Conditions: Preventive Medicine Multi Organ Failure
Keywords: Patients Surviving Open Surgery Ruptured Abdominal Aortic Aneurysm
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
A study to assess effectiveness and safety of a drug FP-1201-lyo (Recombinant Human Interferon Beta-1a) in the Prevention of Multi-Organ Failure on patients after Open Surgery for a Ruptured Abdominal Aortic Aneurysm

Detailed description:
This trial is multicentre, randomised, double-blinded, Phase II, parallel group comparison study of the efficacy and safety of FP-1201-lyo compared to placebo in patients surviving emergency open surgery for an infra-renal ruptured abdominal aortic aneurysm. Investigational medicinal product will be administered as post-surgical preventive treatment either 10µg FP-1201-lyo or placebo. Treatment will be administered daily every 24 hrs for 6 days. The first dose will be given after successful surgery at the point when the patient arrives to the Intensive Care Unit (ICU).

Both treatment groups will receive standard supportive care.

Aim is randomise and initiate treatment of 152 patients. For the final analysis, a minimum of 129 evaluable patients will be required.

Arms:
arm 1: FP-12-lyo 10 µg (Interferon Beta-1a) will be administered once daily as an intravenous bolus injection for 6 days.

Investigational product is lyophilisate for solution for injection which will be reconstituted in water for injection. arm 2: FP-1201-lyo Placebo will be administered once daily as an intravenous bolus injection for 6 days.

Investigational placebo is lyophilisate for solution for injection which will be reconstituted in water for injection

Interventions: intervention 1: Interferon Beta-1A intervention 2: Placebo
Intervention descriptions: intervention 1: Lyophilisate for solution for injection. intervention 2: Lyophilisate for solution for injection as placebo.

Protocol document:
Prot_000.pdf: 
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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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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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  
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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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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.   


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 3  of 6 8  
1 6  A pr 2 0 1 9  
 
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  
 


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 3  of 6 8  
1 6  A pr 2 0 1 9  
 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  
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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 


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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  
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  
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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.   


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 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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C O N FI D E N TI A L  
 
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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 


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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 


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 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. 


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Fi nal Versi o n 0 5  
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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. 
 


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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). 


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Pr ot oc ol N u m ber: F P C LI 0 0 2  
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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. 

SAP_001.pdf: 
 
A Phase II Double-blind, Randomised, Parallel Group 2:1 
Comparison of the Efficacy and Safety of FP-1201-lyo 
(Recombinant Human Interferon beta-1a) and Placebo in 
the Prevention of Multi-Organ Failure on Patients Surviving 
Open Surgery for a Ruptured Abdominal Aortic Aneurysm 
 
 
NCT03119701 
 
SAP Version: Final 
SAP Date: 19 Dec 2019 
 


A Phase II Double-blind, Randomised, Parallel Group 2:1 Comparison of the Efficacy and 
Safety of FP-1201-lyo (Recombinant Human Interferon beta-1a) and Placebo in the 
Prevention of Multi-Organ Failure on Patients Surviving Open Surgery for a Ruptured 
Abdominal Aortic Aneurysm 
Study code: INFORAAA 
Phase II study 
STATISTICAL ANALYSIS PLAN 
NCT03119701


Statistical Analysis Plan 
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Signatures: 
 
 
Statistical Analysis Plan was prepared by: 
 
 
 
 
Date 
 
 
 
 
 
 
Statistical Analysis Plan was reviewed/approved by: 
 
 
 
 
Date 
 
 
 
 Responsible person from the Sponsor 
Date 
 
 


 
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Table of Contents 
 
1 
Abbreviations ............................................................................................................................ 4 
2 
General remark ......................................................................................................................... 4 
3 
Study objective(s) ..................................................................................................................... 4 
4 
Design and type of the study ..................................................................................................... 5 
5 
Study variables .......................................................................................................................... 5 
6 
Sample size considerations ........................................................................................................ 6 
7 
Statistical hypotheses ................................................................................................................ 6 
8 
Analysis datasets ....................................................................................................................... 7 
9 
General statistical considerations ............................................................................................... 7 
9.1 
Adjustment for covariates ................................................................................................... 7 
9.2 
Handling of drop-outs or missing data ................................................................................ 7 
9.3 
Interim analyses and data monitoring .................................................................................. 8 
9.4 
Multicenter studies ............................................................................................................. 8 
9.5 
Multiple comparison/multiplicity ........................................................................................ 8 
9.6 
Examination of subgroups .................................................................................................. 8 
10 
Demographic and other baseline characteristics ..................................................................... 9 
11 
Extent of exposure and compliance ........................................................................................ 9 
12 
Analysis of efficacy ............................................................................................................. 10 
12.1.1 
Primary efficacy variables .......................................................................................... 10 
12.2 
Secondary efficacy variables ...................................................................................... 10 
12.3 
Additional analyses .................................................................................................... 11 
12.3.1 
Pharmacodynamics and tentative disease specific marker analysis .............................. 11 
12.3.2 
Pharmacoeconomic analysis ....................................................................................... 11 
13 
Analysis of safety and tolerability ........................................................................................ 12 
13.1 
Adverse events ........................................................................................................... 12 
13.2 
Laboratory safety variables......................................................................................... 12 
13.3 
Other safety variables ................................................................................................. 13 
14 
Completion and premature discontinuation .......................................................................... 13 
15 
Deviations from the analyses planned in the study protocol .................................................. 13 
16 
Execution of statistical analyses ........................................................................................... 14 
17 
Hardware and software ........................................................................................................ 14 
18 
References ........................................................................................................................... 14 
19 
Appendices .......................................................................................................................... 14 
19.1 
Study flow chart ......................................................................................................... 15 
19.2 
Study procedure flow charts ....................................................................................... 16 
19.3 
Table and figure plan .................................................................................................. 21 
19.4 
Data listing plan ......................................................................................................... 24 
 


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1 
Abbreviations 
AE 
 
Adverse event 
ANOVA 
Analysis of variance 
ATC  
Anatomical Therapeutic Chemical 
FAS-E  
Full analysis set for efficacy 
FAS-S  
Full analysis set for safety 
IAP 
 
Intra-abdominal pressure 
ICU 
 
Intensive care unit 
MedDRA 
Medical dictionary of regulatory authorities 
mRS  
Modified ranking scale 
NAb 
 
Neutralizing antibody 
PD 
 
Pharmacodynamics 
PIM 
 
Potential Inflammatory Markers 
PPS 
 
Per protocol set 
SD 
 
Standard deviation 
SAE 
 
Serious adverse event 
SOFA  
Sequential organ failure assessment 
TEAE  
Treatment emergent adverse event 
VFD  
Ventilator free day 
2 
General remark 
This SAP version further details the SAP dated 17.6.2019, which was generated before performing 
the Interim analysis for the 35 evaluable patients. Study was discontinued after the Interim analysis. 
The earlier version of the SAP concentrated on the primary analyses and this version will entail all 
planned analyses. The analysis plans concerning the primary analyses are not changed from the 
previous version. 
As the study was discontinued, analyses described here, will be performed on the available data 
gathered thus far. 
3 
Study objective(s) 
The primary objective of this study is to evaluate the safety and the efficacy of FP-1201-lyo over 
placebo on all-cause mortality at study day 30; D30 (30 days from the first dose of study 
medication). 
The secondary objectives of this study are 
1. To evaluate the efficacy of FP-1201-lyo treatment by assessing short term outcomes (D30) 
and mid-term outcomes (D90 [3 months]) 
2. To evaluate the safety and tolerability of FP-1201-lyo treatment  


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3. To evaluate the pharmacodynamics (PD) of FP-1201-lyo 
4. To evaluate the Tentative Disease Specific Marker CD73 and Potential Inflammatory 
Markers (PIM) IL-6 and HGF 
5. To evaluate neutralizing antibodies against IFN beta-1a (NAbs) 
4 
Design and type of the study 
This is a multicentre, randomised, double-blind, Phase II, parallel group comparison study of the 
efficacy and safety of FP-1201-lyo compared to placebo in patients surviving emergency open 
surgery for an infra-renal ruptured abdominal aortic aneurysm.  Both treatment groups will receive 
standard supportive care.   
Patients will receive 10 µg FP-1201-lyo or placebo intravenously as a bolus injection once every 24 
hours.  The maximum duration of treatment will be 6 days. Treatment may be discontinued before 6 
days if the patient’s condition improves beyond the need for ICU treatment and if, in the opinion of 
the Investigator, the patient would likely not benefit from continuation of treatment.  
With an estimated screening failure rate of approximately 15%, a maximum of 180 patients were 
planned to be consented and entered into the study in order to randomise and initiate treatment of 
152 patients. 
Study was discontinued after an Interim analysis. 
5 
Study variables 
The following variables will be evaluated 
The demographic and baseline variables 
Gender, age at entry, race, weight (predicted or actual), height, medical history, concomitant 
medications/therapies, major surgical outcomes affecting patient and pregnancy test (females of 
child bearing potential, and peri procedural information (duration of the surgical procedure for 
RAAA, total clamping time, total bleeding volume, total volume substitution, total blood 
substitution, total red blood cells substitution, total platelets substitution, total crystalloids 
substitution and total diuresis volume during procedure and recycling of blood during surgery 
(yes/no)). 
 
The primary efficacy outcome variable 
- 
All-cause mortality at D30 
 
The secondary efficacy outcome variables 
- 
All-cause mortality at D90 (3 months) 
- 
Number of ventilator free days (VFDs) at D30 
- 
Number of days receiving haemodialysis at D30 and D90 
- 
Number of organ failure free days up to D30 by means of the SOFA score  
- 
Prevalence of abdominal compartment syndrome, i.e. intra-abdominal pressure (IAP) 
between treatment groups 
- 
Neutralizing antibodies against IFN beta (NAbs) in whole blood samples up to D30 


 
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- 
Disability on D90 measured by modified ranking scale (mRS) 
 
Safety variables 
Adverse events, vital signs (body temperature, blood pressure, heart rate), physical examination and 
clinical laboratory parameters (biochemistry and haematology). 
 
Pharmacodynamic (PD) and tentative disease specific marker variables 
- 
MxA (protein) concentration in whole blood samples from baseline up to D13 
- 
CD73 concentration in serum samples from baseline up to D6 
- 
Potential Inflammatory Markers (IL-6 and HGF) in serum samples from baseline up to 
D13 
Pharmacoeconomic variables 
- 
Length of ICU stay, in terms of ICU free days at D30 
- 
Length of hospital stay, in terms of hospital free days at D90 
- 
Length of stay at another health care facility at D90 
- 
Length of haemodialysis needed 
 
6 
Sample size considerations 
The primary efficacy endpoint is all cause mortality at D30. Death within 36 hours from the first 
dose of the study treatment leads to exclusion from efficacy analysis. A sample size of 129 eligible 
patients for the primary efficacy analysis, with a 2:1 ratio to active (86) and placebo (43), will 
detect the difference of 22% between the two treatment groups with 80 % power using 2-sided z-
test with 0.05 significance level. To take account of the planned interim analysis, calculations 
assume that 2 sequential tests are made (in addition to final analysis) and the O’Brien-Fleming 
spending function is used to determine the test boundaries. Statistical analysis plan for the interim 
analyses will be presented in a separate document. 
Power calculation assumes 37 % proportion of events on placebo group and 15 % proportion for the 
active treatment group. 
To achieve a sample size of 129 for the primary efficacy analysis, taking account the estimated 
amount of early deaths within 36 hours from first dose of the study treatment (estimated 15 %), 
there should be 152 patients randomised to the study. 
Study was discontinued after the first Interim analysis. Therefore, the sample size did not reach the 
129 patients aimed for. 
7 
Statistical hypotheses 
The primary objective of this study is to evaluate the safety and the efficacy of FP-1201-lyo over 
placebo on reducing all-cause mortality at study day 30, i.e., the null-hypothesis to be tested is 
 
H0 : FP-1201-lyo is not superior to control with respect to all-cause mortality at study day 30 


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against 
H1 : FP-1201-lyo is superior to control with respect to all-cause mortality at study day 30 
8 
Analysis datasets 
Statistical analyses will be performed on the following analysis datasets. 
The Full Analysis Set for Efficacy (FAS-E) consists of all randomised patients receiving study 
treatment but excluding the early deaths (within 36 hours from first dose of study treatment) and 
comprises the analysis set on which the primary efficacy analysis is based. 
The Per Protocol Set (PPS) consists of the patients in the FAS-E excluding patients with major 
protocol violations possibly affecting the primary study endpoint analysis. 
The precise definition of the PPS at the patient level was planned to be identified at the blind review 
conducted both before the second interim and final analysis. The detailed criteria for patient 
classification will be prepared before database lock. Subject classification was to be created first for 
the subjects included in the second interim analysis, and later amended for the final analysis with 
the subjects that were not included in the interim analysis. 
The first Interim analysis (after 35 evaluable patients) was based on FAS-E dataset. No 
classification for PPS was done for the first Interim analysis. 
Statistical analyses for efficacy, PD, tentative disease specific markers and pharmacoeconomic 
variables are performed on both the FAS-E and PPS. 
Study was discontinued after the first interim analysis. Subject classification document defining the 
analysis datasets in detail will be prepared and signed before database lock. 
The Full Analysis Set for Safety (FAS-S) consists of all randomised patients receiving study 
treatment and comprises the analysis set on which the evaluation of safety is based. All safety 
analyses are performed on the FAS-S analysis dataset. 
9 
General statistical considerations 
Summary statistics will include at least the number of subjects, mean, standard deviation, median, 
minimum and maximum for continuous variables, and frequencies and percentages for categorical 
variables. All data collected will be listed by subject. 
In the statistical analyses a p-value less than 0.05 will be considered as an indication of statistical 
significance. If not stated otherwise, all tests will be performed as two-sided tests and two-sided 
95% confidence intervals will be produced. Missing values will not be imputed in the analyses. 
9.1 
Adjustment for covariates 
The primary model will include the stratification factors (age group and gender) used in the 
randomisation as covariates.  
9.2 
Handling of drop-outs or missing data 
Missing values will not be imputed. Primary endpoint is mortality at Day 30 and all evaluable 
patients will be included in the primary analysis.  


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9.3 
Interim analyses and data monitoring 
Two Interim analyses were planned for the study with futility and efficacy stopping criteria using 
O’Brien-Fleming boundaries. 
Study was discontinued after the first interim analysis. 
9.4 
Multicenter studies 
Handling of centers was to be defined before second interim analysis when there would be better 
understanding of the center size. 
Study was discontinued after the first interim analysis. Patient accrual to the different study centers 
was varying in amounts. Center info will not be used directly in the analyses, but country and site 
will be included in the tabulations of patient demographics. 
9.5 
Multiple comparison/multiplicity 
There is one primary efficacy variable in the primary hypothesis of this study; all-cause mortality at 
D30. The primary evaluation of this hypothesis will be based upon the FAS-E dataset. This in itself 
will not give reason to adjustments for multiple comparison/multiplicity. 
However, two interim analyses were to be performed after reaching 35 and 84 evaluable patients for 
the primary efficacy variable. For this reason, the primary efficacy endpoint was to be evaluated 
using O’Brien and Fleming criteria controlling the type I error rate. Using the O’Brien-Fleming 
spending function on the two sequential tests will cause the nominal alpha level for the primary 
efficacy variable in final analysis to be 0.04664. Therefore, for the primary efficacy variable a p-
value less than 0.04664 will be considered as statistically significant. 
As the study was discontinued after the first interim analysis, the planned O’Brien and Fleming 
correction will not be applied to the primary analysis. Instead, the standard p-value of less than 0.05 
will be considered statistically significant.  
9.6 
Examination of subgroups 
Data for the primary efficacy endpoint will also be presented for key, pre-defined subgroups of 
patients. Concomitant use of glucocorticoids will be one key subgroup as earlier studies have 
suggested that it may have effect on the study treatment. As CD73 response (and IL-6 and HIF-1) 
may be also genetically determined/individual, another key subgroups will be CD73 responder 
status (determined by a 2-fold elevation in CD 73 (from baseline to peak value). In addition, if 
analyses indicate yet another, but currently unknown but relevant subgroups, they will be analysed 
as separate subgroup analyses for exploratory purposes 
Key subgroups included in analyses 
- 
Concomitant use of glucocorticoids 
- 
CD 73 responder status (responders vs. non-responders) 
- 
IL-6 responder status 
- 
HIF-1 responder status 


 
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10 Demographic and other baseline characteristics 
Number of patients enrolled into the study at screening and the reasons for screening failures will be 
summarized. The number of patients entering and completing the study will be summarized. All 
patients discontinuing the study will be summarized together with the reason(s) for discontinuation. 
Demographic and baseline characteristics will be summarized by treatment using descriptive 
statistics. Following variables will be analysed. 
- 
Gender 
- 
Age at entry 
- 
Race 
- 
Height 
- 
Weight 
o If actual weight is not available for a patient, then predicted body weight will be 
used in its place 
o Predicted body weight (kg) is calculated using the following formulae: 
▪ Males:  
50 + 0.91(height in cm – 152.4) 
▪ Females: 45.5 + 0.91(height in cm – 152.4) 
- 
Major surgical outcomes affecting patient 
o Open abdomen (yes/no) 
o Left renal vein ligated (yes/no) 
o Clamping time above the renal arteries 
- 
Medical history 
- 
Concomitant medications/therapies 
- 
Pregnancy test (females of child bearing potential). 
Similarly, the duration of the surgical procedure and peri procedural information will be 
summarized by treatment. Additional concomitant procedures will be listed only.  
Medical history and concomitant medications/therapies will be presented only by frequency and 
subject count-based tables according to WHO Anatomical Therapeutic Chemical (ATC) 
classification. 
Pregnancy test results (females of child-bearing potential) will be presented only descriptively by a 
subject count-based table.  
11 Extent of exposure and compliance 
Treatment exposure, study duration and treatment compliance will be summarised by treatment 
groups using descriptive statistics.  


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12 Analysis of efficacy 
12.1.1 Primary efficacy variables 
Primary efficacy variable is the all-cause mortality at D30. The primary efficacy analysis will be 
conducted using logistic regression model for the observed mortality rates in the two treatment 
groups. Stratification factors sex and age used in the randomisation will be included in the model. 
Primary result will be presented as an adjusted odds ratio and a 95% CI for the adjusted odds ratio. 
Also, a 95% exact unconditional confidence interval (CI) for the difference in the observed 
mortality rates will be calculated. As a sensitivity analysis, unadjusted results will also be presented. 
 
For the primary comparison, a p-value less than 0.04664 was planned to be considered as 
statistically significant due to O’Brien-Fleming alpha spending used for the Interim analyses. Due 
to the study discontinuation after the first Interim analysis, two-sided significance level of 0.05 will 
be used for all analyses. 
12.2 
Secondary efficacy variables 
The following secondary endpoints will be analysed: 
• Time and reason/diagnosis of death up to D90 (3 months) 
• Number of VFDs up to D30 
• Number of days receiving hemodialysis at D30* 
• Number of ICU free days up to D30* 
• Organ failure free days up to D30 
• Number of days in hospital up to D30 (length of stay in another 
health care facility)* 
• Prevalence of abdominal compartment syndrome, i.e. intra-abdominal pressure 
(IAP) value differences between study groups 
• Disability on D90 measured by modified ranking scale (mRS) 
• Neutralizing (and anti-drug) antibodies IFN beta (ADAs and NAbs) in whole blood 
samples up to D30 
*ICU free days and number of days in hospital, length of stay in another health care facility and number of days receiving 
hemodialysis at D90 summarized in pharmacoeconomic tables 
All-cause mortality at D90 (3 months) will be compared using Cox regression model including 
stratification factors (if feasible). Estimated hazard ratios will be presented with associated 95% CIs 
and log-rank p-values for the FAS-E. Also, similar logistic regression as for the primary endpoint 
(D30 mortality) will be done. 


 
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For endpoints number of VFDs, number of ICU free days, organ failure-free days, number of days 
on hemodialysis, number of days in hospital, length of stay in another health care facility and IAP 
values, data will be summarised in terms of the mean, median, minimum and maximum, and the 
treatment groups will be compared using the Mann-Whitney U-test. Descriptive tables of IAP grade 
by timepoint will be presented using counts and percentages. Number of days on hemodialysis, 
number of days in hospital, length of stay in another health care facility  and IAP value analyses 
will be performed for all patients and excluding deaths separately. 
Complete data on organ failure free days may be unavailable due to SOFA scores not being 
assessed after ICU treatment. To account for this, the number of organ failure free days will be 
analysed by expressing these as a proportion of the days on which SOFA scores are available. 
Disability measured with mRS will be summarized descriptively and the treatment groups will be 
compared using the Cochran-Mantel-Haenszel test for trend. 
ADAs and NAbs in whole blood samples up to D30 will be summarized using descriptive statistics. 
All secondary analyses are designed to be supportive of the analysis of the primary endpoint and 
there will be no adjustments for the multiplicity of endpoints so that each analysis will be 
undertaken at the two-sided 5% level of significance. 
12.3 
Additional analyses 
Additional analyses are performed on PD and tentative disease specific marker variables and 
pharmacoeconomic variables. 
12.3.1 Pharmacodynamics and tentative disease specific marker analysis 
PD and tentative disease specific marker variables to be analysed are MxA concentration in whole 
blood samples from baseline up to D13, CD73 concentration in serum samples from baseline up to 
D6 and potential Inflammatory Markers (e.g. IL-6 and HIF-1) in serum samples from baseline up 
to D13. 
These will be summarised using descriptive statistics and analysed using Repeated measurements 
ANOVA model with main effects of treatment and day and their interaction. Correlations between 
the repeated observations will be modelled using compound symmetry covariance structure. The 
model will be used to estimate population geometric means (95 % CI) for the treatment groups by 
timepoint. 
12.3.2 Pharmacoeconomic analysis 
Following pharmacoeconomic endpoints were defined for the study:  
- 
Length of ICU stay, in terms of ICU free days at D90 
- 
Length of hospital stay, in terms of hospital free days at D90 
- 
Length of stay at another health care facility at D90 
- 
Length of hemodialysis needed (at D90) 
Due to early discontinuation of the study, these endpoints will not be analysed. 


 
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13 Analysis of safety and tolerability 
All subjects in the SAF-S analysis set (all randomised patients receiving study treatment) will be 
included in the safety and tolerability analysis. Safety variables to be analysed are; adverse events, 
clinical laboratory parameters, vital signs and physical examination. 
13.1 
Adverse events 
All recorded adverse events will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA). Treatment emergent adverse event (TEAE) is defined as an AE that begins 
or worsens in severity after at least one dose of study drug has been administered. Non-treatment 
emergent AEs are listed only. 
TEAEs will be summarized using frequency and subject based tables. TEAEs will be tabulated by 
treatment group, system organ class (SOC), preferred term (PT), causality and severity. For analysis 
purposes, each subject will also be categorized by the maximum severity reported for a given TEAE 
and these will be tabulated by maximum severity. TEAEs will be summarized separately for 
treatment period (D1-D5) and short-term follow-up period (D6-D30). TEAEs are not collected, and 
therefore not reported, during the mid-term follow-up.  
Serious adverse events (SAEs) and AEs leading to discontinuation will be summarized by treatment 
groups. All deaths up to D90 are reported as SAEs. 
13.2 
Laboratory safety variables 
Laboratory safety variables (biochemistry and haematology) to be analyzed are presented in table 1 
below. Descriptive statistics and the frequency and percentage of absolute values below, within and 
above the reference range will be tabulated for the safety laboratory variables at D0 (baseline), D1, 
D2, D3, D4, D5, D6, D9, D13 and D30. Descriptive statistics will include mean, median, standard 
deviation (SD), minimum and maximum. 
In addition, shift tables (within, below and above the normal range) will be provided for each 
parameter in relation to the maximum change from baseline from D0 over the complete 30-day 
follow-up period. 


 
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Table 1. Laboratory Variables 
Biochemistry 
Haematology 
Includes coagulation 
Alanine 
transaminase (ALAT) 
Alkaline 
phosphatase (AFOS) 
Aspartate 
transaminase (ASAT) 
Bicarbonate 
Lactate 
pH 
Bilirubin 
Calcium 
Creatinine 
Potassium 
Sodium (blood gas value 
acceptable) 
Hemoglobin 
Leucocyte differential count 
(absolute) 
Mean cell volume 
Platelet count 
Red cell count 
White cell count 
 
 
13.3 
Other safety variables 
Other safety variable to be analysed are vital signs (body temperature, blood pressure, heart rate) 
and physical examination. 
Vital signs data is summarized by treatment groups separately at D0, D1, D2, D3, D4, D5, D6, D9, 
D13 and D30. Absolute values and changes from baseline are both summarized. In addition, the 
maximum change from baseline over the 30-day follow-up period will be calculated for each patient 
and summarized. Vital signs summaries will be in terms of mean, median, SD, minimum and 
maximum. 
Physical examination covering all the major organ systems will be performed at screening and D30. 
These will be summarized by treatment groups and visits using frequency and percentage of 
normal/abnormal observations. In addition, shift tables will be provided describing the change from 
screening to D30. 
14 Completion and premature discontinuation 
Completion and premature discontinuation will be listed. The reasons for premature discontinuation 
will be presented. 
15 Deviations from the analyses planned in the study protocol 
Study was discontinued after the first Interim analysis. Due to the early discontinuation, the planned 
O’Brien and Fleming correction will not be applied to the primary analysis. Instead, the standard p-
value of less than 0.05 will be considered statistically significant. 


 
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Due to low number of accrued patients, the center effect was not further explored in the analyses. 
Analysis of study centers was limited to summary statistics for baseline information. 
Due to the early discontinuation of the study, the pharmacoeconomic endpoints (see section 12.3.2) 
will not be analysed. 
There are no other major deviations in the statistical analysis plan from the analyses planned in the 
study protocol. 
16 Execution of statistical analyses 
Statistical analyses will be performed by 
. 
17 Hardware and software 
Statistical analysis, tables and patient data listings will be performed with SAS® version 9.4 or later 
for Windows (SAS Institute Inc., Cary, NC, USA). 
18 
References 
Clinical Study Protocol (FP1CLO006), Final Protocol version 05 (16 April 2019), Faron 
Pharmaceuticals Ltd. 
19 
Appendices 
 
 














 
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19.3 
Table and figure plan 
 
Demographic 
Tables 
 
Table 14.1.1 
Disposition of patients 
Table 14.1.2.1 
Demographics (categorical) (FAS-E) 
Table 14.1.2.2 
Demographics (categorical) (PPS) 
Table 14.1.3.1 
Demographics (continuous) (FAS-E) 
Table 14.1.3.2 
Demographics (continuous) (PPS) 
Table 14.1.4.1 
Major surgical outcomes affecting patient (FAS-E) 
Table 14.1.4.2 
Major surgical outcomes affecting patient (PPS) 
Table 14.1.5.1 
Surgical procedure and periprocedual information (FAS-E) 
Table 14.1.5.2 
Surgical procedure and periprocedual information (FAS-E) 
Table 14.1.6.1 
Medical history (FAS-E) 
Table 14.1.6.2 
Medical history (PPS) 
Table 14.1.7.1 
Concomitant medications/therapies (FAS-E) 
Table 14.1.7.2 
Concomitant medications/therapies (PPS) 
Table 14.1.8 
Pregnancy test (FAS-S) 
 
 
Efficacy Tables 
Efficacy 
Table 14.2.1.1.1 
All-cause mortality D30 (FAS-E) 
Table 14.2.1.1.2 
All-cause mortality D30 (PPS) 
Table 14.2.1.2.1 
Logistic regression of All-cause mortality D30 (FAS-E) 
Table 14.2.1.2.2 
Logistic regression of All-cause mortality D30 (PPS) 
Table 14.2.1.3.1 
All-cause mortality D90 (FAS-E) 
Table 14.2.1.3.2 
All-cause mortality D90 (PPS) 
Table 14.2.1.4.1 
Cox regression of All-cause mortality D90 (FAS-E) 
Table 14.2.1.4.2 
Cox regression of All-cause mortality D90 (PPS) 
Table 14.2.1.5.1 
Logistic regression of All-cause mortality D90 (FAS-E) 
Table 14.2.1.5.2 
Logistic regression of All-cause mortality D90 (PPS) 
Table 14.2.1.6.1 
Number of VFDs up to D30 (FAS-E) 
Table 14.2.1.6.2 
Number of VFDs up to D30 (PPS) 
Table 14.2.1.7.1 
Number of ICU free days up to D30 (FAS-E) 
Table 14.2.1.7.2 
Number of ICU free days up to D30 (PPS) 
Table 14.2.1.8.1 
Organ failure free days up to D30 (FAS-E) 
Table 14.2.1.8.2 
Organ failure free days up to D30 (PPS) 
Table 14.2.1.9.1 
Number of days on hemodialysis up to D30 (FAS-E) 
Table 14.2.1.9.2 
Number of days on hemodialysis up to D30 (PPS) 
Table 14.2.1.9.3 
Number of days on hemodialysis up to D30 excluding deaths (FAS-E) 
Table 14.2.1.9.4 
Number of days on hemodialysis up to D30 excluding deaths (PPS) 
Table 14.2.1.10.1 
Number of days in hospital up to D30 (FAS-E) 
Table 14.2.1.10.2 
Number of days in hospital up to D30 (PPS) 
Table 14.2.1.10.3 
Number of days in hospital up to D30 excluding deaths (FAS-E) 
Table 14.2.1.10.4 
Number of days in hospital up to D30 excluding deaths (PPS) 
Table 14.2.1.11.1 
Length of stay in another health care facility up to D30 (FAS-E) 


 
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Study: INFORAAA 
 
Table 14.2.1.11.2 
Length of stay in another health care facility up to D30 (PPS) 
Table 14.2.1.11.3 
Length of stay in another health care facility up to D30 excluding deaths (FAS-E) 
Table 14.2.1.11.4 
Length of stay in another health care facility up to D30 excluding deaths (PPS) 
Table 14.2.1.12.1 
IAP values by timepoint (FAS-E) 
Table 14.2.1.12.2 
IAP values by timepoint (PPS) 
Table 14.2.1.12.3 
IAP values by timepoint excluding early deaths (FAS-E) 
Table 14.2.1.12.4 
IAP values by timepoint excluding early deaths (PPS) 
Table 14.2.1.13.1 
IAP grades by timepoint (FAS-E) 
Table 14.2.1.13.2 
IAP grades by timepoint (PPS) 
Table 14.2.1.13.3 
IAP grades by timepoint excluding early deaths (FAS-E) 
Table 14.2.1.13.4 
IAP grades by timepoint excluding early deaths (PPS) 
Table 14.2.1.14.1 
Disability on D90 measured with mRS (FAS-E) 
Table 14.2.1.14.2 
Disability on D90 measured with mRS (PPS) 
Table 14.2.1.14.1 
Neutralizing antibodies (FAS-E) 
Table 14.2.1.14.2 
Neutralizing antibodies (PPS) 
 
 
 
Pharmacodynamics 
Table 14.2.2.1.1 
MxA concentration (FAS-E) 
Table 14.2.2.1.2 
MxA concentration (PPS) 
Table 14.2.2.2.1 
MxA ANOVA (FAS-E) 
Table 14.2.2.2.2 
MxA ANOVA (PPS) 
Table 14.2.2.3.1 
CD73 concentration (FAS-E) 
Table 14.2.2.3.2 
CD73 concentration (PPS) 
Table 14.2.2.4.1 
CD73 ANOVA (FAS-E) 
Table 14.2.2.4.2 
CD73 ANOVA (PPS) 
Table 14.2.2.5.1 
Potential inflammatory markers (FAS-E) 
Table 14.2.2.5.2 
Potential inflammatory markers (PPS) 
Table 14.2.2.6.1 
PIM ANOVA (FAS-E) 
Table 14.2.2.6.2 
PIM ANOVA (PPS) 
 
 
 
Subgroup analyses 
Table 14.2.1.1.1 
All-cause mortality D30 by subgroups 
Table 14.2.1.2.1 
Logistic regression of All-cause mortality D30 by subgroups 
 
 
Safety Tables 
 
Table 14.3.1 
Extent of exposure and compliance (FAS-S) 
Table 14.3.2 
Summary of TEAEs (FAS-S) 
Table 14.3.3.1 
Treatment emergent adverse events (FAS-S) 
Table 14.3.3.2 
TEAEs by causality (FAS-S) 
Table 14.3.3.3 
TEAEs by severity (FAS-S) 
Table 14.3.3.4 
TEAEs by maximum severity (FAS-S) 
Table 14.3.3.5 
TEAEs by causality and severity (FAS-S) 
Table 14.3.3.6 
TEAEs by causality and maximum severity (FAS-S) 
Table 14.3.4.1 
TEAEs during treatment period (FAS-S) 
Table 14.3.4.2 
TEAEs during treatment period by causality (FAS-S) 
Table 14.3.4.3 
TEAEs during treatment period by severity (FAS-S) 


 
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Study: INFORAAA 
 
Table 14.3.4.4 
TEAEs during treatment period by maximum severity (FAS-S) 
Table 14.3.4.5 
TEAEs during treatment period by causality and severity (FAS-S) 
Table 14.3.4.6 
TEAEs during treatment period by causality and maximum severity (FAS-S) 
Table 14.3.5.1 
TEAEs during short-term follow-up period (FAS-S) 
Table 14.3.5.2 
TEAEs during short-term follow-up period by causality (FAS-S) 
Table 14.3.5.3 
TEAEs during short-term follow-up period by severity (FAS-S) 
Table 14.3.5.4 
TEAEs during short-term follow-up period by maximum severity (FAS-S) 
Table 14.3.5.5 
TEAEs during short-term follow-up period by causality and severity (FAS-S) 
Table 14.3.5.6 
TEAEs during short-term follow-up period by causality and maximum severity (FAS-
S) 
Table 14.3.6 
Listing of other adverse events (FAS-S) 
Table 14.3.7 
TEAEs leading to discontinuation (FAS-S) 
Table 14.3.8 
Serious TEAES (FAS-S) 
Table 14.3.9.1 
Biochemistry - Descriptive statistics (FAS-S) 
Table 14.3.9.2 
Biochemistry - Categorical analysis (FAS-S) 
Table 14.3.9.3 
Biochemistry - Shift tables (FAS-S) 
Table 14.3.10.1 
Haematology - Descriptive statistics (FAS-S) 
Table 14.3.10.2 
Haematology - Categorical analysis (FAS-S) 
Table 14.3.10.3 
Haematology - Shift tables (FAS-S) 
Table 14.3.11.1 
Vital signs - Descriptive statistics (FAS-S) 
Table 14.3.11.2 
Vital signs - Change from baseline (FAS-S) 
Table 14.3.11.3 
Vital signs - Maximum change from baseline (FAS-S) 
Table 14.3.12.1 
Physical examination (FAS-S) 
Table 14.3.12.2 
Physical examination - Shift from screening to D30 
 


 
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Study: INFORAAA 
 
19.4 
Data listing plan 
 
Listing 16.2.1 
Disposition of subjects 
Listing 16.2.2 
Study discontinuations 
Listing 16.2.3 
Extent of exposure 
Listing 16.2.4 
Drug accountability 
Listing 16.2.5 
Inclusion/exclusion criteria 
Listing 16.2.6 
Demographic and other baseline characteristics 
Listing 16.2.7 
Medical history and concomitant diseases 
Listing 16.2.8 
Prior and concomitant medications/therapies 
Listing 16.2.9 
Major surgical outcomes affecting patient 
Listing 16.2.10 
Surgical procedure and peri procedual information 
Listing 16.2.11 
Pregnancy test results 
Listing 16.2.12 
Clinical event data 
Listing 16.2.13 
Death and reasons for death 
Listing 16.2.14 
Daily status data 
Listing 16.2.15 
All-cause mortality data 
Listing 16.2.16 
Number of VFD and ICU free days 
Listing 16.2.17 
Length of stay in hospital and other health care facility 
Listing 16.2.18 
Number of days in hemodialysis 
Listing 16.2.19 
MxA and CD73 concentration data 
Listing 16.2.20 
Potential inflammatory markers data 
Listing 16.2.21 
Neutralizing antibodies data 
Listing 16.2.22 
Intra-abdominal pressure data 
Listing 16.2.23 
Disability measured with mRS 
Listing 16.2.24 
SOFA score data 
Listing 16.2.25 
Non-treatment emergent adverse events 
Listing 16.2.26 
Treatment emergent adverse events 
Listing 16.2.27 
Serious adverse events 
Listing 16.2.28 
Adverse events leading to discontinuation 
Listing 16.2.29 
Biochemistry data 
Listing 16.2.30 
Haematology data 
Listing 16.2.31 
Vital signs data 
Listing 16.2.32 
Physical examination data