ur ns t o t he I C U a n d s u bse q ue ntl y nee ds I C U a d missi o n 
t o  D 3 0,  I C U  free  da ys  will  be  c o u nte d  fr o m  t he  e n d  of  t he  last  peri o d  of  I C U 
disc har ge t o D 3 0.  A peri o d of I C U a d missi o n lasti n g less t ha n 2 4 h o urs i n relati o n t o 
a s ur gical pr oce d ure is c o nsi dere d a n I C U free da y.  If a patie nt is hel d at t he I C U at 
D 2 9 or dies at t he I C U pri or t o D 3 0, I C U free da ys will be zer o.  Patie nts tra nsferre d 
t o a n ot her h os pital or ot her healt h care facilit y will be f oll o we d u ntil D 3 0 t o assess 
t his e n d p oi nt. 
 
Or g a n f ail ure free d ays 
Or ga n fail ure free da ys are assesse d at D 3 0. 
Defi niti o n of or g a n f ail ure free d ays:  
Or ga n fail ure free da ys are defi ne d as t he n u m ber of da ys i n t he first 3 0 da ys after t he 
first d ose of st u d y me dicati o n t hat t he patie nt is ali ve a n d free of or ga n fail ure wit h a 
S O F A sc ore of zer o f or t he f oll o wi n g si x or ga n para meters: res pirati o n, c oa g ulati o n, 
li ver, car di o vasc ular, C N S a n d re nal f u ncti o n (refer t o t he S O F A sc ore ill ustrate d i n 
Ta ble 1). 
T he  t otal  S O F A  sc ore  a n d  t he  i n di vi d ual  ele me nts  of  t he  S O F A  sc ore  are  assesse d 
dail y fr o m baseli ne t o D 3 0 if t he patie nt is i n t he I C U a n d ha ve a n arterial cat heter ( or 
is  o n  t he  war d  b ut  ha ve  a n  arterial  cat heter  s uita ble  f or Pa O 2/ Fi O2 assess me nt), 
i ncl u de: 
a) Pa O 2/ Fi O2 ( m m H g) 
b)  platelets × 1 0 3/ m m3 
c) bilir u bi n ( m g/ dl) 
d)  h y p ote nsi o n 
e) G C S (a n esti mati o n will be use d f or se date d patie nts) 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
3 6  of 6 8  
1 6  A pr 2 0 1 9  
f) creati ni ne ( m g/ dl) 
 
Refer t o Ta ble 8  f or t he S O F A assess me nt sc he d ules. 
Patie nts w h o die wit h o ut ac hie vi n g a S O F A sc ore of zer o will be assi g ne d a n or ga n 
fail ure free da ys val ue of zer o. 
 
T a ble 1:  T he S O F A sc ore 
S O F A sc ore  
0 
1 
2 
3 
4 
Res pir ati o n  
 
 
 
 
 
Pa O 2/ Fi O2, m m H g 
> 4 0 0  
> 3 0 0 £ 4 0 0  
> 2 0 0 £ 3 0 0  
> 1 0 0 £ 2 0 0  
£ 1 0 0  
 
 
 
 
wit h res pirati o n s u pp ort
 
C o a g ul ati o n  
 
 
 
 
 
Platelets × 1 0 3/ µl 
> 1 5 0  
> 1 0 0 £ 1 5 0  
> 5 0 £ 1 0 0  
> 2 0 £ 5 0  
£ 2 0  
 
 
 
 
 
 
Li ver  
 
 
 
 
 
Bilir u bi n, m g/ d l 
< 1. 2  
³ 1. 2 < 2. 0  
³ 2. 0 < 6. 0  
³ 6. 0 < 1 2. 0  
³ 1 2. 0  
( µ m ol/ Ll) 
( < 2 0) 
(³ 2 0 < 3 3)  
(³ 3 3 < 1 0 2)  
(³ 1 0 2 < 2 0 4)  
(³ 2 0 4)  
 
 
 
 
 
 
C ar di o v asc ul ar  
 
 
 
 
 
H y p ote nsi o n a 
N o 
h y p o
te nsi o n 
M A P 
< 7 0  m m H g  
D o pa mi ne ≤5 or 
d o b uta mi ne (a n y 
d ose)  
D o pa mi ne > 5 or 
e pi ne p hri ne ≤0. 1 or 
n ore pi ne p hri ne ≤0. 1  
D o pa mi ne > 1 5 or 
e pi ne p hri ne > 0. 1 or 
n ore pi ne p hri ne > 0. 1  
Ce ntr al ner v o us 
s yste m 
 
 
 
 
 
Glas g o w C o ma 
Scale b, c 
1 5  
1 3 1 4  
1 0 1 2  
6 9 
< 6  
Re n al  
 
 
 
 
 
Creati ni ne, m g/ dl  
< 1. 2  
³ 1. 2 < 2. 0  
³ 2. 0 < 3. 5  
³ 3. 5 < 5. 0  
³ 5. 0  
or µ m ol/ l or  
uri ne o ut p ut  
< 1 1 0  
³ 1 1 0 < 1 7 1  
³ 1 7 1 < 3 0 0  
³ 3 0 0 < 4 4 0 or 
< 5 0 0  m L/ d  
³ 4 4 0 or  
< 2 0 0  m L/ d  
a A dre ner gic a ge nts a d mi nistere d f or at le ast 1  h o ur ( d oses are give n i n µ g/k g/ mi n).  
b F or p atie nts w h o are i nt u b ate d, t he ver b al res p o nse is sc ore d as:  
  
 5 – See ms a ble t o t alk  
  
 3 – Q uesti o n a ble a bility t o t alk  
  
 1 – Ge ner ally u nres p o nsive.  
c F or p atie nts w h o are se d ate d use a n esti m ate d sc ore f or G C S (t he ass u m pti o n is 1 5, if n o 
ot her f act ors t h a n se d ati o n affect G C S)  
A b brevi ati o ns: M A P = me a n arteri al press ure; P a O 2/ Fi O2= p arti al press ure of 
oxy ge n/fr acti o n of i ns pire d oxy ge n; S O F A = Se q ue nti al O r g a n F ail ure Assess me nt. 
 
 
D ays i n h os pit al a n d/ or ot her he alt h c are u nit 
T he le n gt h of a patie nt’s h os pital sta y will be assesse d b y: 
•  t he n u m ber of da ys t he patie nt sta ye d i n h os pital at D 3 0 a n d D 9 0 
•  t he  n u m ber  of  da ys  t he  patie nt  sta ye d  at  a n ot her  pri mar y  or  re ha bilitati n g 
healt h care u nit after h os pital disc har ge at D 3 0 a n d D 9 0. 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
3 7  of 6 8  
1 6  A pr 2 0 1 9  
 
D ays o n h ae m o di alysis 
T he  n u m ber  of  da ys  o n  hae m o dial ysis  will  be  assesse d  at  D 3 0  a n d  D 9 0. 
Hae m o dial ysis at D 9 0 is c o nsi dere d per ma ne nt. 
 
Prev ale nce of c o m p art me nt sy n dr o me as me as ure d by i ntr a- a b d o mi n al 
press ure (I A P) 
I ntra-a b d o mi nal  press ure  (I A P)  is  r o uti nel y  meas ure d  d uri n g  I C U  sta y  via  uri ne 
bla d der  cat heter.  I A P  is  rec or de d  dail y  a n d  a  c o m paris o n  of  I A P  bet wee n  st u d y 
gr o u ps is ma de. 
 
 
S afet y V ari a bles 
 
A dverse Eve nts 
6. 3. 1. 1  
C ollecti o n of A dverse Eve nts 
It  is  t he  res p o nsi bilit y  of  t he  I n vesti gat or  t o  c ollect  all  A Es  ( b ot h  seri o us  a n d  n o n-
seri o us) deri ve d b y o bser vati o n, b y s p o nta ne o us u ns olicite d re p orts of patie nts, a n d, 
w here a p pr o priate, b y r o uti ne o pe n q uesti o ni n g, e. g., “ H o w ha ve y o u felt si nce I last 
sa w y o u?” 
6. 3. 1. 2  Defi niti o ns 
Defi niti o ns of A Es a n d S A Es a n d t he ir d oc u me ntati o n a n d re p orti n g wit hi n t his st u d y 
f oll o w  I nter nati o nal  C o nfere nce  o n  Har m o nisati o n  (I C H)  G o o d  Cli nical  Practice, 
E ur o pea n  U ni o n,  a n d  nati o nal  re g ulati o ns  a n d  re q uire me nts  ( Cli nical  safet y  data 
ma na ge me nt 1 9 9 4). 
A n  A E  is  defi ne d  as  a n y  u nt o war d  me dical  occ urre nce  t hat  occ urs  i n  a  patie nt  or 
cli nical i n vesti gati o n s u bject a d mi nistere d a p har mace utical pr o d uct, a n d w hic h d oes 
n ot  necessaril y  ha ve  t o  ha ve  a  ca usal  relati o ns hi p  wit h  t his  treat me nt.  A n  A E  ca n 
t heref ore be a n y u nfa v o ura ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y 
fi n di n g), s y m pt o m or disease te m p orall y ass ociate d wit h t he use of a n i n vesti gati o nal 
pr o d uct, w het her or n ot it is c o nsi dere d relate d t o t he pr o d uct. 
All A Es u p t o D 3 0 are c ollecte d. All A Es u p t o D 3 0, w hic h lea d t o deat h, are re p orte d 
as  S A Es.  H o we ver,  all  deat hs  u p  t o  D 9 0  will  be  re p orte d  as  S A Es.  C o nc o mita nt 
ill nesses, w hic h e xiste d bef ore e ntr y i nt o t he st u d y, will n ot be c o nsi dere d A Es u nless 
t here  is  a n y  deteri orati o n  fr o m  baseli ne  t hat  is  c o nsi dere d  cli nicall y  rele va nt  or 
si g nifica nt d uri n g treat me nt or f oll o w- u p peri o d u ntil D 3 0 or disc har ge fr o m I C U. All 
A Es   m ust  be  d oc u me nte d,  re gar dless  of  t he  s o urce  of  i de ntificati o n  (e. g.,  p h ysical 
e xa mi nati o n, la b orat or y assess me nt, E C G, re p orte d b y patie nt).   
Pre-e xisti n g  c o n diti o ns  will  be  rec or de d  i n  t he  e C R F  o n  t he  Me dical  Hist or y  or 
a p pr o priate pa ge. 
A T E A E is  defi ne d as a n A E t hat be gi ns or t hat w orse ns i n se verit y after at least o ne 
d ose of st u d y dr u g has bee n a d mi nistere d u p t o D 3 0. 
See 6. 3. 1. 4 f or t he sc he d ule of c ollecti o n of a d verse e ve nts 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
3 8  of 6 8  
1 6  A pr 2 0 1 9  
6. 3. 1. 3  
Assess me nt of A dverse Eve nts 
It  is  rec o g nise d  t hat  t he  patie nt  p o p ulati o n  i n  t he  I C U  will  e x perie nce  a  n u m ber  of 
c o m m o n a berrati o ns i n la b orat or y val ues, si g ns a n d s y m pt o ms d ue t o t he se verit y of 
t heir  u n derl yi n g  disease  a n d  t he  i m pact  of  sta n dar d  t hera pies.  T hese  will  n ot 
necessaril y  c o nstit ute  a n  A E  u nless  t he y  re q uire  si g nifica nt  i nter ve nti o n,  lea d  t o 
disc o nti n uati o n  of  bli n de d  st u d y  dr u g  or  are  c o nsi dere d  t o  be  of  c o ncer n  i n  t he 
I n vesti gat or’s cli nical j u d ge me nt. 
Eac h A E will be assesse d b y t he I n vesti gat or wit h re gar d t o t he f oll o wi n g cate g ories: 
6. 3. 1. 3. 1  Seri o us ness 
A n S A E  is defi ne d as a n y u nt o war d me dical occ urre nce t hat at a n y d ose: 
•  Res ults i n deat h 
•  Is life-t hreate ni n g. T his mea ns t hat t he patie nt is at ris k of deat h at t he ti me of t he 
e ve nt. It d oes n ot mea n t hat t he e ve nt h y p ot heticall y mi g ht ha ve ca use d deat h if it 
were m ore se vere 
•  Re q uires i n patie nt h os pitalisati o n or pr ol o n gati o n of e xisti n g h os pitalisati o n 
•  Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y 
•  Is a c o n ge nital a n o mal y or birt h defect 
•  Is a n i m p orta nt me dical e ve nt t hat ma y n ot be i m me diatel y life-t hreate ni n g or 
res ult i n deat h or h os pitalisati o n b ut t hat ma y je o par dise t he patie nt or re q uire 
i nter ve nti o n t o pre ve nt o ne of t he a b o ve o utc o mes. E xa m ples of s uc h e ve nts are 
i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m; 
bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalisati o n; or 
de vel o p me nt of dr u g de pe n de nc y or dr u g a b use 
 
 “ At a n y d ose” d oes n ot i m pl y t hat t he patie nt is recei vi n g st u d y treat me nt at t he ti me 
of  t he  e ve nt.  St u d y  dr u g  d os es ma y  ha ve  bee n  gi ve n  d uri n g  treat me nt  c ycles  or 
i nterr u pte d te m p oraril y pri or t o t he o nset of t he S A E, b ut ma y ha ve c o ntri b ute d t o t he 
e ve nt. 
6. 3. 1. 3. 2  I nte nsit y 
Classical  re p orti n g  of  mil d,  m o derate  a n d  se vere A Es   ma ki n g a refere nce  t o  t he 
patie nt’s f u ncti o nal stat us is diffic ult f or a ra n d o mise d st u d y i n criticall y ill patie nts. 
Patie nts e nr olle d i n t his st u d y will pri maril y be mec ha nicall y ve ntilate d a n d c o mat ose 
d ue t o t heir u n derl yi n g c o n diti o n a n d/ or t he dr u gs t he y are prescri be d f or se dati o n a n d 
a nal gesia  i n  t he  I C U.  T heref ore,  t he  classical  a p pr oac h  t o A E   re p orti n g,  w hic h 
re q uires patie nt c o m m u nicati o n a n d e val uati o n of t he i m pact o n f u ncti o ni n g will be 
a da pte d  t o  t he  I C U  e n vir o n me nt.  T he  I n vesti gat or  will  be  res p o nsi ble  f or  t he 
assess me nt  of  se verit y,  usi n g  t he  cate g ories  of  mil d,  m o derate or  se vere  t o  descri be 
eac h A E as: 
•  Mil d:  D oes n ot i nterfere wit h patie nt’s us ual f u ncti o n 
•  M o der ate:  I nterferes t o s o me e xte nt wit h patie nt’s us ual f u ncti o n 
•  Se vere:  I nterferes si g nifica ntl y wit h patie nt’s us ual f u ncti o n 
N ote t he disti ncti o n bet wee n seri o us a n d se vere A Es. Se vere  is a meas ure of i nte nsit y 
w hereas  a n  e ve nt  m ust  meet  o ne  of  t he  criteria  f or  seri o us  e ve nts  liste d  i n 
Secti o n 6. 2. 1. 3. 1 t o be c o nsi dere d seri o us; t h us, a se vere reacti o n is n ot necessaril y a 

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seri o us reacti o n. F or e xa m ple, a hea dac he ma y be se vere i n i nte nsit y, b ut w o ul d n ot 
be  classifie d  as  seri o us  u nless  it  met  o ne  of  t he  criteria  f or  seri o us  e ve nts  liste d  i n 
Secti o n 6. 2. 1. 3. 1. 
6. 3. 1. 3. 3  Ca usalit y 
T he I n vesti gat or will assess t he ca usalit y/relati o ns hi p bet wee n t he st u d y dr u g a n d t he 
A E a n d rec or d t hat assess me nt i n t he e C R F. Ca usalit y will be assesse d as: 
•  N ot rel ate d:  A E is o b vi o usl y e x plai ne d b y a n ot her ca use; or  t he ti me of 
occ urre nce of A E is n ot reas o na bl y relate d t o a d mi nistrati o n of t he st u d y dr u g 
•  P ossi bl y rel ate d:  St u d y dr u g a d mi nistrati o n a n d A E occ urre nce are reas o na bl y 
relate d i n ti me; a n d  A E is e x plai ne d e q uall y well b y ca uses ot her t ha n st u d y dr u g 
•  Pr o b a bl y rel ate d:  St u d y dr u g a d mi nistrati o n a n d t he occ urre nce of t he A E are 
reas o na bl y relate d i n ti me; a n d  t he A E is m ore li kel y e x plai ne d b y e x p os ure t o 
st u d y dr u g t ha n b y ot her mec ha nis ms 
T he m ost li kel y ca use of a n A E  (e. g., disease u n der treat me nt, c o nc o mita nt disease, 
c o nc o mita nt  me dicati o n,  ot her)  will  be  i n dicate d  i n  t he  e C R F  wit h  details  of  t he 
c o nc o mita nt disease or me dicati o n or ot her ca use.  
6. 3. 1. 3. 4  Cli nical La b orat or y A d verse E ve nt  
A b n or mal  la b orat or y  fi n di n gs  (e. g.,  bi oc he mistr y,  hae mat ol o g y,  uri nal ysis)  or  ot her 
a b n or mal  assess me nts  (e. g.,  vital  si g ns)  t hat  are  j u d ge d  b y  t he  I n vesti gat or as 
cli nicall y  si g nifica nt  will,  if  certai n  re q uire me nts  are  met,  be  rec or de d  as  A Es  or 
S A Es.  Cli nicall y  si g nifica nt  a b n or mal  la b orat or y  fi n di n gs  or  ot her  a b n or mal 
assessme nts  t hat  meet  t he  defi niti o n  of  a n  A E  or  S A E  a n d  are  detecte d  d uri n g  t he 
st u d y,  or  are  prese nt  at  baseli ne  a n d  si g nifica ntl y  w orse n  f oll o wi n g  t he  start  of  t he 
st u d y,  will  be  re p orte d  as  A Es  or  S A Es.  H o we ver,  cli nicall y  si g nifica nt  a b n or mal 
la b orat or y fi n di n gs or ot her a b n or mal assess me nts t hat are ass ociate d wit h t he disease 
bei n g st u die d ( u nless j u d ge d b y t he I n vesti gat or as m ore se vere t ha n e x pecte d f or t he 
patie nt’s c o n diti o n), or t hat are prese nt or detecte d at t he start of t he st u d y a n d d o n ot 
w orse n, will n ot be re p orte d as A Es or S A Es. 
T he  I n vesti gat or  will  e xercise  t heir  me dical  a n d  scie ntific  j u d g me nt  i n  deci di n g 
w het her  a n  a b n or mal  la b orat or y  fi n di n g  or  ot her  a b n or mal  assess me nt  is  cli nicall y 
si g nifica nt. 
6. 3. 1. 4  Rec or di n g A dverse Eve nts 
A E  re p orti n g will e xte n d fr o m si g ni n g of i nf or me d c o nse nt. A Es  occ urri n g after D 3 0 
s h o ul d  be  re p orte d  t o  t he  S p o ns or  b y  t he  I n vesti gat or  if  t he  I n vesti gat or  c o nsi ders 
t here  is  a  ca usal  relati o ns hi p  wit h  t he  st u d y  dr u g.  H o we ver,  all  deat hs  will  be 
rec or de d a n d re p orte d as S A Es t hr o u g h o ut t he st u d y ( u p u ntil D 9 0). 
All A E re p orts s h o ul d c o ntai n a brief descri pti o n of t he e ve nt, date a n d ti me of o nset, 
date a n d ti me of res ol uti o n, i nte nsit y, treat me nt re q uire d, relati o ns hi p t o st u d y dr u g, 
acti o n  ta ke n  wit h  t he  st u d y  dr u g,  o utc o me,  a n d  w het her  t he  e ve nt  is  classifie d  as 
seri o us. 
Rec or di n g a dia g n osis ( w he n p ossi ble) is preferre d t o rec or d a list of ass ociate d si g ns 
a n d  s y m pt o ms.  H o we ver,  if  a  dia g n osis  is  k n o w n  b ut  t here  are  ass ociate d  si g ns  or 
s y m pt o ms  n ot  ge nerall y  attri b ute d  t o  t he  dia g n osis,  t he  dia g n osis  a n d  eac h  si g n  or 
s y m pt o m m ust be rec or de d se paratel y. 

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6. 3. 1. 5  Re p orti n g Seri o us A dverse Eve nts 
Acc or di n g t o a p plica ble E ur o pea n U ni o n re g ulati o ns a n d re q uire me nts, a n S A E m ust 
be re p orte d t o t he S p o ns or fr o m t he trial site as s o o n as p ossi ble wit hi n 2 4 h o urs  of 
bec o mi n g a ware of t he S A E. A me dicall y q ualifie d pers o n at t he trial site i de ntifie d 
o n t he Dele gati o n of A ut h orit y L o g wit h t his res p o nsi bilit y m ust assess t he S A E. A n y 
me m ber  of  t he  cli nical  trial  site  staff  ca n  assist  i n  re p orti n g  a n  i nitial  S A E.  T he 
Pri nci pal  I n vesti gat or  or  dele gate d  s u b-i n vesti gat ors  are  res p o nsi ble  f or  t he  S A E 
re p orti n g  pr oce d ures  at  t he  site  d uri n g  t he  trial,  a n d  m ust  al wa ys  si g n- off  o n  eac h 
S A E e ve n if ot her site staff ha ve re p orte d t he e ve nt o n be half of t he i n vesti gat ors. A 
dele gati o n  l o g  at  eac h  trial  site  will  clearl y  s h o w  dele gati o n  of  res p o nsi bilities 
re gar di n g S A E re p orti n g. 
T he S A E f or m m ust be c o m plete d wit h all t he rele va nt i nf or mati o n a n d f or war de d t o 
Cr o w n P har mac o vi gila nce b y: 
•  E mail:
 
or  
•  Fa x: 
 I n case of deli ver y fail ure, please c all: 
 
 
If  t he  S A E  is  ur ge ntl y  re p orte d  b y telep h o ne,  a  pa per  S A E  f or m  m ust  al wa ys  be 
c o m plete d a n d f or war de d t o Cr o w n P har mac o vi gila nce as s o o n as p ossi ble. 
T he  I n vesti gat or  a n d  t he  S p o ns or  ( or  S p o ns or’s  desi g nate d  a ge nt)  will  re vie w  eac h 
S A E  re p ort  a n d  t he  seri o us ness  a n d  t he  ca usal  relati o ns hi p  of  t he  e ve nt  t o  st u d y 
treat me nt will be e val uate d. I n a d diti o n, t he S p o ns or ( or S p o ns or’s desi g nate d a ge nt) 
will  e val uate  t he  e x pecte d ness  acc or di n g  t o  t he  refere nce  d oc u me nt  (I n vesti gat or 
Br oc h ure).  Base d  o n  t he  I n vesti gat or  a n d  S p o ns or’s  assess me nt  of  t he  e ve nt,  a 
decisi o n will be ma de c o ncer ni n g t he nee d f or f urt her acti o n. 
If  c o nse ns us  o n  t he  assess me nt  ca n n ot  be  reac he d  bet wee n  t he  parties  (e. g., 
I n vesti gat or  a n d  S p o ns or/ S p o ns or’s  dele gate),  all  o pi ni o ns  will  be  pr o vi de d  i n  t he 
C o u ncil  f or  I nter nati o nal  Or ga nizati o ns  of  Me dical  Scie nces  F or m  I  re p ort  a n d 
re p orti n g  t o  t he  C A  a n d  I E C  s h o ul d  be  base d  o n  t he  hi g hest  de gree  of  ca usalit y 
pr o vi de d. 
Details f or re p orti n g S U S A R s ca n be f o u n d i n Secti o n 6. 3. 1. 7. 
All S A Es will be rec or de d t hat occ ur bet wee n si g ni n g of i nf or me d c o nse nt a n d D 3 0. 
E ve nts occ urri n g after D 3 0 a n d c o mi n g t o t he atte nti o n of t he I n vesti gat or s h o ul d be 
re p orte d o nl y if t he y are c o nsi dere d i n t he o pi ni o n of t he I n vesti gat or t o be ca usall y 
relate d t o t he i n vesti gati o nal dr u g.  H o we ver, all deat hs u p t o D 9 0 will be re p orte d as 
S A Es . 
All S A Es occ urri n g as descri be d a b o ve, m ust be re p orte d wit hi n 2 4 h o urs  b y e mail 
or fa x t o Cr o w n P har mac o vi gila nce.  
T he mi ni m u m i nf or mati o n re q uire d f or a n i nitial re p ort is: 
•  Details of pers o n se n di n g t he re p ort (i.e., na me a n d a d dress of I n vesti gat or) 
•  Patie nt i de ntificati o n details (scree ni n g/ra n d o misati o n n u m ber, a ge, se x, N O T 
patie nt na me) 
•  Pr ot oc ol n u m ber 
•  Descri pti o n of S A E 
•  Ca usalit y assess me nt 
 

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H o we ver, all p oi nts o n t he S A E f or m s h o ul d be c o vere d i n t he i nitial re p ort a n d t he 
c o m plete d S A E f or m itself m ust be e maile d or fa xe d t o Cr o w n P har mac o vi gila nce.  
After  recei pt  of  t he  i nitial  re p ort,  Cr o w n  P har mac o vi gila nce  will  re vie w  t he 
i nf or mati o n  a n d,  if  necessar y,  c o ntact  t he  I n vesti gat or  t o  o btai n  f urt her  i nf or mati o n 
f or  assess me nt  of  t he  e ve nt.  Cr o w n  C R O  will  be  res p o nsi ble  f or  all  i nf or mati o n 
pr ocessi n g a n d re p orti n g acc or di n g t o l ocal le gal re q uire me nts.  
Detaile d  i nstr ucti o ns  c o ncer ni n g  S A E  re p orti n g  pr oce d ures  will  be  descri be d  i n a 
Safet y  Ma na ge me nt  Pla n  writte n  b y  Cr o w n  P har mac o vi gila nce.  S A E  Re p ort  F or m 
a n d c o ntact i nf or mati o n f or re p orti n g S A Es will be pr o vi de d t o t he sites. 
6. 3. 1. 6  F oll o w- u p of A dverse Eve nts  
All  A Es  e x perie nce d  b y  a  patie nt,  irres pecti ve  of  t he  s us pecte d  ca usalit y,  will  be 
m o nit ore d u ntil: t he A E has res ol ve d ; a n y a b n or mal la b orat or y val ues ha ve ret ur ne d 
t o baseli ne or sta bilise d at a le vel acce pta ble t o t he I n vesti gat or a n d Me dical M o nit or; 
t here  is  a  satisfact or y  e x pla nati o n  f or  t he  c ha n ges  o bser ve d; t he  patie nt  is  l ost  t o 
f oll o w- u p; or t he patie nt has die d. 
6. 3. 1. 7  S us pecte d U nex pecte d Seri o us A dverse Re acti o ns  
A n y A E   t hat  is  seri o us,  ass ociate d  wit h  t he  use  of  t he  st u d y  dr u g,  a n d  u ne x pecte d 
( S U S A R) has a d diti o nal re p orti n g re q uire me nts, as descri be d bel o w. 
•  If t he S U S A R is fatal or life t hreate ni n g, ass ociate d wit h use of t he st u d y dr u g a n d 
u ne x pecte d, re g ulat or y a ut h orities a n d I E Cs m ust be n otifie d wit hi n 7 c ale n d ar 
d a ys  after t he S p o ns or lear ns of t he e ve nt. A d diti o nal f oll o w- u p i nf or mati o n 
(ca use of deat h, a ut o ps y re p ort a n d h os pital re p ort) s h o ul d be re p orte d wi t hi n a n 
a d diti o n al 8 d a ys  ( 1 5 da ys t otal). 
•  If t he S U S A R is n ot fatal or life t hreate ni n g b ut is ot her wise seri o us, ass ociate d 
wit h t he use of t he st u d y dr u g a n d u ne x pecte d, re g ulat or y a ut h orities a n d I E Cs 
m ust be n otifie d wit hi n 1 5 c ale n d ar d a ys  after t he S p o ns or lear ns of t he e ve nt. 
 
T he S p o ns or will n otif y t he I n vesti gat ors i n a ti mel y fas hi o n of rele va nt i nf or mati o n 
a b o ut  S U S A Rs  t hat  c o ul d  a d versel y  affect  t he  safet y  of  patie nts.  F oll o w- u p 
i nf or mati o n ma y be s u b mitte d if necessar y. 
T he S p o ns or will als o pr o vi de a n n ual safet y u p dates t o t he re g ulat or y a ut h orities a n d 
I E Cs  res p o nsi ble  f or  t he st u d y.  T hese  u p dates  will  i ncl u de  i nf or mati o n  o n  S U S A Rs 
a n d ot her rele va nt safet y fi n di n gs. 
6. 3. 1. 8  Pre g n a ncy 
M o nit ori n g  of  pre g na ncies  is  n ot  a p plica ble  t o  t his  st u d y  beca use  pre g na nc y  is  a n 
e xcl usi o n  criteri o n  a n d  a  pre g na nc y  test  is  perf or me d  i n  all  w o me n  of  c hil d beari n g 
p ote ntial  at  scree ni n g.  O wi n g  t o  t he  nat ure  of  t he  st u d y  i n v ol vi n g  s h ort  ( 6- da y) 
treat me nt  wit h  t he  st u d y  dr u g  i n  a n  I C U  setti n g,  it  is  n ot  p ossi ble  f or  w o me n  t o 
bec o me pre g na nt d uri n g treat me nt a n d f or t here t o be a n y f o etal e x p os ure t o t he st u d y 
dr u g. 
 L a b or at ory V ari a bles 
T he  bi oc he mistr y  a n d  hae mat ol o g y  a nal ysis  will  be  perf or me d  at  t he  h os pital 
la b orat ories of t he i n di vi d ual I n vesti gat or sites. T hese a nal yses are m ostl y i ncl u de d i n 
t he sta n dar d care of R A A A patie nts. C o pies of la b orat or y accre ditati o n a n d rele va nt 

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refere nce  ra n ges  will  be  pr o vi de d  t o  t he  S p o ns or  or  re prese ntati ve  pri or  t o  t he 
a nal ysis of t he first patie nt sa m ple at t hat site. 
T he la b orat or y varia bles meas ure d i n t he st u d y will be as detaile d i n Ta ble 2. 
Bl o o d  sa m ples  f or  deter mi nati o n  of  bi oc he mistr y  a n d  hae mat ol o g y  will  be  ta ke n at 
pre- d ose o n D 0  ( baseli ne val ue), D 1, D 2, D 3, D 4, D 5 , D 6 , D 9, D 1 3 a n d D 3 0 ( or o n a 
partic ular date if a patie nt is disc har ge d fr o m i nitial o perati n g h os pital or disc o nti n ues 
fr o m  t he  st u d y  after  D 6  b ut  pri or  t o  D 3 0),  as  detaile d  i n  t he  st u d y  fl o w  c harts  i n 
Ta bles 5 & 6. Patie nt is n ot i n vite d t o la b orat or y visit, o nce disc har ge d fr o m h os pital, 
e xce pt  o n  D 3 0  f or  assess me nt  of  N A bs.  T he  date  a n d  ti me  of  c ollecti o n  will  be 
rec or de d i n t he e C R F. 
 
T a ble 2:  L a b or at or y V ari a bles 
Bi oc he mistr y  
H ae m at ol o g y  
I ncl u des c o a g ul ati o n 
Ot her  
Ala ni ne 
tra nsa mi nase ( A L A T) 
Al kali ne 
p h os p hatase  ( A F O S) 
As partate 
tra nsa mi nase ( A S A T) 
Bicar b o nate  
Lactate  
p H  
Bilir u bi n  
Calci u m  
Creati ni ne  
P otassi u m  
S o di u m ( bl o o d gas val ue 
acce pta ble) 
Ha e m o gl o bi n 
Le uc oc yte differe ntial c o u nt 
(a bs ol ute) 
Mea n cell v ol u me  
Platelet c o u nt  
Re d cell c o u nt  
W hite cell c o u nt  
 
 
Pre g na nc y test  
 
 
T otal  v ol u me  of  bl o o d  re q uire d  f or  bi oc he mistr y  a n d  hae mat ol o g y  sa m ples  per 
patie nt are s h o w n bel o w i n Ta ble 3 . 
 
T a ble 3:  T ot al V ol u me of Bl o o d re q uire d f or Bi oc he mistr y/ H ae m at ol o g y 
S a m ples 
Assess me nt  
N u m ber of 
S a m ples  
Per S a m ple 
V ol u me ( m L)  
T ot al V ol u me 
( m L) 
Bi oc he mistr y  
9  
6  
5 6  
H ae m at ol o g y  
9  
9  
8 1  
Pre g n a nc y test  
1  
4  
4  
 
 
 
1 4 1  
 

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 Vit al Si g ns 
Vital si g ns are rec or de d at D 0 pre- d ose ( baseli ne) a n d c o nti n u o usl y d uri n g I C U sta y, 
a n d at least dail y d uri n g h os pital care. Re p orti n g p oi nts D 0 pre- d ose ( 0 hrs), D 1, D 2, 
D 3, D 4, D 5, D 6, D 9, D 1 3 a n d D 3 0 ( or o n a partic ular date if a patie nt wit h dra ws fr o m 
t he st u d y after D 6 b ut pri or t o D 3 0), as detaile d i n t he st u d y fl o w c harts.  T he date 
a n d ti me of c ollecti o n of eac h para meter will be rec or de d i n t he e C R F. 
Vital si g n varia bles i ncl u de: 
•  Bl o o d press ure ( B P) ( m m H g): t o be rec or de d i ntra-arteria ll y or usi n g a de vice 
wit h a n a p pr o priate c uff size f or t he patie nt. 
•  Heart rate ( H R) ( b p m): meas ure d as per cli nical practice o n eac h I C U 
•  Te m perat ure  ( C˚):  a uric ular  ( preferre d,  b ut  ot her  cli nicall y  use d  r o uti ne 
met h o ds are als o acce pta ble) te m perat ure  
 
P hysic al e x a mi n ati o n  
A  p h ysical  e xa mi nati o n  c o veri n g  t he  maj or  or ga n  s yste ms  will  be  perf or me d  at 
scree ni n g ( baseli ne) a n d D 3 0 ( or w he n a patie nt is disc har ge d fr o m t he h os pital pri or 
t o D 3 0).  
At scree ni n g t he p h ysical e xa mi nati o n als o i ncl u des:  
•  pre dicte d  b o d y  wei g ht  if  act ual  wei g ht  is  n ot  attai na ble.  Patie nt  re p orte d 
wei g ht  is  acce pta ble.  Calc ulate  t he  pre dicte d  b o d y  wei g ht ( k g)  usi n g  t he 
f oll o wi n g f or m ulae: 
i.  
♂ 5 0 + 0. 9 1( hei g ht i n c m   1 5 2. 4) 
ii.  
♀ 4 5. 5 + 0. 9 1( hei g ht i n c m   1 5 2. 4) 
•  act ual hei g ht (i n c m) re p orte d b y patie nt 
 
B aseli ne c h ar acteristics a n d dis p ositi o n 
As  per  St u d y  Fl o w  C hart  baseli ne  assess me nts  c o nsist  of  t h ose  assess me nts  carrie d 
o ut  after  t he  i nf or me d  c o nse nt  has  bee n  o btai ne d  i n  t he  scree ni n g  peri o d  a n d  t h ose 
carrie d  o ut  pri or  t o  t he  first  d ose  of  st u d y  me dicati o n  o n  D 0.  Peri  pr oce d ural 
i nf or mati o n is c ollecte d as it ma y ha ve i m pact o n t he patie nt o utc o mes. T hese i ncl u de 
d urati o n  of  t he  s ur gical  pr oce d ure  f or  R A A A,  t otal  cla m pi n g  ti me,  t otal  blee di n g 
v ol u me,  t otal  v ol u me  s u bstit uti o n,  t otal  bl o o d  s u bstit uti o n,  t otal  re d  bl o o d  cells 
s u bstit uti o n,  t otal  platelets  s u bstit uti o n,  t otal  cr ystall oi ds  s u bstit uti o n a n d  t otal 
di uresis v ol u me d uri n g pr oce d ure. Rec ycli n g of bl o o d d uri n g s ur ger y ( yes/ n o).  
De m o gra p hic  a n d  baseli ne  c haracteristics  are  s u m marise d  b y  treat me nt  gr o u p  a n d 
o verall. Statistical c o m paris o ns are u n derta ke n t o c o m pare treat me nt gr o u ps f or a n y 
of t hese para meters. 
Dis p ositi o n a n d reas o ns f or disc o nti n uati o n are s u m marise d f or all patie nts t o get her 
wit h treat me nt e x p os ure a n d st u d y d urati o n b y treat me nt gr o u p. 
 
P h ar m ac oec o n o mic E v al u ati o n 
T o calc ulate t he e x pecte d i ncre me ntal c ost effecti ve ness of i ntra ve n o us F P - 1 2 0 1-l y o 
c o m pare d wit h sta n dar d care i n t he treat me nt of patie nts wit h R A A A a n d perf or me d 
o pe n a ortic re pair, t he f oll o wi n g para meters will be meas ure d/c ollecte d: 
•  A Es bet wee n t he first d ose of st u d y me dicati o n at D 0 0 pre- d ose a n d D 3 0 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
4 4  of 6 8  
1 6  A pr 2 0 1 9  
•  c o nc o mita nt me dicati o ns a n d t hera pies as rec or de d fr o m Scree ni n g t o D 3 0 
•  t he n u m ber of da ys i n I C U fr o m D 0 pre- d ose t o D 3 0 
•  t he n u m ber of da ys i n h os pital fr o m D 0 pre- d ose t o D 9 0 ( 3 m o nt hs) 
•  t he n u m ber of da ys at a n ot her healt h care facilit y fr o m D 0 pre- d ose t o D 9 0 
•  t he n u m ber of da ys o n hae m o dial ysis fr o m Scree ni n g t o D 3 0 a n d D 9 0 
•  t he n u m ber of or ga n fail ure free da ys fr o m D 0 pre- d ose t o D 3 0 
•  t he n u m ber of V F Ds fr o m D 0 pre- d ose t o D 3 0 
 
E x pl or at or y V ari a bles 
 
Me t h o ds a n d Ti mi n g f or Assessi n g, Rec or di n g a n d A n alysi n g 
P h ar m ac o dy n a mic P ar a meters 
Bl o o d sa m ples f or t he N A bs assess me nts are c ollecte d at D 0 pre- d ose ( baseli ne) a n d 
at D 3 0. Bl o o d sa m ples f or t he M x A, Te ntati ve Disease S pecific Mar ker ( C D 7 3) a n d 
P ote ntial I nfla m mat or y Mar kers (I L- 6 a n d H G F)  assess me nts are c ollecte d at D 0 pre-
d ose ( baseli ne),  at  D 1,  D 2,  D 3,  D 4,  D 5,  D 6,  D 9  a n d  D 1 3  ass u mi n g  t he  patie nt  is 
h os pitalize d as detaile d i n t he st u d y fl o w c harts i n Ta bles 5 a n d 6.  
M x A, C D 7 3, N A bs a n d PI M bl o o d sa m ple pre parati o n a n d sa m ple st ora ge details are 
pr o vi de d i n t he st u d y s pecific La b orat or y Ma n ual. It is esse ntial t hat t he act ual ti me 
a n d date of c ollecti o n of eac h P D sa m ple be rec or de d i n t he sa m ple c ollecti o n f or m 
pr o vi de d wit h t he la b orat or y kits. 
M x A, C D 7 3 a n d N A bs sa m ples are a nal yse d ce ntrall y b y 
 
, a n d PI Ms i n 
. 
T he t otal v ol u me of bl o o d re q uire d f or sa m ples per patie nt is s h o w n bel o w i n Ta ble 4. 
T a ble 4   T ot al V ol u me of Bl o o d re q uire d f or M x A, C D 7 3 a n d P I Ms 
P D P ar a meter 
N u m ber of 
S a m ples 
Per S a m ple 
V ol u me ( m L) 
T ot al V ol u me 
( m L) 
C D 7 3 
9 
2. 5 
2 2. 5 
M x A 
9  
2  
1 8 
PI M  
9 
2. 5 
2 2. 5 
N A bs  
2  
2. 5  
5 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P 1 C LI 0 0 6  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
4 8  of 6 8  
1 6  A pr 2 0 1 9  
*  
Assess me nts pri or t o D 3 0 are o nl y perf or me d if patie nt is still h os pitalise d i n t he sa me 
h os pital  i nitiall y  o perate d.    If  t he  patie nt  is  m o ve d  t o  a  differe nt  h os pital,  assess me nts 
will n ot be d o ne.  If st u d y treat me nt is ter mi nate d earl y b y I n vesti gat or decisi o n d ue t o 
patie nt i m pr o ve me nt, t he st u d y assess me nt sc he d ule s h o ul d be f oll o we d as n or mal.  
* *    Fr o m D 6 t o D 3 0  assess me nt of vital si g ns, patie nt stat us a n d p h ysical  e xa mi nati o n are 
perf or me d  as  sc he d ule d  if  h os pitalise d (i.e.  i n  h os pital  w here  i nitiall y  o perate d). 
Bi oc he mistr y, h ae mat ol o g y, M x A , C D 7 3 a n d PI M are assesse d o n D 9 a n d D 1 3 if patie nt 
is h os pitalize d. D 9  t o D3 0  assess me nts s h o ul d be perf or me d at t he sa me ti me of da y as 
D 6 assess me nts. N ote: W here a patie nt’s c o n diti o n precl u des a n assess me nt ta ki n g place 
as sc he d ule d, t he assess me nt s h o ul d be perf or me d wit hi n ± 2 h o urs of t he sc he d ule d ti me 
a n d if t his is n ot p o ssi ble, t he assess me nt will n ot be perf or me d a n d t he reas o n f or n o n-
perf or ma nce will be rec or de d.   
v  
S O F A sc ores are assesse d dail y i n t he I C U fr o m D 0 p ost -d ose t o D 3 0 , as a p plica ble b y 
sta n dar d cli nical treat me nt at t hat p oi nt. ( Theref ore , if a patie nt does  n ot ha ve a n arterial 
li ne, n o arterial bl o o d sa m pli n g s h o ul d be ta ke n.) 
 
 
Assess me nt of Disc o nti n ue d P atie nts 
If a patie nt is disc har ge d fr o m t he h os pital (t o a n ot her h os pital, h o me, etc.) pri or t o 
D 3 0 , a c o m plete fi nal e val uati o n s h o ul d be ma de at t he da y of disc har ge as descri be d 
bel o w i n ta ble 7.    
If a patie nt is disc har ge d fr o m t he h os pital (t o a n ot her h os pital, h o me, etc.) after D 3 0 , 
t he  assess me nts  will  be  perf or me d i n all   t he  l o n g-ter m  f oll o w- u p  ti me  p oi nts as 
descri be d bel o w i n ta ble 7. 
 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
5 1  of 6 8  
1 6  A pr 2 0 1 9  
 
Pr oce d ures b y Visit 
 Pre -scree ni n g Ev al u ati o n a n d scree ni n g l o g  
Patie nts  will  be  c o nsi dere d  f or  e ntr y  i nt o  t he  st u d y  w he n  a  dia g n osis  of  R A A A  has 
bee n  ma de.  Bef ore  e nteri n g  t he  st u d y,  patie nts  are  assesse d  t o  e ns ure  t hat  all 
eli gi bilit y  criteria  are  met.    Patie nts  n ot  meeti n g  t he  eli gi bilit y  criteria  m ust  n ot  be 
e ntere d i nt o t he st u d y.  
W he n  c o nsi deri n g  patie nts  f or  t he  st u d y  t he  i n vesti gati o nal  site  will  re vie w  t he 
f oll o wi n g: 
•  All eli gi bilit y criteria are met (refer t o Secti o ns 4. 1   4. 3) 
o  I n  s o me  cases,  t he  a m o u nt  of  ti me  e x pe n da ble  fr o m  E R  t o  O R  (e. g. 
se verel y u nsta ble hae m o d y na mics) ma y be s o li mite d t hat a n a de q uate 
ti me  or  state  f or  e nr ol me nt  ca n n ot  be  ac hie ve d.  F or  t hese  patie nts  a 
c o nse nt fr o m t he ne xt of ki n ca n be s o u g ht after s uccessf ul s ur ger y. 
o  H o we ver,  f or  t he  p ossi ble  e nr ol me nt  of  patie nts,  i n vesti gati o nal  sites 
m ust  be  acti ve  i n  i nc or p orati n g  t he  pre-st u d y  e val uati o n  i n  t heir  o w n 
s ur gical e mer ge nc y pr ot oc ols. 
Pr o visi o n  of  i nf or me d  c o nse nt.  St u d y  s pecific  pr oce d ures  m ust  be  perf or me d  after 
i nf or me d c o nse nt f or t he st u d y is gi ve n. N ote:  W he n t he E R, O R a n d I C U sta n dar d 
pr oce d ures  are  i n  li ne  wit h  st u d y  pr oce d ures  a n d  if  t he  ti mi n g  of  R A A A  dia g n osis, 
c o nse nt,  o pe n  a ortic  re pair  a n d  d osi n g  precl u de  re petiti o n  of  pr oce d ures  f or  t he 
p ur p oses  of  t he  st u d y,  sta n dar d  patie nt  care  test  res ults  ma y  be  use d  f or  scree ni n g 
e ve n pri or t o c o nse nt. 
I n vesti gati o nal sites will re vie w all E R patie nts wit h s y m pt o ms of R A A A i n or der t o 
i de ntif y p ote ntial patie nts f or t his st u d y.  I n vesti gati o nal sites will mai ntai n a l o g of all 
R A A A patie nts see n i n t heir E R a n d will rec or d t he f oll o wi n g i nf or mati o n: 
•  Date of a d missi o n t o E R 
•  Met a n d u n met i ncl usi o n criteria 
•  Me t a n d u n met e xcl usi o n criteria 
•  Reas o n f or n o n-eli gi bilit y 
If t he patie nt d oes n ot e nter t he st u d y t he reas o n f or t his will be rec or de d. 
T he  l o g  is  se nt  t o  t he  S p o ns or  o n  a  m o nt hl y  basis  w hilst  t he  i n vesti gati o nal  site  is 
o pe n f or recr uit me nt.   
 
 
Scree ni n g  Assess me nts a n d Pre- d ose Pr oce d ures 
7. 4. 2. 1  Scree ni n g assess me nts t o be perf or me d after di a g n osis of R A A A pri or t o 
s ur gic al tre at me nt a n d t he first d ose of st u d y me dic ati o n 
Scree ni n g assess me nts will be carrie d o ut after i nf or me d c o nse nt is o btai ne d a n d m ust 
be  c o m plete d  bef ore  t he  first  d ose  of  st u d y  me dicati o n  is  a d mi nistere d.   T he  first 
d ose of t he st u d y me dic ati o n is a d mi nistere d at arri v al t o t he I C U (l atest 4 h o urs 
after R A A A o per ati o n). 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
5 2  of 6 8  
1 6  A pr 2 0 1 9  
T he f oll o wi n g para meters are re vie we d a n d t he data is rec or de d i n t he e C R F o nce t he 
patie nt has bee n c o nse nte d (refer t o ta ble 5 a n d t he fl o w c hart i n fi g ure 1): 
•  Date a n d ti me of i nf or me d c o nse nt 
•  All ocate d patie nt scree ni n g n u m ber  
•  Me dical hist or y i ncl u di n g: 
o   c hr o nic c o n diti o ns  
o  c urre ntl y treate d c o n diti o ns  
o  c o nc o mita nt me dicati o ns  
•  Re vie w of t he i ncl usi o n a n d e xcl usi o n criteria 
•  De m o gra p hic data i ncl u di n g se x, a ge at e ntr y a n d race 
•  P h ysical E xa mi nati o n of maj or b o d y s yste ms i ncl u di n g pre dicte d b o d y wei g ht 
(refer t o Secti o n 6. 3. 4 f or t he calc ulati o n f or m ula) a n d hei g ht 
•  Rec or di n g of c o nc o mita nt me dicati o ns a n d t hera pies 
T he data m ust be c ollecte d d uri n g t he scree ni n g assess me nt b ut ca n be e ntere d i n t he 
e C R F after s ur ger y. 
7. 4. 2. 2    Pr e- d ose pr oce d ures t o be perf or me d o n D 0 bef ore t he first d ose of st u dy 
me dic ati o n is a d mi nistere d 
O n D 0 all pre- d ose pr oce d ures a n d assess me nts are t o be perf or me d bef ore t he first 
d ose  of  st u d y  me dic ati o n .   N ote:   W here  a  patie nt’s  c o n diti o n  precl u des  a n 
assess me nt ta ki n g place as sc he d ule d, t he assess me nt s h o ul d be perf or me d as s o o n as 
p ossi ble. If t his is n ot p ossi ble, t he assess me nt will n ot be perf or me d a n d t he reas o n 
f or n o n- perf or ma nce will be rec or de d.  H o we ver, all D 0 pre- d ose assess me nts m ust be 
perf or me d  pri or  t o  t he  first  d ose  of  st u d y  me dicati o n  bei n g  a d mi nistere d  a n d  e ver y 
eff ort m ust be ma de t o perf or m all assess me nts.  
T he f oll o wi n g pr oce d ures a n d assess me nts are perf or me d a n d t he data is rec or de d i n 
t he e C R F (refer t o t he fl o w c harts i n Ta ble 5): 
•  Re vie w of t he i ncl usi o n a n d e xcl usi o n criteria t o e ns ure c o nti n ue d eli gi bilit y 
•  Ra n d o misati o n: ra n d o misati o n n u m ber a n d date a n d ti me of ra n d o misati o n are 
rec or de d 
•  He m o d y na mic c olla pse bef ore cr oss cla m pi n g ( yes/ n o) 
•  Vital si g ns ( b o d y te m perat ure, bl o o d press ure, p ulse) 
•  M o difie d ra n ki n g scale ( m R S) (e val uati o n of t he val ue bef ore s ur ger y) 
•  Bl o o d bi oc he mistr y (refer t o Secti o n 6. 3. 2 f or s pecific bi oc he mistr y varia bles) 
•  Bl o o d pre g na nc y test if rele va nt ( o nl y f or fe males u n der a ge of 6 0 years) 
•  Hae mat ol o g y (refer t o Secti o n 6. 3. 2 f or s pecific hae mat ol o g y varia bles) 
•  P har mac o d y na mics ( P D): M x A sa m ple f or ce ntral testi n g wit hi n 1 hr pre- d ose 
•  Sec o n dar y efficac y: Ne utralizi n g a nti b o dies I F N- beta ( N A bs) sa m ple wit hi n 1 
hr pre- d ose 
•  Te ntati ve Disease S pecific Mar ker C D 7 3 a n d P ote ntial I nfla m mat or y Mar ker 
( PI M) sa m ples f or ce ntral testi n g wit hi n 1 hr pre- d ose 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
5 3  of 6 8  
1 6  A pr 2 0 1 9  
•  Rec or di n g of c o nc o mita nt me dicati o ns a n d t hera pies 
•  C ollecti o n of A d verse E ve nts fr o m t his ti me p oi nt o n war d: All A d verse E ve nts 
a n d  Seri o us  A d verse  E ve nts  will  be  c ollecte d  fr o m  t he  ti me  of  i nf or me d 
c o nse nt si g nat ure a n d t hr o u g h o ut t he st u d y u ntil t he last f oll o w- u p visit. 
•  Rec or di n g of maj or s ur gical o utc o mes affecti n g patie nt 
o  o pe n a b d o me n ( yes/ n o) 
o  left re nal vei n li gate d ( yes/ n o) 
o  Cla m pi n g ti me a b o ve t he re nal arteries 
 
I n practice, at arri val at t he I C U sta n dar d arter y-astr u p a nal ysis f or hae mat ol o g y a n d 
bi oc he mistr y  are  perf or me d.  T u bes  f or  disease  a n d  me dicati o n  s pecific  mar kers  are 
dra w n at t he sa me ti me a n d st ore d i n t he I C U. After sa m pli n g, t he st u d y me dicati o n is 
be g u n. T he st u d y me dicati o n is als o st ore d i n t he I C U. 
 
T R E A T M E N T P E RI O D  ( D 0 t o D 5) a n d S H O R T T E R M f oll o w- u p peri o d 
( D 6 t o D 3 0): S T U D Y M E DI C A TI O N A D MI NI S T R A TI O N, P A TI E N T 
C A R E, A N D A S S E S S M E N T S 
T he  st u d y  treat me nt  peri o d  c o m prises  D 0  t o  D 5  i ncl usi ve.  M ost  pr oce d ures  a n d 
assess me nts t o be perf or me d o n D 0 are pre- d ose ( wit h t he e xce pti o n of rec or di n g of 
S O F A sc ori n g, c o nc o mita nt me dicati o ns a n d t hera pies a n d A E re p orti n g) a n d t he y are 
detaile d i n Secti o n 7. 4. 2. 2.   
T he  pr oce d ures  a n d  assess me nts  t o  be  perf or me d  o n  D 0  fr o m  t he  ti me  of  st u d y 
me dicati o n a d mi nistrati o n t o D 5 are detaile d i n Secti o n 7. 5. 1.    
T he pr oce d ures a n d assess me nts t o be perf or me d i n t he s h ort-ter m f oll o w- u p peri o d 
are detaile d i n Secti o n 7. 5. 2. 
Assess me nts  fr o m  D 0  a n d  pri or  t o  D 3 0  are  o nl y  perf or me d  if  t he  p atie nt  is 
h os pit alise d  i n  t he  o per ati n g  h os pit al  ( w here  t he  p atie nt  w as  o per ate d  a n d 
recr uite d i n t he tri al).  
 
Sc he d ule of assess me nts f or D 0 t o D 5 
D ay 0 0 hrs a n d p ost d ose: 
T he  first  d ose  of  st u d y  me dicati o n  will  be  a d mi nistere d  o n  D 0 at 0 hrs  ( wit h 
ma xi m u m  of  4  h o urs  after  t he  R A A A  s ur ger y).  T he  f oll o wi n g  D 0  st u d y  me dicati o n 
a d mi nistrati o n pr oce d ures a n d p ost d ose assess me nts are perf or me d (refer t o Ta ble 5) 
a n d t he data is rec or de d i n t he e C R F: 
•  A d mi nistrati o n of st u d y me dicati o n: F P- 1 2 0 1-l y o or place b o, a d mi nistere d as 
a b ol us i ntra ve n o us i njecti o n, f oll o we d b y a 5 ml fl us h of sterile sali ne 
•  S O F A sc ore assess me nt f or baseli ne 
•  Rec or di n g of c o nc o mita nt me dicati o ns a n d t hera pies 
•  A E re p orti n g c o m me nces after t he c o nse nt has bee n o btai ne d. 
D ay 1  t o D ay 5: 
Fr o m  D 1  t o  D 5  i ncl usi ve,  t he  f oll o wi n g  st u d y  assess me nts  a n d  pr oce d ures  will  be 
perf or me d  ( patie nt  will  n ot  be  s u bjecte d  f or  a d diti o nal  i n vasi ve  assess me nts  if  n ot 
sta n dar d f or patie nt care i n I C U/ h os pital war d): 
•  C hec k if patie nt is o n ve ntilati o n (refer t o V F D defi niti o n i n Secti o n 6. 2. 3) 
•  C hec k if patie nt is i n t he I C U 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
5 4  of 6 8  
1 6  A pr 2 0 1 9  
•  C hec k if patie nt is o n or ga n s u p p ort 
•  T he n u m ber of or ga n fail ure free da ys b y mea ns of S O F A.  S O F A sc ores are 
assesse d  dail y  i n  t he  I C U  (refer  t o  Ta ble  1  a n d  Ta ble  8  f or  t he  S O F A 
c o m p ositi o n  a n d  sc he d ules. N ote:   T he  w orst  dail y  val ue  of  eac h  ele me nt 
s h o ul d be use d t o calc ulate t he o verall S O F A sc ore. 
•  Vital si g ns (te m perat ure, B P a n d H R) m ust be meas ure d a n d rec or de d bet wee n 
6 a m  t o  1 0 a m  usi n g  t he  val ues  cl osest  t o  8 a m  (ass u mi n g  t hese  val ues  are 
re prese ntati ve of t he patie nt’s c o n diti o n).  All vital si g ns assess me nts m ust be 
ma de at t he sa me ti me p oi nt w he n p ossi ble. 
•  Bl o o d bi oc he mistr y : sa m ples m ust be ta ke n bet wee n 6 a m t o 1 0 a m (refer t o 
Secti o n 6. 3. 2. f or s pecific bi oc he mistr y varia bles) 
•  Hae mat ol o g y: sa m ples m ust be ta ke n bet wee n 6 a m t o 1 0 a m (refer t o Secti o n 
6. 3. 2. f or s pecific hae mat ol o g y varia bles) 
•  I ntra-a b d o mi nal  press ure  (I A P)  m ust  be  meas ure d  dail y  bet wee n  6 a m  t o 
1 0 a m d uri n g I C U sta y or u ntil c o m plete res ol uti o n of ele vate d press ure. N ot 
a p plica ble if a b d o me n was left o pe n at i n de x o perati o n 
•  Dail y rec or di n g of maj or s ur gical o utc o mes affecti n g patie nt 
o  o pe n a b d o me n: yes/ n o (t o detect ti me of cl os ure or re- o pe ni n g) 
o  l o wer li m b e m b olizati o n ( yes/ n o), c o nse q ue nt r ha b d o m y ol ysis ( yes/ n o) 
o  E x pl orati ve la par ot o m y f or blee di n g ( yes/ n o), rec or d bl o o d l oss 
o  E x pl orati ve la par ot o m y a n d b o wel resecti o n ( yes/ n o) 
•  M x A,  C D 7 3  a n d  PI M  sa m ples  f or  ce ntral  testi n g  wit hi n  t he  ti mefra me  of 
2 2 h o urs  ±  2 h o urs  after  t he  pre vi o us  da y’s  a d mi nistrati o n  of  st u d y 
me dicati o n, h o we ver bef ore t he ne xt st u d y dr u g d ose 
•  Rec or di n g of c o nc o mita nt me dicati o ns a n d t hera pies 
•  A E re p orti n g  
N ote:  W here a patie nt’s c o n diti o n precl u des a n assess me nt ta ki n g place as sc he d ule d, 
t he assess me nt s h o ul d be perf or me d wit hi n ± 2 h o urs of t he sc he d ule d ti me a n d, if t his 
is  n ot  p ossi ble,  t he  assess me nt  will  n ot  be  perf or me d  a n d  t he  reas o n  f or  n o n-
perf or ma nce  will  be  rec or de d.    H o we ver,  e ver y  eff ort  m ust  be  ma de  t o  perf or m  all 
assess me nts.  
Eac h  da y  o n  D 0  t o  D 5  i ncl usi ve,  t he  st u d y  me dicati o n, F P - 1 2 0 1-l y o  or  place b o,  is 
a d mi nistere d  as  a  b ol us  i ntra ve n o us  i njecti o n 2 4 h o urs ± 1 h o ur  after  t he  pre vi o us 
d a y’s a d mi nistr ati o n of st u d y me dic ati o n  a n d t he f oll o wi n g st u d y assess me nts a n d 
pr oce d ures are perf or me d p ost st u d y me dic ati o n a d mi nistr ati o n: 
•  Rec or di n g of c o nc o mita nt me dicati o ns a n d t hera pies 
•  A E re p orti n g c o m me nces after o btai ni n g t he i nf or me d c o nse nt. 
 
Sc he d ule  of  assess me nts  f or  t he  s h ort-ter m  f oll o w- u p  peri o d  ( D 6  t o 
D 3 0) 
Dail y assess me nts are perf or me d u p t o D 3 0 if t he st u d y patie nt is still h os pitalize d i n 
t he  sa me  h os pital  w here  i nitiall y  o perate d.    If  t he  patie nt  is  m o ve d  t o  a  differe nt 
h os pital  ( or  h o me),  assess me nts  will  n ot  be  d o ne.  All  assess me nts  s h o ul d  be 
perf or me d  at  t he  sa me  ti me  of a da y  as  t he  D 6  assess me nts  were  perf or me d. N ote:  

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
5 5  of 6 8  
1 6  A pr 2 0 1 9  
W here t he patie nt’s c o n diti o n precl u des a n assess me nt ta ki n g place as sc he d ule d, t he 
assess me nt s h o ul d be perf or me d wit hi n ± 2 h o urs of t he sc he d ule d ti me, a n d if t his is 
n ot  p ossi ble,  t he n  t he  assess me nt  will  n ot  be  perf or me d  a n d  t he  reas o n  f or  n o n-
perf or ma nce  will  be  rec or de d.    H o we ver,  e ver y  eff ort  m ust  be  ma de  t o  perf or m  all 
assess me nts.  
T he f oll o wi n g st u d y assess me nts a n d pr oce d ures will be perf or me d as bel o w fr o m D 6 
t o D 3 0 (refer t o fl o w c harts i n Ta ble 6):    
•  C hec k if patie nt is o n ve ntilati o n (refer t o V F D defi niti o n i n Secti o n 6. 2. 3) 
Pati e nts  still  o n  p ositi ve  press ure  ve ntilati o n  w h o  are  tra nsferre d  t o  a n ot her 
h os pital  or  healt hcare  facilit y  pri or  t o  D 3 0  will  be  f oll o we d  u p  t o  assess  t he 
V F D o utc o me at D 3 0.   
•  C hec k if patie nt is i n t he I C U 
Patie nts still o n I C U w h o are tra nsferre d t o a n ot her h os pital or healt hcare I C U 
facilit y pri or t o D 3 0 will be f oll o we d u p t o assess t he da ys o n I C U at D 3 0.   
•  C hec k if patie nt is o n or ga n s u p p ort  
•  T he n u m ber of or ga n fail ure free da ys b y mea ns of S O F A (arterial bl o o d gas 
a nal ysis s h o ul d n ot be d o ne if n ot part of sta n dar d care at t his p oi nt). 
•  P h ysical E xa mi nati o n of maj or b o d y s yste ms 
•  Vital si g ns (te m perat ure, B P a n d H R) m ust be meas ure d a n d rec or de d bet wee n 
6 a m  t o  1 0 a m  usi n g  t he  val ues  cl osest  t o  8 a m  (ass u mi n g  t hese  are 
re prese ntati ve of t he patie nt’s c o n diti o n).  All vital si g ns assess me nts m ust be 
ma de at t he sa me ti me p oi nt w he n p ossi ble. 
•  Bl o o d  bi oc he mistr y   D 6  a n d  D 3 0  o nl y,  a n d  D 9  a n d  D 1 3  if  patie nt  is 
h os pitalise d.  Sa m ples  m ust  be  ta ke n  bet wee n  6 a m  t o  1 0 a m  (refer  t o 
Secti o n 6. 3. 2. f or s pecific bi oc he mistr y varia bles) 
•  Hae mat ol o g y   D 6  a n d  D 3 0  o nl y,  a n d  D 9  a n d  D 1 3  if  patie nt  is  h os pitalise d. 
Sa m ples  m ust  be  ta ke n  at  t he  sa me  ti me  of  da y  as  D 6  assess me nts  (refer  t o 
Secti o n 6. 3. 2. f or s pecific hae mat ol o g y varia bles) 
•  I ntra-a b d o mi nal  press ure  (I A P)  m ust  be  meas ure d  dail y  bet wee n  6 a m  t o 
1 0 a m d uri n g I C U sta y or u ntil c o m plete res ol uti o n of ele vate d press ure 
•  O n D 6 M x A, C D 7 3 a n d PI M sa m ples f or ce ntral testi n g wit hi n t he ti mefra me 
of  2 2  h o urs  ±  2 h o urs  after  t he  pre vi o us  da y’s  a d mi nistrati o n  of  st u d y 
me dicati o n.  I n  a d diti o n,  o n  D 9  a n d  o n  D 1 3  bet wee n  6 a m  t o  1 0 a m,  if  t he 
patie nt is h os pitalise d. 
•  Ne utralizi n g  a nti b o dies  I F N- beta  ( N A bs)  sa m ple 
D 3 0  o nl y .  F or  t his 
assess me nt t here is ± 5 D visit wi n d o w. 
•  Da ys o n vas oacti ve dr u gs 
•  M ortalit y (I C U a n d h os pital) at D 3 0 o nl y  
•  Rec or di n g of c o nc o mita nt me dicati o ns a n d t hera pies 
•  A E re p orti n g  
 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
5 6  of 6 8  
1 6  A pr 2 0 1 9  
 
Dis c h ar ge 
 
Disc h ar ge pri or t o D 3 0 
If  a  patie nt  is  disc har ge d  fr o m  t he  o perati n g  h os pital  pri or  t o  D 3 0  a n d  n ot 
disc o nti n ue d, a c o m plete fi n al e v al u ati o n s h o ul d be ma de at t he d a y of disc h ar ge  as 
descri be d bel o w (refer t o Ta ble 7):    
•  C hec k if patie nt is o n ve ntilati o n (refer t o V F D defi niti o n i n Secti o n 6. 2. 3) 
All p atie nts, w het her still o n or alrea d y off p ositi ve press ure ve ntilati o n, w h o 
are  tra nsferre d  t o  a n ot her  h os pital  or  healt hcare  facilit y  pri or  t o  D 3 0  will  be 
f oll o we d u p t o assess t he V F D o utc o me at D 3 0.   
•  C hec k if patie nt is i n t he I C U 
Patie nts t hat are tra nsferre d t o a n ot her h os pital or healt hcare I C U facilit y pri or 
t o D 3 0 will be f oll o we d u p t o assess t he da ys i n I C U at D 3 0.   
•  C hec k if patie nt is o n or ga n s u p p ort  
•  T he n u m ber of or ga n fail ure free da ys b y mea ns of S O F A (arterial bl o o d gas 
a nal ysis s h o ul d n ot be d o ne if n ot part of sta n dar d care at t his p oi nt).   
•  P h ysical E xa mi nati o n of maj or b o d y s yste ms 
•  Vital si g ns (te m perat ure, B P a n d H R) m ust be meas ure d a n d rec or de d bet wee n 
6 a m  t o  1 0 a m  usi n g  t he  val ues  cl osest  t o  8 a m  (ass u mi n g  t hese  val ues  are 
re prese ntati ve of t he patie nt’s c o n diti o n).  All vital si g ns assess me nts m ust be 
ma de at t he sa me ti me p oi nt w he n p ossi ble. 
•  I ntra-a bd o mi nal  press ure  (I A P)  m ust  be  meas ure d  dail y  bet wee n  6 a m  t o 
1 0 a m d uri n g I C U sta y or c o m plete res ol uti o n of ele vate d press ure 
•  Da ys o n vas oacti ve dr u gs 
•  Rec or di n g of c o nc o mita nt me dicati o ns a n d t hera pies 
•  A E re p orti n g 
•  Patie nt  is  i n vite d  f or  a  la b orat or y  visit  t o  assess N A bs  a n d  ot her  D 3 0 
assess me nts o n D 3 0.  
•  M ortalit y  f oll o w- u p:  F or  all  patie nts  w h o  wit h dra w  fr o m  t he  st u d y  pri or  t o 
D 3 0,  m ortalit y  will  be  assesse d  at  D 3 0  a n d  D 9 0  ( 3 m o nt hs). N ote:  A  ti me 
wi n d o w of + 1 4 da ys is gi ve n f or D 9 0 assess me nt. 
I n  t he  case  of  a n  o n g oi n g  A E,  a p pr o priate  safet y  e val uati o ns  a n d/ or  a d diti o nal  tests 
ma y  be  perf or me d  at  a n y  ti me  w he n  cli nicall y  i n dicate d  at  t he  discreti o n  of  t he 
I n vesti gat or, u ntil res ol uti o n or D 3 0, w hic he ver is t he s o o ner.   
A n y o n g oi n g A Es s h o ul d be f oll o we d u p t o res ol uti o n or st u d y D 3 0, w hic he ver is t he 
s o o ner.    
If t he patie nt ref uses a n y of t he a b o ve assess me nts or is l ost t o f oll o w- u p, t his is n ote d 
i n t he e C R F. 
If a patie nt is l ost t o f oll o w- u p, m ortalit y data will be s o u g ht fr o m alter nate s o urces 
s uc h  as  t he  patie nt’s  l ocal  p h ysicia n  or  a vaila ble  nati o nal  data bases,  w he ne ver 
p ossi ble.  

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
5 7  of 6 8  
1 6  A pr 2 0 1 9  
 
Fi n al F O L L O W- U P at D 9 0 ( 3 m o nt hs) 
T he  st u d y  has  a  fi nal  f oll o w  u p  at  D 9 0  ( 3  m o nt hs)  f or  assess me nt  of  t he  fi nal 
o utc o me,  nee d  of  or ga n  s u p p ort  ( mai nl y  he m o dial ysis),  a n d  use  of  healt h  care 
ser vices. M o difie d ra n ki n g scale ( m R S) at D 9 0 will be use d t o e val uate st u d y s u bject 
disa bilit y. Data will be gat here d fr o m patie nt c harts, nati o nal data bases or b y p h o ne 
directl y  fr o m  t he  patie nt  or  a  healt h  care  facilit y.  If  a  patie nt  is  o n  he m o dial ysis  at 
D 9 0, it is c o nsi dere d as per ma ne nt i n t his st u d y. Ac ute re nal fail ure relate d t o R A A A 
ofte n res ol ves wit hi n 3 m o nt hs if it is re versi ble. 
If t he patie nt ref uses a n y of t he a b o ve assess me nts or is l ost t o f oll o w- u p, t his is n ote d 
i n t he e C R F. 
 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
5 8  of 6 8  
1 6  A pr 2 0 1 9  
 
S T A TI S TI C A L M E T H O D S 
Detaile d i nf or mati o n re gar di n g statistical met h o ds will be pr o vi de d se paratel y i n t he 
Statistical A nal ysis Pla n ( S A P).  A n y de viati o ns fr o m t he pla n ne d a nal yses s pecifie d 
wit hi n t he S A P will be j ustifie d i n writi n g a n d prese nte d wit hi n t he fi nal cli nical st u d y 
re p ort. 
 
P o p ul ati o ns f or a n al ysis 
T he f oll o wi n g a nal ysis sets will be defi ne d f or statistical a nal ysis: 
T he  F ull  A n al ysis  Set  f or  Effic ac y  ( F A S- E )  c o nsists  of  all  ra n d o mise d  patie nts 
recei vi n g  st u d y  treat me nt  b ut  e xcl u di n g  t he  earl y  deat hs  ( wit hi n  3 6  h o urs  fr o m  first 
d ose  of  t he  st u d y  treat me nt)  a n d  c o m prises  t he  a nal ysis  set  o n  w hic h  t he  pri mar y 
efficac y a nal ysis is base d. 
T he  Per  Pr ot oc ol  Set  ( P P S)   c o nsists  of  t he  patie nts  i n  t he  F A S  e xcl u di n g  patie nts 
wit h maj or pr ot oc ol vi olati o ns. A rele va nt list of t he maj or pr ot oc ol vi olati o ns will be 
detaile d  i n  t he  S A P.  T he  precise  defi niti o n  of  t he  P P S  at  t he  patie nt  le vel  will  be 
i de ntifie d at t he bli n d re vie w c o n d ucte d b ot h bef ore i nteri m a n d fi nal a nal ysis. 
Statistical  a nal yses  f or  t he  pri mar y  a n d  sec o n dar y  e n d p oi nts  are  perf or me d  o n  b ot h 
t he F A S- E a n d P P S. 
T he  F ull  A n al ysis  Set  f or  S afet y  ( F A S- S )  c o nsists  of  all  ra n d o mise d  patie nts 
recei vi n g  st u d y  treat me nt  a n d  c o m prises  t he  a nal ysis  set  o n  w hic h  t he  e val uati o n  of 
safet y  is  base d.  A  patie nt  recei vi n g  t he  wr o n g  treat me nt  acc or di n g  t o  t he 
ra n d o misati o n  will  be  a nal yse d  f or  safet y  a n d  t olera bilit y  i n  t he  treat me nt  gr o u p 
c orres p o n di n g t o t he treat me nt recei ve d. 
 
S a m ple size esti m ati o n 
T he  pri mar y  efficac y  e n d p oi nt  is  all  ca use  m ortalit y  at  D 3 0.  Deat h  wit hi n  3 6  h o urs 
fr o m  t he  first  d ose  of  t he  st u d y  treat me nt  lea ds  t o  e xcl usi o n  fr o m  efficac y  a nal ysis 
(see secti o n 8. 5. 1 Efficac y A nal ysis). 
A  sa m ple  size  of  1 2 9  eli gi ble  patie nts  f or  t he  pri mar y  efficac y  a nal ysis,  wit h  a  2: 1 
rati o  t o  acti ve  ( 8 6)  a n d  place b o  ( 4 3),  will  detect  t he  differe nce  of  2 2 %  bet wee n  t he 
t w o treat me nt gr o u ps wit h 8 0 % p o wer usi n g 2-si de d test wit h 0, 0 5 si g nifica nce le vel. 
Beca use  of  t he  pla n ne d  i nteri m  a nal yses,  t he  calc ulati o ns  ass u me  t hat  2  se q ue ntial 
tests  are  ma de  a n d  t he  O’ Brie n- Fle mi n g  s pe n di n g  f u ncti o n  is  use d  t o  deter mi ne  t he 
test b o u n daries. 
P o wer  calc ulati o n  ass u mes  3 7  %  pr o p orti o n  of  e ve nts  o n  place b o  gr o u p  a n d  1 5  % 
pr o p orti o n f or t he acti ve treat me nt gr o u p. 
T o ac hie ve a sa m ple size of 1 2 9 f or t he pri mar y efficac y a nal ysis, ta ki n g acc o u nt t he 
esti mate d  a m o u nt  of  earl y  deat hs  wit hi n  3 6  h o urs  fr o m  first  d ose  of  t he  st u d y 
treat me nt (esti mate d 1 5 %), t here s h o ul d be 1 5 2 patie nts ra n d o mise d t o t he st u d y.  
T he sa m ple size calc ulati o ns will be re-e val uate d after t he i nteri m has bee n perf or me d 
(c o m prisi n g at least 3 1 eli gi ble patie nts f or t he pri mar y efficac y a nal ysis).  
 
B A S E LI N E C H A R A C T E RI S TI C S A N D DI S P O SI TI O N 
As per Secti o n 6. 4., t he baseli ne assess me nts c o nsist of t h ose assess me nts carrie d o ut 
i n  t he  scree ni n g  peri o d  a n d  t h ose  carrie d  o ut  pri or  t o  t he  first  d ose  of  t he  st u d y 
me dicati o n o n D 0.   

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
5 9  of 6 8  
1 6  A pr 2 0 1 9  
De m o gra p hic  a n d  baseli ne  c haracteristics  are  s u m marise d  b y  treat me nt  gr o u p  a n d 
o verall.  
Di s p ositi o n  a n d  reas o ns  f or  disc o nti n uati o n  are  s u m marise d  f or  all  patie nts  t o get her 
wit h treat me nt e x p os ure a n d st u d y d urati o n b y treat me nt gr o u p. 
 
E v al u ati o n of s afet y 
All  patie nts  w h o  recei ve  a  mi ni m u m  of  o ne  a d mi nistrati o n  of  st u d y  me dicati o n  are 
i ncl u de d i n t he safet y a nal ysis. 
A dverse Eve nts 
Treat me nt E mer ge nt A d verse Effects ( T E A Es) a n d S A Es are classifie d acc or di n g t o 
t he  Me dical  Dicti o nar y  f or  Re g ulat or y  Acti vities ( Me d D R A)  S O C  a n d  t he  preferre d 
ter m. T he i nci de nce of t hese e ve nts will be s u m marise d b y treat me nt gr o u p i n ta bles 
w hic h will als o i ncl u de i nf or mati o n o n se verit y a n d relati o ns hi p t o st u d y me dicati o n. 
T hese s u m maries will be base d o n t he Safet y Set. T he fre q ue nc y of c o m plicati o ns is 
s u m marise d b y treat me nt gr o u ps i n ter ms of c o u nts. 
Vit al Si g ns 
Vital  si g ns  data  ( B P,  H R  a n d  te m perat ure)  is  s u m marise d  b y  treat me nt  gr o u p 
se paratel y at D 0, D 1, D 2, D 3, D 4, D 5, D 6, D 9, D 1 3 a n d D 3 0. T he ma xi m u m c ha n ge 
fr o m baseli ne o ver t he 3 0- da y f oll o w- u p peri o d will be calc ulate d f or eac h patie nt a n d 
s u m marise d. 
Vital  si g ns  s u m maries  will  be  i n  ter ms  of  mea n,  me dia n,  sta n dar d  de viati o n ( S D), 
mi ni m u m a n d ma xi m u m. 
Cli nic al L a b or at ory P ar a meters 
Descri pti ve statistics ( mea n, me dia n, S D, mi ni m u m a n d ma xi m u m) f or bi oc he mistr y 
a n d  hae mat ol o g y  will  be  o btai ne d  a n d  ta b ulate d  b y  treat me nt  gr o u p  at  D 0,  D 1,  D 2, 
D 3,  D 4,  D 5,  D 6  a n d  D 3 0.  Descri pti ve  statistics  ( mea n,  me dia n,  S D,  mi ni m u m  a n d 
ma xi m u m). 
S hift ta bles ( wit hi n, bel o w a n d a b o ve t he n or mal ra n ge) will als o be pr o vi de d f or eac h 
para meter  i n  relati o n  t o  t he  ma xi m u m  c ha n ge  fr o m  baseli ne  fr o m  D 0  o ver  t he 
c o m plete 3 0- da y f oll o w- u p peri o d. 
 
E v al u ati o n of effic ac y 
 
Ev al u ati o n of pri m ary effic acy e n d p oi nt 
T he pri mar y e n d p oi nt of t he st u d y will be: 
•  A ll-ca use m ortalit y at D 3 0 
T o be eli gi ble f or efficac y a nal ysis eac h patie nt m ust recei ve at least t w o d oses of t he 
st u d y me dicati o n wit h a n effect ti me of 1 2 h o urs after sec o n d d ose. T his mea ns t hat a 
deat h wit hi n 3 6 h o urs fr o m t he first d ose of st u d y treat me nt lea ds t o e xcl usi o n fr o m 
efficac y a nal ysis. T his deri ves fr o m t he fact t hat base d o n t he pri or cli nical p hase I/II 
st u dies wit h i nterfer o n beta- 1a, its effect o n t he e x pressi o n of C D 7 3 a n d pr o d ucti o n of 
a de n osi ne  will  re q uire  1 2  t o  2 4  h o urs  fr o m  a d mi nistrati o n  of  t he  dr u g.  T h us, 
t hera pe utic  le vels  will  n ot  be  reac he d  u ntil  1 2  h o urs  fr o m  t he  sec o n d  d ose,  i.e.  3 6 
h o urs fr o m t he first d ose. Meas uri n g efficac y a gai nst m ulti- or ga n fail ure pri or t o t his 
p oi nt is mislea di n g beca use t hera pe utic le vels ha ve n ot yet bee n reac he d.   

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Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
6 0  of 6 8  
1 6  A pr 2 0 1 9  
T he  efficac y  a nal yses  will  be  c o n d ucte d  usi n g  l o gistic  re gressi o n  m o del  f or  t he 
o bser ve d m ortalit y rates i n t he t w o treat me nt gr o u ps. Stratificati o n fact ors use d i n t he 
ra n d o misati o n  will  be  i ncl u de d  i n  t he  m o del.  Pri mar y  res ult  will  be  prese nte d  as  a n 
a dj uste d o d ds rati o a n d a 9 5 % CI f or t he a dj uste d o d ds rati o. Als o , a 9 5 % c o nfi de nce 
i nter val ( CI) f or t he differe nce i n t he o bser ve d m ortalit y rates will be calc ulate d.  A 
t w o-si de d si g nifica nce le vel of 0. 0 5 will be use d f or all a nal yses. 
T here will a d diti o nall y be a n e val uati o n of t he h o m o ge neit y of t he treat me nt effect b y 
i n vesti gati n g treat me nt b y ce ntre a n d treat me nt b y baseli ne fact or i nteracti o ns i n t he 
l o gistic m o del. Data f or t he pri mar y efficac y e n d p oi nt will als o be prese nte d f or ke y, 
pre- defi ne d  s u b gr o u ps  of  patie nts  t o get her  wit h  9 5 %  CIs  f or  t he  differe nce  i n  t h ose 
rates  t o  s u p ple me nt  t he  i n vesti gati o n  of  h o m o ge neit y.  M ortalit y  at  D 3 0  will  be 
ill ustrate d  als o  usi n g  s ur vi val  f u ncti o n  a n d  Ka pla n- Meier  c ur ves  i ncl u di n g  l o g-ra n k 
test as a n e x pl orat or y a nal ysis. 
 
Ev al u ati o n of sec o n d ary effic acy e n d p oi nts 
B y wa y of f urt her c o nfir mat or y meas ures of efficac y, t he f oll o wi n g e n d p oi nts will be 
a nal ys e d: 
•  Ti me a n d reas o n/ dia g n osis of deat h u p t o D 9 0 ( 3 m o nt hs)  
•  N u m ber of V F Ds u p t o D 3 0 
•  N u m ber of da ys recei vi n g he m o dial ysis at D 3 0 a n d D 9 0 
•  N u m ber of I C U free da ys u p t o D 3 0 
•  Or ga n fail ure free da ys u p t o D 3 0 
•  Ne utralizi n g a nti b o dies I F N beta ( N A bs) i n w h ole bl o o d sa m ples u p t o D 3 0 
•  N u m ber of da ys i n h os pital u p t o D 3 0 a n d D 9 0 (le n gt h of sta y i n a n ot her 
healt h care facilit y) 
•  Pre vale nce of a b d o mi nal c o m part me nt s y n dr o me, i.e. i ntra-a b d o mi nal press ure 
(I A P) val ue differe nces bet wee n st u d y gr o u ps 
•  Disa bilit y o n D 9 0 meas ure d b y m o difie d ra n ki n g scale ( m R S) 
All -ca use  m ortalit y  at  D 9 0  ( 3 m o nt hs)  will  be  c o m pare d  usi n g  met h o ds  f or  t he 
e val uati o n  of  ti me  t o  e ve nt  e n d p oi nts.  Hazar d  rati os  f or  eac h  of  t hese  ti me  peri o ds 
will be prese nte d wit h ass ociate d 9 5 % CIs a n d l o g-ra n k p- val ues f or t he F A S. Als o , 
si milar  l o gistic  re gressi o n  m o del  t ha n  f or  t he  pri mar y  e n d p oi nt  ( D 3 0  m ortalit y)  will 
be d o ne.  
F or  e n d p oi nts  n u m ber  of  V F Ds,  n u m ber  of  I C U  free  da ys,  or ga n  fail ure-free  da ys, 
n u m ber of da ys o n he m o dial ysis, I A P val ues data will be s u m marise d i n ter ms of t he 
mea n, me dia n, mi ni m u m a n d ma xi m u m, a n d t he treat me nt gr o u ps will be c o m pare d 
usi n g  t he  Ma n n- W hit ne y  U-test.  C o m plete  data  o n  or ga n  fail ure  free  da ys  ma y  be 
u na vaila ble d ue t o S O F A sc ores n ot bei n g assesse d after I C U treat me nt. T o acc o u nt 
f or t his, t he n u m ber of or ga n fail ure free da ys will be a nal yse d b y e x pressi n g t hese as 
a  pr o p orti o n  of  t he  da ys  o n  w hic h  S O F A  sc ores  are  a vaila ble.  Disa bilit y  meas ure d 
wit h  m R S  will  be  s u m marize d  descri pti vel y  a n d  t he  treat me nt  gr o u ps  will  be 
c o m pare d usi n g t he C oc hra n- Ma ntel- Hae nzel test. 
All  sec o n dar y  a nal yses  are  desi g ne d  t o  be  s u p p orti ve  of  t he  a nal ysis  of  t he  pri mar y 
e n d p oi nt  a n d  t here  will  be  n o  a dj ust me nts  f or  t he  m ulti plicit y  of  e n d p oi nts  s o  t hat 
eac h a nal ysis will be u n derta ke n at t he t w o-si de d 5 % le vel of si g nifica nce. 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
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6 1  of 6 8  
1 6  A pr 2 0 1 9  
 
I N T E RI M A N A L Y SI S 
A n  i nteri m a nal ysis will be perf or me d after t here are 1) at least 3 1 a n d 2) 8 4 patie nts 
t hat  are  eli gi ble  f or  t he  pri mar y  efficac y  e n d p oi nt  a nal ysis  (e xcl u di n g  earl y  deat hs 
wit hi n  3 6  h o urs  fr o m  first  d ose  of  st u d y  treat me nt,  si milarl y  t ha n  f or  pri mar y 
a nal ysis). At t his p oi nt t he st u d y ca n be st o p pe d f or efficac y or f utilit y de pe n di n g o n 
t he i nteri m a nal ysis res ults. T he first i nteri m is br o u g ht f urt her u p as t he recr uit me nt 
rate has mar ke dl y sta g nate d, mai nl y d ue t o c ha n ges i n treat me nt practices of R A A A. 
T he sa m ple size calc ulati o ns will be re-e val uate d after t he first i nteri m.  
Pri mar y  efficac y  e n d p oi nt  will  be  e val uate d  usi n g  O’ Brie n  a n d  Fle mi n g  criteria 
c o ntr olli n g t he t y pe I err or rate. If t he st u d y g oal is reac he d, t he st u d y ca n be st o p pe d 
earl y f or efficac y. T he first i nteri m a nal ysis f oc uses mai nl y f or t he f utilit y st o p pi n g, as 
t he p o wer is l o w t o reac h t he efficac y criteria. T he p o wer t o reac h t he st u d y g oal at 
t he sec o n d i nteri m a nal ysis wit h 8 4 e val ua ble patie nts is a p pr o xi matel y 4 0 %, b ut als o 
t his calc ulati o n will be re-e val uate d after t he first i nteri m.   
I n a d diti o n, t here will p ossi bilit y t o st o p t he st u d y f or f utilit y at t he i nteri m a nal yses. 
Pre defi ne d criteria f or f utilit y st o p pi n g will be defi ne d i n t he i nteri m a nal ysis pla n.  
Statistical a nal ysis pla n f or t he fi nal a n d i nteri m a nal ysis will be pre pare d bef ore t he 
i nteri m a nal ysis. A bli n d re vie w of data will be perf or me d bef ore t he i nteri m a nal ysis 
t o c o nfir m a nal ysis ass u m pti o ns f or e. g. o verall n u m ber of e ve nts. 
 
 

Far o n P har mace uticals Lt d  
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1 6  A pr 2 0 1 9  
 
E T HI C A L, L E G A L A N D A D MI NI S T R A TI V E A S P E C T S 
 
D at a Q u alit y Ass ur a nce 
T he  S p o ns or  or  S p o ns or’s  desi g nee  will  c o n d uct  a  site  visit  t o  eac h  st u d y  ce ntre  t o 
verif y t he q ualificati o ns of eac h I n vesti gat or, i ns pect t he site facilities a n d i nf or m t he 
I n vesti gat or  of  t heir  res p o nsi bilities  a n d  t he  pr oce d ures  f or  e ns uri n g  a de q uate  a n d 
c orrect d oc u me ntati o n. 
T he  I n vesti gat or  is  re q uire d  t o  pre pare  a n d  mai ntai n  a de q uate  a n d  acc urate  case 
hist ories desi g ne d t o rec or d all o bser vati o ns a n d ot her data perti ne nt t o t he st u d y f or 
eac h  st u d y  partici pa nt.  All  i nf or mati o n  rec or de d  i n  t he e C R F  f or  t his  st u d y  m ust  be 
c o nsiste nt wit h t he patie nts’ s o urce d oc u me ntati o n (i.e., me dical rec or ds). 
 D at a b ase M a n a ge me nt a n d Q u ality C o ntr ol 
All st u d y-relate d  data  ge nerate d  b y  site  pers o n nel  will  be  ca pt ure d  electr o nicall y  at 
eac h st u d y ce ntre usi n g t he e C R F. 
Ce ntral la b orat or y assa ys (e. g., P D ) will be ma na ge d b y t he ce ntral la b orat ories a n d 
res ults will be tra nsferre d f or i ncl usi o n i n t he st u d y a nal ysis data base. 
O nce t he e C R F cli nical data ha ve bee n s u b mitte d, c orrecti o ns t o t he data fiel ds will be 
ca pt ure d  i n  a n  a u dit  trail.  T he  reas o n  f or  c ha n ge,  t he  na me  of  t he  pers o n  w h o 
perf or me d t he c ha n ge, a n d t he ti me a n d date will be l o g ge d t o pr o vi de a n a u dit trail. 
T he s pecific pr oce d ures t o be use d f or data e ntr y a n d q uer y res ol uti o n usi n g t he e C R F 
will  be  pr o vi de d  t o  st u d y  sites  i n  e C R F  c o m pleti o n  i nstr ucti o ns.  I n  a d diti o n,  site 
pers o n nel  will  recei ve  trai ni n g  o n  t he  e C R F.  O nce  t he  s o urce  data  verificati o n  is 
c o m plete a n d all q ueries are cl ose d, Data Ma na ge me nt will  freeze t he e C R F pa ge. 
 
C ase Re p ort F or ms a n d S o urce D oc u me nt ati o n 
All data o btai ne d d uri n g t his st u d y m ust be pr o m ptl y e ntere d i n t he e C R F. All s o urce 
d oc u me nts  fr o m  w hic h  e C R F  e ntries  are  deri ve d  s h o ul d  be  place d  i n  t he  patie nt’s 
me dical  rec or ds.  Meas ure me nts  f or  w hic h  s o urce  d oc u me nts  are  us uall y  a vaila ble 
i ncl u de la b orat or y assess me nts. 
Data  t hat  will  be  e ntere d  directl y  i nt o  t he  e C R F  (i.e.,  f or  w hic h  t here  is  n o  pri or 
writte n or electr o nic rec or d) are c o nsi dere d s o urce data. 
T he  e C R F  e ntries  f or  eac h  patie nt will   be  c hec ke d  a gai nst  s o urce  d oc u me nts  at  t he 
st u d y site b y t he C R A. 
 D at a C ollecti o n  
T he I n vesti gat ors (a n d a p pr o priatel y a ut h orise d staff) will be gi ve n access t o a n o nli ne 
we b - base d  electr o nic  data-ca pt ure  s yste m  t hat is c o m plia nt  wit h  U S  F o o d  a n d  Dr u g 
A d mi nistrati o n  Title  2 1  C o de  of  Fe deral  Re g ulati o ns  Part  1 1.  T his  s yste m  is 
s pecificall y  desi g ne d  f or  t he  c ollecti o n  of  cli nical  data  i n  electr o nic  f or mat.  Access 
ri g hts t o t he electr o nic data-ca pt ure s yste m will be caref ull y c o ntr olle d a n d c o nfi g ure d 
acc or di n g  t o  eac h  i n di vi d ual’s  r ole  t hr o u g h o ut  t he  st u d y.  O nl y  t he  I n vesti gat or  a n d 
a ut h orise d staff will be a ble t o e nter a n d c orrect data i n t he e C R F. 
T he  e C R F  s h o ul d  be  c o m plete d  f or  eac h  patie nt  i ncl u de d  i n  t he  st u d y  a n d  s h o ul d 
reflect t he latest o bser vati o ns o n t he patie nts partici pati n g i n t he st u d y. T heref ore, t he 
e C R F is t o be c o m plete d as s o o n as p ossi ble d uri n g or i m me diatel y after t he patie nt’s 
visit or assess me nt. T he I n vesti gat or m ust verif y t hat all data e ntries i n t he e C R F are 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
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C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
6 3  of 6 8  
1 6  A pr 2 0 1 9  
acc urate a n d c orrect. If s o me assess me nts ca n n ot be d o ne, or if certai n i nf or mati o n is 
u na vaila ble,  n ot  a p plica ble  or  u n k n o w n,  t he  I n vesti gat or  s h o ul d  i n dicate  t his  i n  t he 
e C R F. 
C o m p uterise d  data-c hec k  pr o gra ms  a n d  ma n ual  c hec ks  will  i de ntif y  a n y  data 
discre pa ncies  f or  res ol uti o n.  C orres p o n di n g  q ueries  will  be  ge nerate d  i n  t he  s yste m 
a n d t he site will be i nf or me d o nli ne a b o ut ne w iss ues t o be res ol ve d. All discre pa ncies 
m ust be res ol ve d o nli ne directl y b y t he I n vesti gat or or b y staff a ut h orise d t o d o t his b y 
Dele gati o n of A ut h orit y. 
After  c o m pleti o n,  t he  I n vesti gat or  will  be  re q uire d  t o  electr o nicall y  si g n  off  t he 
cli nical data. 
 
Access t o S o urce D at a 
D uri n g t he st u d y, t he C R O site C R A will m a ke re g ular site visits t o re vie w pr ot oc ol 
c o m plia nce,  c o n d uct  s o urce  data  verificati o n  b y  c o m pari n g  e C R F  e ntries  a n d 
i n di vi d ual  patie nt’s  me dical  rec or ds,  assess  dr u g  acc o u nta bilit y  a n d  ma na ge me nt, 
assess la b orat or y pr oce d ures a n d e ns ure t hat t he st u d y is bei n g c o n d ucte d acc or di n g t o 
perti ne nt re g ulat or y a n d pr ot oc ol re q uire me nts. T he re vie w of me dical rec or ds will be 
perf or me d i n a ma n ner t hat e ns ures patie nt c o nfi de ntialit y is mai ntai ne d. 
S o urce  data  verificati o n  will  be  re q uire d  t o  m o nit or  t he  pr o gress  of  t he  st u d y. 
M ore o ver, re g ulat or y a ut h orit y, I E Cs a n d/ or t he S p o ns or’s Cli nical Q ualit y Ass ura nce 
Gr o u p or desi g nee ma y wis h t o carr y o ut s uc h s o urce data c hec ks a n d/ or o n-site a u dit 
i ns pecti o ns.  Direct  access  t o  s o urce  data  will  be  re q uire d  f or  t hese  i ns pecti o ns  a n d 
a u dits;  t he y  will  be  carrie d  o ut  gi vi n g  d ue  c o nsi derati o n  t o  data  pr otecti o n  a n d 
me dical  c o nfi de ntialit y.  T he I n vesti gat or  m ust  ass ure  t he  C R O  a n d  t he  S p o ns or  t hat 
t he y will pr o vi de t he necessar y s u p p ort at all ti mes. 
 
Arc hi vi n g St u d y Rec or ds 
Acc or di n g t o I C H g ui deli nes, esse ntial d oc u me nts s h o ul d be retai ne d f or a mi ni m u m 
of 2 years after t he last a p pr o val of a mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil 
t here are n o pe n di n g or c o nte m plate d mar keti n g a p plicati o ns i n a n I C H re gi o n or at 
least 2 years ha ve ela pse d si nce t he f or mal disc o nti n uati o n of cli nical de vel o p me nt of 
t he i n vesti gati o nal pr o d uct. H o we ver, t hese d oc u me nts s h o ul d be retai ne d f or a l o n ger 
peri o d if re q uire d b y t he a p plica ble le gal re q uire me nts. F or e xa m ple, i n Fi nla n d data 
nee ds t o be st ore d at least f or 1 5 years. 
 
G o o d Cli nic al Pr actice 
T he pr oce d ures set o ut i n t his st u d y pr ot oc ol are desi g ne d t o e ns ure t hat t he S p o ns or 
a n d  I n vesti gat or  a bi de  b y  t he  pri nci ples  of  t he  G o o d  Cli nical  Practice  g ui deli nes  of 
t he I C H a n d t he Declarati o n of Helsi n ki.( Declarati o n of Helsi n ki 2 0 1 3) T he st u d y will 
als o be carrie d o ut i n kee pi n g wit h l ocal le gal re q uire me nts. 
 
I nf or me d C o nse nt 
T he I n vesti gat or at eac h i n vesti gati o nal site is res p o nsi ble f or e ns uri n g t hat i nf or me d 
c o nse nt ( writte n si g ne d or wit nesse d) f or st u d y partici pati o n is gi ve n b y eac h patie nt 
pri or t o c ollecti o n of st u d y data a n d a d mi nistrati o n of t he st u d y dr u g. T he i nf or me d 
c o nse nt  s h o ul d  be  s o u g ht  fr o m  t he  patie nt,  b ut  d ue  t o  e mer ge nc y  nat ure  of  t he 
c o n diti o n it ma y be i n t he best i nterest of t he patie nt t o m o ve strai g ht o n f or s ur ger y 

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Cli nical St u d y Pr ot oc ol  
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Fi nal Versi o n 0 5  
6 4  of 6 8  
1 6  A pr 2 0 1 9  
a n d  a n  a de q uate  a m o u nt  of  ti me  ca n n ot  be  s pe nt  o n  c o nse nti n g.  T his  will  be 
deter mi ne d  b y  t he  i n vesti gat or  i n  t he  best  i nterest  of  t he  patie nt.  I n  s uc h  a  case  t he 
i n vesti gat or ca n see k i nf or me d c o nse nt fr o m t he ne xt of ki n d uri n g a f o ur- h o ur ti me 
peri o d  w he n  t he  patie nt  m o ves  fr o m  t he  O R  t o  t he  I C U  a n d  t he  dr u g  m ust  be 
a d mi nistere d.  
If c o nse nt has n ot bee n o btai ne d, a patie nt ca n n ot be ra n d o mise d i nt o t he st u d y. 
If a pr ot oc ol a me n d me nt is re q uire d, t he I C D ma y nee d t o be re vise d t o reflect t h ose 
c ha n ges. If t he I C D is re vise d, it m ust be re vie we d a n d a p pr o ve d b y t he a p pr o priate 
I E C, a n d si g ne d b y all patie nts ( or t heir re prese ntati ves) s u bse q ue ntl y e nr olle d i n t he 
st u d y as well as t h ose c urre ntl y e nr olle d i n t he st u d y. 
9. 6. 1.  C o nse nt Pr oce d ure 
I nf or me d c o nse nt m ust be o btai ne d fr o m t he patie nt.  T he patie nt is i nf or me d a b o ut 
t he st u d y b y t he Pri nci pal I n vesti gat or or b y a me m ber of t he researc h tea m t o w h o m 
t he Pri nci pal I n vesti gat or has all o we d dele gati o n of t he c o nse nt pr ocess.   
T he  patie nt  is  gi ve n  a  c o p y  of  t he Pa tie nt  I nf or me d  C o nse nt  D oc u me nt  ( PI C D).  
I nf or me d  patie nts  are  gi ve n  a n  a de q uate  a m o u nt  of  ti me  t o  c o nsi der  t heir  decisi o n 
a b o ut  e nteri n g  t he  st u d y.  H o we ver,  t he  re q uire me nt  t o  i nitiate  s ur ger y  ca n 
si g nifica ntl y  li mit  t he  a m o u nt  of  ti me  a vaila ble  a n d  t he  o perati n g  vasc ular  s ur ge o n 
will deter mi ne t he ti me t hat ma y be use d f or t his, as c o nsi dere d best f or t he patie nt.  
If  a  patie nt  deci des  t o  e nter  t he  st u d y  he  or  s he  is  as ke d  t o  si g n  t he  c o nse nt.  If  t he 
patie nt  is  u na ble  t o  si g n  t he  c o nse nt  d oc u me nt  d ue  t o  o n g oi n g  pre parati o ns  f or 
o perati o n or e. g. st o mac h pai n, or a n y ot her rele va nt reas o n, a n d i na bilit y t o sit u p f or 
si g ni n g, a ver bal c o nse nt ca n be gi ve n wit h a wit ness of o ne me m bers of me dical staff 
e xcl u di n g  t he  st u d y  pers o n nel.  T he  c o nse nt  d oc u me nt is  t he n  c o u ntersi g ne d  b y  a 
me m ber  of  t he  st u d y  tea m  t o  w h o m  o btai ni n g  of  c o nse nt  has  bee n  dele gate d.    O ne 
c o p y  of  t he  d oc u me nt  is  retai ne d  b y  t he  patie nt.    A n ot her  c o p y  is  place d  i n  t he 
patie nt’s  me dical  rec or ds  ( o nl y  if  it  is  re q uire d  l ocall y).    T he  ori gi nal  d oc u me nt  is 
retai ne d i n t he I n vesti gat or Site File. 
If t here is n ot a de q uate ti me t o c o nse nt t he patie nt pri or t o s ur ger y, b ut ot her wise t he 
patie nt w o ul d be eli gi ble f or t he st u d y (c o m plete u nc o nsci o us ness lea ds t o e xcl usi o n), 
t he  i n vesti gat or  ca n  see k  c o nse nt  fr o m  t he  ne xt  of  ki n  after  t he  s ur ger y.  If  t his 
a p pr oac h is ta ke n writte n i nf or me d c o nse nt nee ds t o be ta ke n fr o m t he st u d y s u bject at 
t he s o o nest p ossi ble m o me nt. 
 
9. 6. 2.  Wit h dr a w al of C o nse nt 
Patie nts ma y wit h dra w fr o m t he st u d y at a n y ti me, f or a n y reas o n a n d s uc h a decisi o n 
will  n ot  affect  sta n dar d  care  gi ve n  t o  t he  patie nt.  Data  rec or de d  u p  t o  t he  p oi nt  of 
wit h dra wal is i ncl u de d i n t he st u d y a nal ysis.   
If a patie nt re q uests ter mi nati o n of t he a d mi nistrati o n of st u d y me dicati o n d uri n g t he 
treat me nt peri o d, t he a d mi nistrati o n of st u d y me dicati o n is ter mi nate d b ut t he patie nt 
will c o nti n ue i n t he st u d y a n d all f oll o w- u p assess me nts are perf or me d.   
If a patie nt wit h dra ws c o nse nt d uri n g t he treat me nt peri o d, t he a d mi nistrati o n of st u d y 
me dicati o n is ter mi nate d a n d n o f urt her acti ve st u d y assess me nts are perf or me d fr o m 
t hat  p oi nt  o n.  H o we ver,  per missi o n  will  be  s o u g ht  t o  access  t he  patie nt’s  me dical 
rec or ds  f or  data  rele va nt  t o  t he  st u d y  (e. g.,  m ortalit y,  Ve ntilat or  Free  Da ys  [ V F Ds] 
etc.) a n d t he patie nt will be as ke d t o c o m plete t he D 3 0 p h ysical f oll o w u p. 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
6 5  of 6 8  
1 6  A pr 2 0 1 9  
If a patie nt wit h dra ws c o nse nt after t he treat me nt peri o d t he n n o f urt her acti ve st u d y 
assess me nts  will  be  perf or me d  fr o m  t hat  p oi nt  o n.  H o we ver,  per missi o n  will  be 
s o u g ht  t o  access  t he  patie nt’s  me dical  rec or ds  f or  data  rele va nt  t o  t he  st u d y  (e. g., 
m ortalit y,  V F Ds,  etc.)  a n d  t he  patie nt  will  be  as ke d  t o  c o m plete  t he  D 3 0  p h ysical 
f oll o w u p.   
9. 7.  Pr ot oc ol A p pr o v al a n d A me n d me nt 
F or  t he  st u d y  t o  start,  all  re q uire d  d oc u me ntati o n  m ust  be  a p pr o ve d b y  t he  I E C  a n d 
C o m pete nt A ut h orit y, i n acc or da nce wit h l ocal le gal re q uire me nts. T he S p o ns or m ust 
e ns ure t hat all et hical a n d le gal re q uire me nts ha ve bee n met bef ore t he first patie nt is 
e nr olle d i n t he st u d y. 
T his  pr ot oc ol  is  t o  be  f oll o we d  e xactl y.  T o  alter  t he  pr ot oc ol,  a me n d me nts  m ust  be 
writte n, recei ve a p pr o val fr o m t he a p pr o priate pers o n nel, a n d recei ve I E C/c o m pete nt 
a ut h orit y a p pr o val pri or t o a n i m ple me ntati o n (if a p pr o priate). 
A d mi nistrati ve  c ha n ges  ( n ot  affecti n g  t he  patie nt  be nefit/ris k  rati o)  ma y  be  ma de 
wit h o ut t he nee d f or a f or mal a me n d me nt. All a me n d me nts will be distri b ute d t o all 
pr ot oc ol reci pie nts, wit h a p pr o priate i nstr ucti o ns. 
9. 8.  I n de pe n de nt D at a M o nit ori n g C o m mittee 
A n I D M C will be esta blis he d f or t he st u d y. T he d ut y of t he c o m mittee is t o pr otect 
et hical a n d safet y i nterests of patie nts a n d all ot hers w h o ma y p ossi bl y be e x p ose d t o 
t he st u d y me dicati o n a n d t o ma ke rec o m me n dati o ns t o t he i n vesti gat ors. T he I D M C 
will  re vie w  safet y  data  retrie ve d  f or  i nteri m  a nal ysis  (i.e.  A Es  a n d  S A Es)  i n  a n 
u n bli n de d  ma n ner  a n d  will  gi ve  rec o m me n dati o ns  t o  t he  S p o ns or  re gar di n g  st u d y 
m o dificati o n  a n d/ or  ter mi nati o n.  T he  I D M C  will  c o m prise  at  least  t hree  me m bers, 
i ncl u di n g  at  least  o ne  i n de pe n de nt  bi ostatisticia n  a n d  tw o   cli nicia ns  n ot  ot her wise 
i n v ol ve d i n t he st u d y. 
A n I D M C c harter is esta blis he d, w hic h d oc u me nts i n m ore detail t he res p o nsi bilities, 
d uties a n d o bjecti ves of t he i n di vi d uals a n d of t he c o m mittee.  
9. 9.  Pre m at ure Ter mi n ati o n of t he St u d y 
T he  S p o ns or  reser ves  t he  ri g ht  t o  st o p  t he  st u d y  at  a n y  ti me  o n  t he  basis  of  ne w 
i nf or mati o n re gar di n g safet y or efficac y (e. g., disc o ver y of a n u ne x pecte d, si g nifica nt 
or  u nacce pta ble  ris k  t o  t he  patie nts  e nr olle d  i n  t he  st u d y),  or  if  st u d y  pr o gre ss  is 
u nsatisfact or y (e. g., fail ure t o e nr ol patie nts at a n acce pta ble rate), or f or ot her vali d 
reas o ns  (e. g.,  S p o ns or  deci des  t o  s us pe n d  or  disc o nti n ue  de vel o p me nt  of  t he  dr u g). 
After  s uc h  a  decisi o n  is  ma de,  t he  I n vesti gat or  m ust  i nf or m  all o n-st u d y  patie nts 
wit hi n  1 wee k.  All  deli vere d  st u d y  materials  m ust  be  c ollecte d  a n d  all  e C R F  pa ges 
c o m plete d t o t he e xte nt p ossi ble. 
9. 1 0.  C o nfi de nti alit y 
All  st u d y  fi n di n gs  a n d  d oc u me nts  will  be  re gar de d  as  c o nfi de ntial.  T he  I n vesti gat or 
a n d me m bers of t heir researc h tea m m ust n ot discl ose a n y i nf or mati o n wit h o ut pri or 
writte n a p pr o val fr o m t he S p o ns or. 
T he  a n o n y mit y  of  partici pati n g  patie nts  m ust  be  mai ntai ne d.  O nl y  patie nt  n u m ber 
(c o de)  will  be  rec or de d  i n  t he  e C R F.  D oc u me nts  t hat  i de ntif y  t he  patie nt  will  be 
c o de d b y usi n g o nl y patie nt n u m ber c o des. 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
6 6  of 6 8  
1 6  A pr 2 0 1 9  
9. 1 1.  Ot her Et hic al a n d Re g ul at or y Iss ues 
If  a  si g nifica nt  safet y  iss ue  is  i de ntifie d,  eit her  fr o m  a n  i n di vi d ual  case  re p ort  or 
re vie w of a g gre gate data, t he n t he S p o ns or will iss ue pr o m pt n otificati o n t o all parties 
 re g ulat or y a ut h orities, I n vesti gat ors a n d I E C/ E C. 
A  si g nifica nt  safet y  iss ue  is  o ne  t hat  has  a  si g nifica nt  i m pact  o n  t he  c o urse  of  t he 
cli nical  st u d y  or  pr o gra m me   (i ncl u di n g  t he  p ote ntial  f or  s us pe nsi o n  of  t he 
de vel o p me nt pr o gra m me  or a me n d me nts t o pr ot oc ols) or warra nts i m me diate u p date 
of i nf or me d c o nse nt. 
9. 1 2.  P u blic ati o n P olic y 
A n y ma n uscri pt, a bstract or ot her p u blicati o n or prese ntati o n of res ults or i nf or mati o n 
arisi n g  i n  c o n necti o n  wit h  t he  st u d y  (i ncl u di n g  a n y  a ncillar y  st u d y  i n v ol vi n g  st u d y 
patie nts)  m ust  be  pre pare d  i n  c o nj u ncti o n  wit h  t he  st u d y  S p o ns or  a n d  m ust  be 
s u b mitte d t o t he S p o ns or f or re vie w a n d c o m me nt at least 4 5 da ys pri or t o s u b missi o n 
f or  p u blicati o n  or  prese ntati o n.  N o  si n gle  ce ntre  or  gr o u ps  of  ce ntres  ma y  p u blis h 
i n di vi d uall y.  T he  S p o ns or’s  c o m me nts  o n  t he  pr o p ose d  p u blicati o n  s hall  be 
c o nsi dere d i n g o o d fait h b y t he a ut h ors. T he S p o ns or ma y dela y s uc h s u b missi o n b y a 
ma xi m u m  of  9 0  da ys  if  it  reas o na bl y  belie ves  t hat  p u blicati o n  of  res ults  ma y 
c o m pr o mise its i ntellect ual pr o pert y ri g hts or ma y i nsist t hat s uc h i nf or mati o n or data 
is re m o ve d fr o m t he pr o p ose d p u blicati o n. P u blicati o n of t he res ults will n ot i ncl u de 
c o nfi de ntial i nf or mati o n wit h o ut t he per missi o n of t he S p o ns or. 
T he ori gi nal e C R F pa ges a n d all data ge nerate d d uri n g t he st u d y u n der t his pr ot oc ol 
will bec o me t he pr o pert y of t he S p o ns or. 
T he S p o ns or ma y a n n o u nce q ualit y-ass ure d s u m mar y data i n or der t o c o m pl y wit h t he 
re q uire me nts of fi na ncial re g ulat or y a ut h orities, w hile e ns uri n g s o far as p ossi ble t hat 
s uc h a n n o u nce me nts will n ot c o m pr o mise t he I n vesti gat ors’ a bilit y t o p u blis h t he data 
i n a p pr o priate scie ntific f or u ms. 
 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
6 7  of 6 8  
1 6  A pr 2 0 1 9  
1 0.  R E F E R E N C E LI S T 
1.  
Alric et al. R u pt ure d a ne ur ys m of i nfrare nal a b d o mi nal a orta: i m pact of a ge a n d 
p ost o perati ve c o m plicati o ns o n m ortalit y. A n n als of V asc ul ar S ur gery 2 0 0 3; 
1 7( 3): 2 7 7- 2 8 3. 
2.  
Belli n ga n et al. T he effect of i ntra ve n o us i nterfer o n- beta- 1a ( F P- 1 2 0 1) o n l u n g 
C D 7 3 e x pressi o n a n d o n ac ute l u n g i nj ur y m ortalit y: a n o pe n-la bel st u d y. T he 
La ncet Res pirat or y Me dici ne 2 0 1 4; 2: 9 8- 1 0 7. 
3.  
Bia ncari F, Ve ner m o M, Fi n nis h Arterial Disease I n vesti gat ors. O pe n re pair of 
r u pt ure d a b d o mi nal a ortic a ne ur ys m i n patie nts a ge d 8 0 years a n d ol der. Br J 
S ur g . 2 0 1 1; 9 8( 1 2): 1 7 1 3- 1 7 1 8. 
4.  
B o w n MJ, Nic h ols o n M L, Bell P R, Sa yers R D ( 2 0 0 1) C yt o ki nes a n d 
i nfla m mat or y pat h wa ys i n t he pat h o ge nesis of m ulti ple or ga n fail ure f oll o wi n g 
a b d o mi nal a ortic a ne ur ys m re pair. E ur J Vasc E n d o vasc S ur g 2 2: 4 8 5 4 9 5. 
5.  
B o w n et al. A meta-a nal ysis of 5 0 years of r u pt ure d a b d o mi nal a ortic a ne ur ys m 
re pair. Britis h J o ur n al of S ur gery 2 0 0 2; 8 9: 7 1 4- 7 3 0. 
6.  
B o w n MJ, C o o per NJ, S utt o n AJ, et al. T he p ost- o perati ve m ortalit y of r u pt ure d 
a b d o mi nal a ortic a ne ur ys m re pair. E ur J V asc E n d ov asc S ur g . 2 0 0 4; 2 7( 1): 6 5-
7 4. 
7.  
Castr o p H  et al. I m pair me nt of t u b ul o gl o mer ular fee d bac k re g ulati o n of G F R i n 
ect o- 5’- n ucle oti dase/ C D 7 3- deficie nt mice. J Cli n I n vst 2 0 0 4; 1 1 4: 6 3 4- 6 4 2. 
8.  
Cli nical safet y data ma na ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d 
Re p orti n g ( E 2 A - A p pr o ve d b y t he C P M P i n N o ve m ber 1 9 9 4 f or st u dies 
c o m me nci n g after 1 st J u ne 1 9 9 5 [ N ote f or G ui da nce 3 C 6 1 4 A]; A p pr o ve d b y 
F D A wit h effecti ve date 1 st Marc h 1 9 9 5 [ 6 0 F R 1 1 2 8 4]).  
9.  
C ol ga n S P et al. P h ysi ol o gical r oles f or ect o- 5'- n ucle oti dase ( C D 7 3). P uri ner gic 
Si g nal 2 0 0 6; 2: 3 5 1- 3 6 0.  
1 0.  Declarati o n of Helsi n ki (as a d o pte d b y t he 1 8 t h W orl d Me dical Asse m bl y, 1 9 6 4 
a n d as re vise d b y t he 2 9 t h W orl d Me dical Asse m bl y, T o k y o 1 9 7 5, t he 3 5t h 
W orl d Me dical Asse m bl y, Ve nice 1 9 8 3, t he 4 1st W orl d Me dical Asse m bl y, 
H o n g K o n g 1 9 8 9, a n d t he 4 8 t h Ge neral Asse m bl y, S o merset West, Re p u blic of 
S o ut h Africa, 1 9 9 6, 5 2 n d W M A Ge neral Asse m bl y, E di n b ur g h, Sc otla n d, 
Oct o ber 2 0 0 0). 
1 1.  Ec kle T et al. Car di o pr otecti o n b y ect o- 5'- n ucle oti dase ( C D 7 3) a n d A 2 B 
a de n osi ne rece pt ors. Circ ulati o n. 2 0 0 7 Mar 2 7; 1 1 5( 1 2): 1 5 8 1- 9 0. 
1 2.  Eltzsc hi g H ol ger  et al. P uri ner gic si g nali n g d uri n g i nfla m mati o n. N EJ M 2 0 1 2 
Dec 1 3; 3 6 7( 2 4): 2 3 2 2- 3 3. 
1 3.  Gre nz A  et al. T he re n o- vasc ular A 2 B a de n osi ne rece pt or pr otects ki d ne ys fr o m 
isc he mia. Pl os Me d 2 0 0 8; 5: 1 3 7. 
1 4.  Hart M et al. H y p o xia-i n d uci ble fact or- 1 al p ha de pe n da nt pr otecti o n fr o m 
i ntesti nal isc he mia/re perf usi o n i nj ur y i n v ol ves ect o- 5’- n ucle oti dase ( C D 7 3) a n d 
t he  A 2 B a de n osi ne rece pt or. J I m m u n ol 2 0 1 1; 1 8 6: 4 3 6 7- 4 3 7 4. 
1 5.  I C H Har m o nise d Tri partite G ui deli ne f or G o o d Cli nical Practice (J u ne 1 9 9 6), as 
rec o m me n de d f or a d o pti o n t o t he t hree re g ulat or y parties t o I C H.  Tra ns mitte d 
t o t he C P M P i n J ul y 1 9 9 6 a n d a p pr o ve d o n 1 7t h J ul y 1 9 9 6 ( C P M P/I C H/ 1 3 5/ 9 5).  
T he pr o p ose d date f or c o mi n g i nt o o perati o n is (f or st u dies c o m me nci n g after) 
1 7 t h Ja n uar y 1 9 9 7. A p pr o ve d b y F D A o n 9t h Ma y 1 9 9 7 a n d effecti ve 9t h Ma y 
1 9 9 7 ( 6 2 F R 2 5 6 9 2). 

Far o n P har mace uticals Lt d  
Cli nical St u d y Pr ot oc ol  
Pr ot oc ol N u m ber: F P C LI 0 0 2  
C O N FI D E N TI A L  
 
Fi nal Versi o n 0 5  
6 8  of 6 8  
1 6  A pr 2 0 1 9  
1 6.  I M P R O V E trial i n vesti gat ors, P o well J T, S weeti n g MJ, et al. E n d o vasc ular or 
o pe n re pair strate g y f or r u pt ure d a b d o mi nal a ortic a ne ur ys m: 3 0 da y o utc o mes 
fr o m I M P R O V E ra n d o mise d trial. B MJ . 2 0 1 4; 3 4 8(ja n 1 3 2):f 7 6 6 1-f 7 6 6 1. 
1 7.  Jal ka ne n J, Ma ksi m o w M, Jal ka ne n S, Ha k o virta H. H y p o xia-i n d uce d 
i nfla m mati o n a n d p uri ner gic si g nali n g i n cr oss cla m pi n g t he h u ma n a orta. 
S pri n ger pl us. S pri n ger I nter nati o nal P u blis hi n g; 2 0 1 6; 5: 2. 
1 8.  Ka nt o ne n et al. M ortalit y i n r u pt ure d a b d o mi nal a ortic a ne ur ys m. T he Fi n n vasc 
St u d y Gr o u p. E ur o pe a n J o ur n al of V asc ul ar a n d E n d ov asc ul ar S ur gery 1 9 9 9; 
1 7( 3): 2 0 8- 2 1 2. 
1 9.  Kart hi kesali n ga m  A,  H olt  PJ,  Vi dal- Diez  A,  et  al.  M ortalit y  fr o m  r u pt ure d 
a b d o mi nal a ortic a ne ur ys ms: cli nical less o ns fr o m a c o m paris o n of o utc o mes i n 
E n gla n d a n d t he U S A. L a ncet . 2 0 1 4; 3 8 3( 9 9 2 1): 9 6 3- 9 6 9. 
2 0.  Kiss J  et al. I nterfer o n- beta pr otects f or m ac ute l u n g i nj ur y via u pre g ulati o n of 
C D 7 3. E ur o pea n J o ur nal of I m m u n ol o g y, 2 0 0 7; 3 7( 1 2): 3 3 4- 3 3 8. 
2 1.  K or h o ne n SJ, Ka nt o ne n I, Pettilä V, Kerä ne n J, Sal o J A, Le pä ntal o M. L o n g-
ter m s ur vi val a n d healt h-relate d q ualit y of life of patie nts wit h r u pt ure d 
a b d o mi nal a ortic a ne ur ys m. E ur J V asc E n d ov asc S ur g . 2 0 0 3; 2 5( 4): 3 5 0- 3 5 3 
2 2.  K oszal ka P  et al. Tar gete d disr u pti o n of c d 7 3/ Ect o- 5’- n ucle oti dase alters 
t hr o m b ore g ulati o n a n d a u g me nts vasc ular i nfla m mat or y res p o nse. Circ Res 
2 0 0 4; 9 5: 8 1 4- 8 2 1. 
2 3.  Le n n o n P E  et al. Ne utr o p hil- deri ve d 5’-a de n osi ne m o n o p h os p hate pr o m otes 
e n d ot helial barrier f u ncti o n via C D 7 3- me diate d c o n versi o n t o a de n osi ne a n d 
e n d ot helial A 2 B rece pt or acti vati o n. J E x p Me d 1 9 9 8; 1 8 8( 8): 1 4 3 3- 1 4 4 3. 
2 4.  Ma kar R R et al. T he i nfla m mat or y res p o nse t o r u pt ure d a b d o mi nal a ortic 
a ne ur ys m is altere d b y e n d o vasc ular re pair. I nt J Vasc Me d. 2 0 1 3: 4 8 2 7 2 8. 
2 5.  Nie melä J  et al. I F N-a  i n d uce d a de n osi ne pr o d ucti o n i n t he e n d ot heli u m: a 
mec ha nis m me diate d b y C D 7 3 (ect o- 5’- n ucle oti dase) u p-re g ulati o n. J o ur nal of 
I m m u n ol o g y 2 0 0 4; 1 7 2: 1 6 4 6- 1 6 5 3. 
2 6.  T h o m ps o n L F  et al. Cr ucial r ole f or ect o- 5’- n ucle oti dase ( C D 7 3) i n vasc ular 
lea ka ge d uri n g h y p o xia. J E x p Me d 2 0 0 4; 2 0 0: 1 3 9 5- 1 4 0 5. 
2 7.  V ol mer J B. Ect o- 5’- n ucle oti dase ( C D 7 3)- me diate d a de n osi ne pr o d ucti o n is 
tiss ue pr otecti ve i n a m o del of ble o m yci n-i n d uce d l u n g i nj ur y. J I m m u n ol 2 0 0 6; 
1 7 6: 4 4 4 9- 4 4 5 8. 
2 8.  Vä n ni V, T urtiai ne n J, Ha kala T, et al. Vasc ular c o m or bi dities a n d 
de m o gra p hics of patie nts wit h r u pt ure d a b d o mi nal a ortic a ne ur ys ms. S ur gery . 
2 0 1 6; 1 5 9( 4): 1 1 9 1- 1 1 9 8. 
2 9.  Zi m mer ma n n H. 5’- N ucle oti dase: m olec ular str uct ure a n d f u ncti o nal as pects. 
Bi oc he m J 1 9 9 2; 2 8 5.